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Prescribing Outlook

New Medicines

September 2013

A resource for the NHS to help with budget setting,

prescribing planning and medicines management.

Contents

Foreword ..............................................................................................................................1

Abbreviations .......................................................................................................................3

Key ........................................................................................................................................4

Summary of predicted launch dates ..................................................................................5

Highlights .............................................................................................................................8

Table 1. Pipeline drugs ..................................................................................................... 11

BNF 1. Gastrointestinal system ................................................................................................................... 11

BNF 2. Cardiovascular system .................................................................................................................... 13

BNF 3. Respiratory system .......................................................................................................................... 18

BNF 4. Central nervous system ................................................................................................................... 20

BNF 5. Infections .......................................................................................................................................... 22

BNF 6. Endocrine system ............................................................................................................................ 26

BNF 7. Obstetrics, gynaecology, and urinary-tract disorders ...................................................................... 29

BNF 8. Malignant disease and immunosuppression ................................................................................... 30

BNF 9. Nutrition and blood ........................................................................................................................... 51

BNF 10. Musculoskeletal and joint diseases ............................................................................................... 53

BNF 11. Eye ................................................................................................................................................. 56

BNF 13. Skin ................................................................................................................................................ 57

BNF 14. Vaccines ........................................................................................................................................ 59

Table 2. Drugs in Prescribing Outlook 2012 - development delayed .......................... 60

Table 3. Recent UK drug launches or licence extensions ............................................ 61

BNF 1. Gastrointestinal system .................................................................................................................... 61

BNF 2. Cardiovascular system ..................................................................................................................... 61

BNF 3. Respiratory system ........................................................................................................................... 61

BNF 4. Central nervous system .................................................................................................................... 62

BNF 5. Infections ........................................................................................................................................... 62

BNF 6. Endocrine system ............................................................................................................................. 63

BNF 7. Obstetrics, gynaecology, and urinary-tract disorders ....................................................................... 63

BNF 8. Malignant disease and immunosuppression .................................................................................... 64

BNF 9. Nutrition and blood ............................................................................................................................ 66

BNF 10. Musculoskeletal and joint diseases ................................................................................................ 66

BNF 11. Eye .................................................................................................................................................. 66

BNF 12. Ear, nose and oropharynx .............................................................................................................. 67

BNF 13. Skin ................................................................................................................................................. 67

Patent expiries 2013 - 2015 ............................................................................................... 68

Biosimilar developments .................................................................................................. 69

Index ................................................................................................................................... 71

Acknowledgements ........................................................................................................... 73

UKMi September 2013 Solely for use within the NHS and not for commercial use. page 1 No responsibility is accepted for the content of documents derived from this original publication.

Foreword

Managing new medicines

Underpinning the strategic direction for managing new

medicines is the Department of Health's report Innovation

Health and Wealth, Accelerating Adoption and Diffusion in

the NHS document (2011, updated 2012) . It sets out the

Government’s support for the NHS to embrace innovation

to meet current and future healthcare challenges and

outlines the importance of early adoption and diffusion of

clinically and cost effective innovative practices, including

medicines. Horizon scanning is essential at many

organisational levels so that new medicines that improve

patient outcomes can be planned for and adopted.

Since April 2013, NHS England Area Teams have a

strategic medicines management role and are responsible

for commissioning the majority of high cost drugs as well

as all cancer chemotherapy. The detail of the operational

mechanisms underpinning these responsibilities is yet to

be fully outlined although a number of interim

commissioning documents relevant to medicines have

been published including:

Individual funding requests (IFRs) – for when drugs are

not routinely commissioned.

Implementation and funding of NICE guidance

Experimental and unproven treatments

On-going treatment following a NHS England funded

trial

On-going treatment following non-commercially funded

clinical trials

On-going access to treatment following a trial of

treatment

On-going access to treatment following industry

sponsored clinical trials or funding

Specialised Services Commissioning Innovation Fund

(SSCIF)

The cancer drug fund (CDF), set up to facilitate patient

access to cancer treatments that fail to get NICE approval,

is being managed by NHS England until the end of 2013.

The most recent list of drugs funded by the CDF can be

accessed via the NHS England website. The intention is

that the CDF will cease as value based pricing (VBP) is

implemented in January 2014. Under VBP, different pricing

strategies will apply to different indications for drugs based

on the assessed ‘value’ for each indication. The

mechanism for VBP is still to be decided but NICE will have

a central role in the process and be responsible for the full

value assessment of medicines (see terms of reference).

There are already situations where the same medicine has

a different price for different indications. This is especially

true for medicines that have an orphan designation. In this

case, the medicine will have a different brand name for

non-orphan and orphan indications.

The majority of new medicines highlighted in this document

are due to be launched in 2014 or beyond. Their launch will

be affected by VBP reimbursement negotiations, but exactly

how is currently uncertain. For high cost new medicines

that are in the NICE work programme manufacturers have

the option to submit a proposal for a Patient Access

Schemes (PAS). This allows NICE to recommend

treatments that it might otherwise not have been found to be

cost effective. PAS are either cost (discounts, free stock

etc) or outcome (price variation linked to patient outcomes)

based. A list of NICE technologies with an approved PAS

can be viewed on the NICE website. In Prescribing Outlook

current PAS schemes are highlighted if they are relevant to

a new medicine in the same therapeutic area, and, although

this will not give an indication of the likely cost of the new

medicine, it suggests that subsequent treatment options will

have to be competitive.

The role of NICE is expanding to include support for

implementation of NICE guidance. Where relevant, links

are provided in Prescribing Outlook to NICE pathways,

commissioning guidance and quality standards. Quality

standards are designed to drive and measure quality

improvements within a particular area of care and be

reflected in commissioning frameworks. NICE

implementation tools for launched drugs include costing

templates and these may provide relevant information for

drugs yet to be launched. The NICE Medicines and

Prescribing Centre (MPC) has produced good practice

guidance on developing and updating local formularies in

response to Innovation Health and Wealth, Accelerating

Adoption and Diffusion in the NHS. It advises that local

systems and processes for accessing medicines support

innovation where appropriate and recommends horizon

scanning is included as a standing agenda item in local

formulary decision-making meetings.

It is estimated more than 70% of the secondary care drugs

bill can be accounted for by ‘high cost’ drugs excluded from

the Payment by Results (PbR) tariff, the national system for

paying trusts for activity. Standard tariff prices do not

always allow fair reimbursement of some interventions so a

list of drugs and services excluded from the tariff has been

developed. The majority of drugs appearing on this list

(previously known as ‘PbR exclusions’, now referred to as

‘Specified high cost drugs’) are likely to be commissioned

by NHS England via specialised commissioning systems

but the detail of exactly which drugs and how the funding

streams operate is awaited. The Manual outlining which

services (and treatments) are commissioned by NHS

England has been published but will be updated shortly.

As of April 2013 the Department of Health is no longer

responsible for managing PbR; Monitor has been charged

with this and is currently consulting on the future direction

of the Tariff. There are few changes for the 2013/14 PbR

tariff (see tab 19 for high cost drugs detailed list) but

payment mechanisms for high cost drugs in 2014/15 could

be influenced by the outcome of the consultation. In

previous editions of Prescribing Outlook an ‘educated

guess’ as to the potential tariff positioning of each new

medicine has been made. Current uncertainty now makes

this difficult. In the absence of additional guidance for

2014/15, estimates of tariff positioning in this document are

based on historical assumptions. An ‘educated guess’ is

also made on the likely commissioning route for individual

http://www.dh.gov.uk/prod_consum_dh/groups/dh_digitalassets/documents/digitalasset/dh_131784.pdf



http://www.england.nhs.uk/wp-content/uploads/2013/04/cp-03.pdf











http://www.england.nhs.uk/wp-content/uploads/2013/08/sscif-guide.pdf

http://www.england.nhs.uk/wp-content/uploads/2013/08/sscif-guide.pdf

http://www.england.nhs.uk/ourwork/cdf/

http://www.2020selection.co.uk/images/pdfs/value-based-pricing.pdf

http://www.nice.org.uk/media/9A4/92/DH_VBP_Terms_of_Reference.pdf

http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000029.jsp&murl=menus/regulations/regulations.jsp&mid=WC0b01ac05800240ce

http://www.nice.org.uk/aboutnice/howwework/paslu/ListOfPatientAccessSchemesApprovedAsPartOfANICEAppraisal.jsp

http://www.nice.org.uk/mpc/goodpracticeguidance/GPG1.jsp

http://webarchive.nationalarchives.gov.uk/20130107105354/http:/www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/DH_131299

http://webarchive.nationalarchives.gov.uk/20130107105354/http:/www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/DH_131299

http://www.england.nhs.uk/wp-content/uploads/2012/12/pss-manual.pdf

http://www.monitor.gov.uk/

http://www.monitor.gov.uk/sites/default/files/publications/ToPublishTheNationalTariff201415AnEngagementDoc13June13.pdf

https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/210979/07_-_Tariff_information_spreadsheet_2013-14_v6.xls

https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/210979/07_-_Tariff_information_spreadsheet_2013-14_v6.xls


medicines to take into account new commissioning

arrangements outlined above.

For the pharmaceutical industry, the cost of bringing a new

drug to the market is high. It is inevitable that more effort is

being put into looking for new uses for, or new formulations

of, currently licensed products. Applications for licence

extensions are processed through licensing systems faster

than those for new drugs as less safety and technical data

are required. Data collection of pipeline licence extensions

and new formulations has also improved over recent years.

As a result an increased number of potential licence

extensions appear in this document. This year, to manage

this, there are two types of monograph; a full monograph

with all the information previously included and an

abbreviated entry (highlighted in blue) containing basic

information for those drugs with an anticipated launch date

in 2015 or beyond. This enables us to highlight drugs near

and slightly further away from launch in the same

therapeutic area.

As in previous editions of Prescribing Outlook, drugs with

patents due to expire in the near future are highlighted as

they are then open to generic competition. It is important

that the possibility of generic options is considered as part

of the wider medicines management agenda, hence their

inclusion in this document together with an ‘educated

guess’ as to which have the potential for generic

competition and an indication whether generic product

licence applications are currently in progress in the EU.

For the first time we have included a separate section on

biosimilar drugs. Although there are a small number of

biosimilar drugs already on the market there are many

more in the pipeline that could have a potentially cost

saving impact on medicines budgets. It is estimated about

50% of the current UK market for biological medicines

spend may be subject to biosimilar competition by 2019.1

There are a number of regulatory schemes that impact on

the availability of new medicines. Those that allow earlier

access to medicines in the EU and UK include ‘individual

patient supply’ and ‘conditional approval’. Where relevant,

and if known, details of these are included in this

document. Details of a scheme which would allow patients

access to new medicines prior to licensing were put out for

consultation by the Medicines and Healthcare products

Regulatory Agency (MHRA) in July 2012. The intention of

the scheme is to widen access to "promising new

medicines that will treat, diagnose or prevent life

threatening, chronic or seriously debilitating conditions

without adequate treatment options". The outcome of the

consultation is awaited.

1. Anon. What are biosimilars and are they important? Drug and

Therapeutics Bulletin 2013; 51(5): 57-60.

About Prescribing Outlook

The aim of the annually published Prescribing Outlook

series produced by UK Medicines Information (UKMi) is to

assist NHS organisations in planning, implementing and

budgeting for new medicines or licence extensions and

national guidance. It provides support to commissioners

and providers by highlighting new medicines and service

developments that may require dialogue about financial

and operational resource implications. The Prescribing

Outlook series is produced for primary and secondary care

NHS organisations and has a national perspective. This

document is the first in the series that comprises

Prescribing Outlook - New Medicines and Prescribing

Outlook - National Developments, and is supported by an

electronic Cost Calculator. These are all available at

www.ukmi.nhs.uk. The component documents of the

Prescribing Outlook series are published each autumn in

line with annual budget planning timeframes and key

outputs from NICE. Updates on the progress of individual

medicines at other times throughout the year can be found

on the UKMi New Drugs Online database.

The content and presentation of the Prescribing Outlook

series has evolved following consultation with users. These

documents they are all now only published electronically

but are formatted to make them suitable for printing.

Further specialist medicines information not included in the

series can also be obtained from local and regional

medicines information centres. See www.ukmi.nhs.uk.

Prescribing Outlook – New Medicines. It aims to provide

advance information about new medicines (and new

licensed indications or formulations) with anticipated

market launches in the next 18 to 24 months. In addition,

brief details of drugs launched in the last 12 months are

included as this is often useful for local planning purposes.

The content is not comprehensive but focuses on

medicines with the potential for significant clinical or

financial impact on the NHS. Estimates of potential uptake,

patient, service and financial implications are included

where possible. Reference is made to relevant national

guidance and links to in-depth independent reviews are

included, where available.

How is the content decided?

Various criteria are applied to prioritise those medicines in

the pipeline likely to have the largest impact. These

include considering whether:

the medicine is expected to provide a significant

improvement in disease management,

the medicine is first-in-class or has a major new

indication,

there are limited alternatives,

the medicine cost will be high,

the target population is large,

there is likely to be a significant effect on service

implications e.g. route/ formulation/ method of delivery,

the medicine or disease area is an NHS priority,

the medicine has significant additional indications in the

advanced pipeline stage,

the medicine is in the EU licensing process,

there is likely to be significant media interest.

http://www.mhra.gov.uk/Publications/Consultations/Medicinesconsultations/MLXs/CON173755

http://www.ukmi.nhs.uk/



There will be additional, unquantifiable, factors that have

implications for the NHS such as local demographics and

prescribing preferences which cannot be accommodated in

a national document.

More detailed information on the medicines listed can be

obtained from the UKMi New Drugs Online (NDO)

database which can be accessed directly from the generic

name hyperlink in this document.

Please direct comments on Prescribing Outlook – New

Medicines to the editor: Helen Davis, North West

Medicines Information Centre, Pharmacy Practice Unit.

[email protected].

Other UKMi horizon scanning resources

Prescribing Outlook – National Developments estimates

the impact on clinical practice and prescribing budgets of

national guidance, mainly that issued by NICE. It is

intended to inform discussions between commissioners

and providers, and highlight issues around implementation

of guidance. Access is via www.ukmi.nhs.uk.

Prescribing Outlook – Cost Calculator is an Excel

spreadsheet tool to facilitate estimates of potential

prescribing changes for a local population. Access is via

www.ukmi.nhs.uk.

Please direct comments on Prescribing Outlook – National

Developments and the Cost Calculator to: Devika Sennik

or David Erskine, London and South East Medicines

Information Centre, Guy’s and St. Thomas’ NHS

Foundation Trust. [email protected],

[email protected]

New Drugs Online (NDO) database includes information

on medicines in clinical development from phase II trials to

product launch and includes links to evaluated information

on medicines up to one year post launch. This database is

maintained by UKMi and forms the basis of the content of

Prescribing Outlook – New Medicines. This dynamic

horizon scanning tool is updated daily and can be used to

produce reports based on a number of criteria including

possible launch date, stage of clinical development or

pharmaceutical company. Access is free to all with an NHS

email address via www.ukmi.nhs.uk but requires individual

registration. Access is. Limited access is also freely

available to non-NHS users via Evidence search

(www.evidence.nhs.uk).

Please direct comments and enquiries on New Drugs

Online to: Alexandra Denby, London Medicines Information

Service-Northwick Park, Northwick Park & St Mark's

Hospitals. [email protected]

Horizon scanning and new medicines support materials are available via www.ukmi.nhs.uk

The information in these resources is the best available at the time of publication but is subject to significant change with time.

Abbreviations

AWMSG All Wales Medicines Strategy Group

BNF British National Formulary

CCG Clinical Commissioning Group

DH Department of Health

EMA European Medicines Agency

EU European Union

HR Hazard ratio

HRG Healthcare Resource Group (definition)

i.m. Intramuscular

i.v. Intravenous

L(C)NDG London (Cancer) New Drugs Group

MHRA Medicines and Healthcare products Regulatory agency

MTRAC Midland Therapeutics Review & Advisory Committee

NDO New Drugs Online

NETAG North East Treatment Advisory Group

NHSE NHS England

NIHR-HSC National Institute for Health Research Horizon Scanning Centre

NICE National Institute for Health and Care Excellence

NICE-MPC NICE Medicines and Prescribing Centre

NNH Number needed to harm

NNT Number needed to treat

NPC National Prescribing Centre (now the NICE Medicines and Prescribing Centre – MPC)

ns Not significant

PAS Patient Access Scheme

PbR Payment by Results

RDTC Regional Drug & Therapeutics Centre, Newcastle

s.c. Subcutaneous

SIGN Scottish Intercollegiate Guidelines Network.

SMC Scottish Medicines Consortium

SmPC Summary of Product Characteristics

TBC To be confirmed

UKMi United Kingdom Medicines Information

US United States

mailto:[email protected]






http://www.evidence.nhs.uk/



http://www.hscic.gov.uk/hrg


Key

Generic name and formulation

Brand name

Company

Medicines

are listed by BNF category and linked to relevant publicly available pages of the NDO database.

The company that holds the marketing rights in the EU is listed together with a co-promoter company if relevant.

Included in abbreviated entries.

Indication

The indication

for the product.

The closer the drug is to launch the more specific this can be.


Current status

PII/III – in phase two/three trials.

Filed – licence application has

been submitted.

Recommended for approval – opinion of the advisory committee of the licensing authority suggests the medicine should be licensed. In the EU a full licence is likely within three months. Relevant links are included.

Licensed – the product has been

granted a marketing licence. The company determines launch date.

Launched – the medicine is

marketed in the EU. If launched elsewhere in the world, but not the UK, there are links to prescribing data.

Orphan status – If a medicine has a designated orphan status this is indicated (see definition page 7).

The following apply to US expediated programmes for serious or life-threatening conditions and suggest the drug will pass through licensing systems faster:

Breakthough therapy status –preliminary evidence indicates substantial improvement over existing therapies on clinically significant outcomes.

Fast-track status –potential to address unmet needs.

Priority review – provides significant improvement in safety or effectiveness.


Predicted UK launch or licence extension

An informed estimate based on knowledge of processes and timescales involved in licensing systems.

It is easier to predict when a product will be available once it is has entered the licensing process as known time frames apply. However, once a licence has been granted the company decides when and where to launch the product.


National guidance: Relevant publications (funding source).

NICE - National Institute for Health and

Care Excellence: www.nice.org.uk (DH).

SIGN - Scottish Intercollegiate Guidelines

Network. www.sign.ac.uk (NHS

Scotland).

SMC - Scottish Medicines Consortium.

www.scottishmedicines.org.uk (NHS

Scotland).

AWMSG - All Wales Medicines Strategy

Group. www.wales.nhs.uk/awmsg (NHS).

Reviews: Independent reviews and regional guidance that is accessible to all NHS sectors published between 2011 and 2013. Included in abbreviated entries.

NICE-MPC: NICE Medicines and

Prescribing centre (DH).

NIHR-HSC - NIHR Horizon Scanning

Centre. www.nhsc-healthhorizons.org.uk.

(NIHR).

NPC - National Prescribing Centre (now

the NICE-MPC. www.npc.co.uk. (Legacy

site for reviews prior to May 2012).

UKMi - United Kingdom Medicines

Information. www.ukmi.nhs.uk (NHS).

L(C)NDG - London (Cancer) New Drugs

Group (NHS organisations in Greater

London).

MTRAC - Midlands Therapeutics Review

& Advisory Committee. www.mtrac.co.uk.

(Primary Care NHS organisations in the

Midlands).

NETAG - North East Treatment Advisory

Group. www.netag.nhs.uk (legacy site of

sub-group of North East Specialised

Commissioning Group).

RDTC - Regional Drug & Therapeutics

Centre. rdtc.nhs.uk. (NHS organisations

in the North East of England).

Target population: Data

on prevalence (number with the disease) and incidence (number of new cases each year) are reported for a 100,000 population, if possible.

Sector: An indication of which sector in the NHS the medicine is likely to impact, at least initially, in terms of service provision.

Implications: Factors highlighted include patient options, monitoring or testing requirements

and service implications related to medicine delivery.

Financial implications: Cost implications are assessed based on a number of assumptions such as whether the medicine is added to existing therapy or is a competitor in areas where budgets are established. Factors that are difficult to quantify include likely uptake of the medicine within the target population. For launched products, costs are taken from the latest published NHS costs, or, for generic prices, from the Drug Tariff. Where a patient access scheme (PAS) may apply this is indicated. Unless stated, costs do not include VAT.

Likely commissioning route: An estimate of the potential commissioning route based on NHS structures implemented since Apr 2013 i.e. CCG or NHS England (NHSE). Included in abbreviated entries.

Payment by Results (PbR): The actual or anticipated tariff position based on historical

assumptions. For drugs not yet launched this becomes an educated guess. Drugs previously referred to as ‘PbR exclusions’ are now known as ‘Specified high cost drugs’. If a drug is not likely to be a specified high cost drug it is therefore, by default, likely to be included within tariff and will be listed as ‘HRG included’. Included in abbreviated entries.

Pharmacology: Therapeutic class and/or mode of action and administration details. Included in abbreviated entries.

Efficacy: Key studies with a link to trial details, especially when relevant for licence application. Primary outcome data and patient, rather than disease, orientated outcomes are preferentially included where available.

Safety: For medicines already marketed for other indications a link to the product information is included. For new

medicines, information is included where it is thought adverse effects reported to date may influence licensing requirements e.g. increased monitoring or where they differ significantly from those associated with current treatments.

http://www.regulations.gov/#!documentDetail;D=FDA-2013-D-0575-0002

http://www.regulations.gov/#!documentDetail;D=FDA-2013-D-0575-0002

http://www.nice.org.uk/

http://www.sign.ac.uk/

http://www.scottishmedicines.org.uk/

http://www.wales.nhs.uk/awmsg

http://www.nhsc-healthhorizons.org.uk/

http://www.npc.co.uk/


http://www.mtrac.co.uk/

http://www.netag.nhs.uk/

http://rdtc.nhs.uk/


Summary of predicted launch dates

This list summarises the earliest predicted UK launch date for pipeline drugs listed in Table 1 – Pipeline drugs.

Refer to the index for a full list of generic and proprietary names. *Indicates which drugs have been assigned

orphan status in the EU (see page 7 for more details).

BNF Drug Indication Page

Late 2013

1 Golimumab Ulcerative colitis 11

2 Lomitapide Hypercholesterolaemia- familial

16

2 Defibrotide* Hepatic veno-occlusive disease

17

3 Indacaterol/ glycopyrronium

Chronic obstructive pulmonary disease

18

3 Nalfurafine* Dialysis-related pruritus 19

4 Lurasidone Schizophrenia 20

5 Tobramycin* Cystic fibrosis 22

5 Bedaquiline Tuberculosis 22

5 Cobicistat HIV infection (booster) 23

5 Dolutegravir HIV infection 23

6 Alogliptin Type 2 diabetes mellitus 26

6 Canagliflozin Type 2 diabetes mellitus 26

6 Dapagliflozin/ metformin

Type 2 diabetes mellitus

27

6 Follitropin alfa Biosimilar 70

7 Botulinum A toxin

Overactive bladder 29

8 Cabozantinib* Thyroid cancer 31

8 Afatinib Non-small cell lung cancer

31

8 Trastuzumab emtansine

Breast cancer 33

8 Trastuzumab/ hyaluronidase

Breast cancer 34

8 Masitinib* Pancreatic cancer 36

8 Regorafenib Colorectal cancer 37

8 Sipuleucel-T Prostate cancer 39

8 Radium-223 chloride

Prostate cancer 40

8 Dabrafenib Malignant melanoma 43

8 Bendamustine Non-Hodgkin’s lymphoma

45

8 Rituximab Non-Hodgkin’s lymphoma

45

8 Bortezomib Multiple myeloma 46

8 Alemtuzumab Multiple sclerosis 48

8 Laquinimod Multiple sclerosis 49

8 Dimethyl fumarate

Multiple sclerosis 50

8 Teriflunomide Multiple sclerosis 50

9 Eltrombopag Thrombocytopenia 51

9 Sodium phenylbutyrate

Urea cycle disorders 52


9 Alipogene tiparvovec*

Lipoprotein lipase deficiancy

52

10 Canakinumab* Juvenile idiopathic arthritis

53

10 Ustekinumab Psoriatic arthritis 54

10 Ataluren* Duchenne muscular dystrophy

55

10 Pegloticase Gout prophylaxis 55

11 Aflibercept Macular oedema 56

13 Afamelanotide* Erythropoietic protoporphyria

58

14 Meningococcal group-B vaccine

Meninitis B 59

2014

1 Vedolizumab Ulcerative colitis 11

1 Teduglutide* Short bowel syndrome 12

1 Vedolizumab Crohn's disease 12

2 Apixaban Venous thromboembolism treatment

13

2 Dabigatran Venous thromboembolism treatment and secondary prevention

13

2 Rivaroxaban Secondary prevention of atherothrombotic events in acute coronary syndrome

14

2 Rivaroxaban Acute coronary syndrome- prevention of stent thrombosis

14

2 Cangrelor Acute coronary syndrome – thrombosis prevention

15

2 Vorapaxar Secondary prevention of cardiovascular events

15

2 Riociguat Pulmonary arterial hypertension

16

2 Clevidipine Hypertension, perioperative

17

3 Umeclidinium Chronic obstructive pulmonary disease

18

3 Umeclidinium /vilanterol

Chronic obstructive pulmonary disease

18

3 Budesonide/ formoterol (Bufomix)

Asthma 19

3 Omalizumab Urticaria 19

4 Loxapine Agitation associated with schizophrenia and bipolar disorder

20



4 Dextrometh-orphan/quinidine

Pseudobulbar affect 21

4 Liraglutide Obesity 21

5 Simeprevir Hepatitis C 24

5 Sofosbuvir Hepatitis C 24

6 Bazedoxifene/ conjugated estrogens

Postmenopausal osteoporosis and menopausal symptoms

28

6 Insulin degludec /insulin aspart

Type 1 and 2 diabetes mellitus

27

6 Pasireotide* Acromegaly 28

6 Tolvaptan Polycystic kidney disease

29

6 Follitropin alfa Biosimilar 70

7 Collagenase clostridium histolyticum

Peyronie's disease 30

8 Sorafenib Thyroid cancer 30

8 Lenvatinib* Thyroid cancer 31

8 Enobosarm Non-small cell lung cancer

33

8 Trastuzumab emtansine

Breast cancer 34

8 Bevacizumab Breast cancer 34

8 Everolimus Breast cancer 35

8 Regorafenib Gastrointestinal stromal tumours

36

8 Doxorubicin heat-sensitive*

Hepatocellular carcinoma

37

8 Sorafenib Renal cell carcinoma 38

8 Apaziquone Bladder cancer 38

8 Ipilimumab Prostate cancer - treatment

39

8 Pazopanib Ovarian cancer 40

8 Bevacizumab Ovarian cancer 41

8 Vintafolide* Ovarian cancer 41

8 Paclitaxel* Ovarian cancer 41

8 Ipilimumab Malignant melanoma 42

8 Ipilimumab Malignant melanoma 43

8 Trametinib Malignant melanoma 44

8 Dasiprotimut-T* Non Hodgkin’s lymphoma

45

8 Carfilzomib* Multiple myeloma 46

8 Obinutuzumab* Chronic lymphocytic leukaemia

47

8 Ofatumumab* Chronic lymphocytic leukaemia

47

8 Chlormethine* Cutaneous T cell lymphoma

48

8 Peginterferon beta 1a

Multiple sclerosis 49

8 Teriflunomide Multiple sclerosis 51

8 Trastuzumab Biosimilar 70


9 Elosulfase alfa* Mucopolysaccharidosis IVA

51

10 Golimumab Juvenile idiopathic arthritis

53

10 Apremilast Psoriatic arthritis 54

10 Idebenone* Duchenne muscular dystrophy

56

11 Aflibercept Diabetic macular oedema

56

13 Apremilast Psoriasis 57

13 Tofacitinib Psoriasis 57

13 Secukinumab Psoriasis 58

13 Propranolol Infantile haemangioma 58

2015 or 2016

1 Obeticholic acid Cirrhosis 12

1 Infliximab Biosimilar 70

2 Desmoteplase Stroke 15

2 Evolcumab Hyperlipidaemia 16

2 Alirocumab Hypercholesterolaemia 16

3 Masitinib Asthma 19

3 Ataluren* Cystic fibrosis 20

3 Lumacaftor Cystic fibrosis 20

5 ABT450/ ritonavir / ABT-267/ ABT333

Hepatitis C 25

5 Asunaprevir/ daclatasvir

Hepatitis C 25

5 Sofosbuvir/ ledipasvir

Hepatitis C 25

5 Actoxumab/ bezlotoxumab

Clostridium difficile infection

25

6 Insulin inhaled Type 1 and 2 diabetes mellitus

27

6 Exenatide implant

Type 2 diabetes mellitus

27

6 Insulin glargine Biosimilar 70

8 Brain cancer vaccine*

Glioblastoma 30

8 Afatinib Head and neck cancer 30

8 Afatinib Non-small cell lung cancer

32

8 Belagen-pumatucel-L

Non-small cell lung cancer

32

8 LDK378 Non-small cell lung cancer

32

8 Eribulin Non- small cell lung cancer

32

8 Dacomitinib Non-small cell lung cancer

32

8 Ganetespib Non-small cell lung cancer

32

8 Anamorelin Cancer cachexia 33

8 Sorafenib Breast cancer 35

8 Palbociclib Breast cancer 35



8 Ramucirumab* Hepatocellular carcinoma

37

8 Sorafenib* Hepatocellular carcinoma

37

8 Custirsen Prostate cancer 39

8 Cabozantinib Prostate cancer 40

8 Trebananib Ovarian cancer etc. 42

8 Olaparib* Ovarian cancer 42

8 Eribulin* Sarcoma 42

8 Talimogene laherparepvec

Malignant melanoma 44

8 Cobimetanib Malignant melanoma 44

8 Erismodegib Basal cell carcinoma 44

8 Daratumumab Multiple myeloma 46

8 Ibrutinib* Mantle cell lymphoma 47

8 Idelalisib Chronic lymphocytic leukaemia

47

8 Vosaroxin* Acute myeloid leukaemia

47

8 Ibrutinib Chronic lymphocytic leukaemia

48


8 Rigosertib* Myelodysplastic syndromes

48

8 Daclizumab Multiple sclerosis 50

8 Fingolimod Multiple sclerosis 50

9 Sebelipase alfa* Liposomal acid lipase deficiency

52

10 Masitinib Rheumatoid arthritis 53

10 Secukinumab Rheumatoid arthritis 53

10 Secukinumab Ankylosing spondylitis 54

10 Secukinumab Psoriatic arthritis 54

10 Lesinurad Gout 55

10 Odanacatib Osteoporosis in men 55

10 Infliximab Biosimilar 70

11 Aflibercept Macular oedema 57

Uncertain

2 Serelaxin Heart failure 17

8 Omacetaxine* meppesuccinate

Chronic myelogenous leukaemia

46

*Indicates which drugs have been assigned orphan status in the EU. To qualify for orphan designation, a medicine must meet one of these criteria:

It is intended for a life-threatening or chronically debilitating condition affecting no more than 5 in 10,000 (50 in 100,000)

people in the EU;

It is intended for a life-threatening, seriously debilitating or serious and chronic condition and without incentives it is

unlikely that the revenue after marketing would cover the investment in its development.

In both cases, there must also be either no satisfactory method of diagnosis, prevention or treatment of the condition concerned

authorised, or, if such a method exists, the medicine must be of significant benefit to those affected by the condition.

Manufacturers of drugs that have received orphan designation benefit from incentives to support development of medicines to

treat rare diseases.

The US definition of an orphan drug is different. It is defined as a rare disease occurring in less than 200,000 individuals.

Assuming a US population of about 311 million this translates to a prevalence of about 65 in 100,000. The definition of an ultra

orphan condition used by NICE is a UK prevalence of less than 1 in 50,000.

http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000393.jsp&murl=menus/regulations/regulations.jsp&mid=WC0b01ac0580024c5a


Highlights

The drugs listed below have been selected from table 1 (drugs not yet marketed) as warranting special

consideration due to their expected overall NHS impact taking account of financial implications, service provisions,

place in therapy and target population. Such data are limited so the list is for guidance only and will not take

account of local factors or perspective which will vary by sector, geography and speciality. You may also want to

refer to table 3 (recently launched drugs) to identify those requiring active management locally.

Drug Indication Reasons for highlighting

Defibrotide

page 17

Hepatic

veno-

occlusive

disease

(VOD).

In haematopoietic stem-cell transplant VOD is a leading cause of morbidity and mortality.

Supportive care is the current treatment option. Defibrotide will be the first specific therapy

for VOD. It is likely to be expensive; based on a dose of 25mg/kg/day, current named

patient cost is around £40,000 for 21 days treatment.

Likely commissioning route: NHSE. PbR: Specified high cost drug.

Rivaroxaban

page 14

Acute

coronary

syndrome

(ACS).

Rivaroxaban 2.5mg twice daily will be used for prevention of atherosclerotic events in

patients with elevated cardiac biomarkers in combination with one or more antiplatelets.

However, bleeding risks may be a concern, especially in older patients. Cost will be in

addition to existing therapy; price is currently uncertain.

Likely commissioning route: CCG. PbR: HRG included.

Dextro-

methorphan/

quinidine

page 21

Pseudo-

bulbar

affect

(PBA).

PBA can develop in several neurological diseases such as multiple sclerosis, or following

brain injury. The estimated prevalence of PBA is up to 500 per 100,000 people. This is the

first drug licensed for PBA. Diagnosis needs confirmation before treatment and may

increase referrals to specialist neurosciences. It is likely to be considerably more expensive

than unlicensed alternatives.

Likely commissioning route: NHSE. PbR: Likely HRG included.

Insulin

degludec/

insulin aspart

page 27

Type 1 and

type 2

diabetes

mellitus.

Estimated UK prevalence of diagnosed diabetes was 2.9 million people in 2011and a

further 850,000 are undiagnosed. Prevalence is projected to increase to 5 million by 2025.

Spending on analogue insulin is increasing and combination use of analogues is likely to

increase.


Tolvaptan

page 29

Autosomal-

dominant

polycystic

kidney

disease

(ADPKD)

ADPKD has a prevalence of 100-1,300 per 100,000 people. In 2007 polycystic kidney

disease accounted for 12.7% of patients receiving renal transplants. There are currently no

therapies that modify disease course and slow decline in renal function. Current options

include anti-hypertensives, dialysis and renal transplant. Tolvaptan 60mg/day costs over

£4,100/month.

Likely commissioning route: Uncertain -depending on statge of renal failure.

PbR: Specified high cost drug.

Everolimus

Trastuzumab

emtansine

pages 34,35

Breast

cancer

(BC),

advanced

HER2-

positive –

first-,

second- or

third-line.

The incidence of metastatic BC in the UK is about 32 per 100,000 people. 25% are HER2-

positive with a worse prognosis. About 70% of patients do not respond to first-line

trastuzumab and the rest develop resistance within the first year.

Adding everolimus first-line may improve response rates and delay need for second-line

chemotherapy; it will compete with i.v. pertuzumab and costs will be additive. Used second

or third-line everolimus is an alternative to lapatinib for overcoming trastuzumab resistance.

Current monthly cost of everolimus is £2,250 to £2,970.

First-in-class trastuzumab emtansine is an antibody conjugate of trastuzumab and an anti-

mitotic agent, maytansinoid DM1. Used first-line in combination with pertuzumab it would

prevent the need for first-line chemotherapy and could result in a delay in disease

progression and improved quality of life. Cost is unknown but it would displace

trastuzumab plus taxane therapy. US cost is $9,800 a month. When used second or third-

line trastuzumab emtansine will compete with other second-line options including biological

therapies, chemotherapies and hormonal therapies.

Likely commissioning route: NHSE. PbR: Chemotherapy is locally negotiated.

http://www.ukmi.nhs.uk/applications/ndo/record_view_open.asp?newDrugID=5725




Trastuzumab/

hyaluronidase

page 34

Breast

cancer - s.c.

formulation.

Trastuzumab is co-formulated with recombinant human hyaluronidase to facilitate

absorption of trastuzumab through subcutaneous tissue. Compared to the i.v. formulation

which is given as a 30 minute infusion, s.c. trastuzumab will reduce preparation and

administration time. Cost is currently unknown.


Masitinib

page 36

Pancreatic

cancer,

advanced –

first-line.

UK incidence of pancreatic cancer is 13 per 100,000 people; 90% have advanced disease

at diagnosis and 3% survive 5 years. Masitinib may extend life in patients with few options.

It will be given in addition to gemcitabine, which is recommended by NICE for patients with

a Karnofsky score of ≥50. A test for the prognostic genetic biomarker is being developed.


Regorafenib

page 37

Colorectal

cancer

(CRC),

metastatic –

third- or

fourth-line.

UK incidence of CRC is 67 per 100,000 people; 20-55% of patients present with metastatic

disease. Management is mainly palliative with surgery and chemo/radiotherapy. For

patients with no further treatment options, regorafenib may delay disease progression and

improve quality of life. Regorafenib will be additive to other therapies. UK cost is unknown

but US cost is $9,350 per month.


Pazopanib

Bevacizumab

Vintafolide

pages 40, 41

Ovarian

cancer

(OC).

UK incidence of OC is 21 per 100,000 people. 75% receive first-line platinum

chemotherapy; between 70 and 80% respond. Of these 55-75% relapse within 2 years and

most receive platinum chemotherapy a second or third time before developing resistance.

Pazopanib will be used as maintenance after first-line chemotherapy in addition to current

therapies, and may delay need for second-line chemotherapy. Monthly cost of 800mg daily

is £2,200.

Bevacizumab will be used in addition to chemotherapy in advanced platinum-resistant

disease. Current cost of 10 doses (15mg/kg) for a 65kg woman is £23,000.

Vintafolide will be used in advanced platinum-resistant, folate receptor (FR)-positive

disease and a radiopharmaceutical diagnostic test is needed to identify FR-positive

tumours (90% of patients). Vintafolide will be used in addition to doxorubicin.


Ipilimumab

Trametinib

Dabrafenib

pages 42, 43,

44

Malignant

melanoma.

UK incidence of malignant melanoma is about 21 per 100,000 people, and is doubling

every 10-20 years. 7% of 15-64 year olds present with advanced (III/IV) disease compared

with 20% aged ≥65 years. Median survival is 6-9 months, with 40-50% of stage III patients

surviving 5 years.

Ipilimumab will be used in resected high-risk stage III disease (first-line adjuvant therapy) to

delay or prevent recurrence, and in unresectable or metastatic disease (first-line with

dacarbazine). There is currently no standard adjuvant therapy. In combination with first-line

standard of care dacarbazine, ipilimumab will be an option for patients whose tumours do

not have BRAF mutations. Ipilimumab costs £52,500 per dose for a 70kg person.

Oral trametinib will be used in unresectable or metastatic BRAF-positive disease (first-or

second-line monotherapy and first-line in combination with dabrafenib). Trametinib, like

dabrafenib and vemurafenib, are alternatives to i.v. dacarbazine. A test is needed to

identify BRAF-positive patients. Combination therapy offers the possibility of improved

survival and better tolerability. US cost of trametinib is $8,700 for a 30-day supply.

Dabrafenib, used alone for first-line therapy, is likely to be similarly priced to vemurafenib

(£7,000 per month).


Rituximab

page 45

Non-

Hodgkin's

lymphoma

(NHL) - s.c.

formulation.

Rituximab s.c. will be an option for all patients with NHL for whom i.v. rituximab is currently

indicated. Those with poor venous access may be initial candidates. It could reduce

outpatient preparation and administration time. Rituximab s.c. is likely to cost the same as

the current i.v. formulation but future availability of biosimilar i.v. formulations may affect

pricing strategy.





Obinutuzu-

mab

Ofatumumab

page 47

Chronic

lymphocytic

leukaemia

(CLL).

UK annual incidence of CLL is 4.2 per 100,000 people, increasing to over 30 per 100,000

in those over 80 years of age.

Obinutuzumab and ofatumumab are humanised anti-CD20 monoclonal antibodies and

alternatives for patients with co-morbidities who cannot have FCR (fludarabine,

cyclophosphamide, rituximab). Current options for these patients include chlorambucil or

bendamustine (both with/ without rituximab) or reduced dose FCR. Ofatumumab 100mg

costs £1,820 per month. Alternative costs are chlorambucil £56, bendamustine £966,

rituximab £1,572.


Alemtuzumab

Laquinimod

Dimethyl

fumarate

Teriflunomide

pages 48, 49,

50

Multiple

sclerosis -

relapsing-

remitting

(RRMS).

In a population of 100,000, 39 will have relapsing-remitting disease (RRMS). 31% of these

receive, disease modifying agents; 74% interferons and 26% glatiramer. The availability of

more convenient and acceptable oral preparations could increase the proportion of patients

treated. NICE estimated that fingolimod, the first licensed oral preparation for RRMS, could

take up to 15% of the interferon market share. There may be price competition as more

oral agents become available.

Alemtuzumab will be for active RRMS defined by clinical or imaging features. As a single

annual i.v. treatment it may be attractive. Use is likely to be in the second-line setting.

Acquisition cost may be similar to other options but there may be additional monitoring

costs. Oral laquinimoddimethyl fumarate and teriflunomide will compete with fingolimod

which costs about £19,500/year although there is a PAS in place.

Likely commissioning route: NHSE. PbR: Specified high cost drugs.

Eltrombopag

page 51

Thrombo-

cytopenia

(TCP)

associated

with

hepatitis C

(HepC).

About 216,000 people in the UK are infected with hepatitis C (340 per 100,000); estimates

of the prevalence of HepC-associated TCP ranges from 0.16 - 45.4%. TCP may interfere

with diagnostic procedures, such as liver biopsy, and may exclude patients from antiviral

treatment. Eltrombopag will be used where TCP prevents starting, or limits the ability to

maintain, optimal interferon-based therapy. Eltrombopag costs between £770 and £3,080

for 28 days treatment.

Likely commissioning route: Uncertain – depending on complexity of patient.


Elosulfase

alfa

page 51

Mucopoly-

saccharid-

osis IVA.

Mucopolysaccharidosis type IVA affects less than 15 in 100,000 people in the EU and there

are currently no licensed treatments. Elosulfase is likely to be expensive and similar to

other treatments for mucopolysaccharidosis diseases (galsulfase, idursulfase, laronidase).

Likely commissioning route: NHSE. PbR: Likely specified high cost drug.

Apremilast

page 54

Plaque

psoriasis,

moderate to

severe.

Estimated prevalence of psoriasis in England is 1.63%; about 20 per 100,000 people have

moderate to severe disease. Plaque psoriasis is the most common form, affecting 80-90%

of people; about 1.1% are eligible for biological treatment. Apremilast is likely to be

licensed for use after conventional systemic therapies, but as an oral preparation may be

considered preferable to parenteral biological therapies. Acquisition and administration cost

may be lower than for biologicals.

Likely commissioning route: CCG. PbR: Likely specified high cost drug.

Ataluren

page 55

Duchenne

muscular

dystrophy,

nonsense-

mutation

(nmDMD).

DMD affects 1 in 3,600 to 6,000 male births in the UK; about 100 boys are diagnosed

annually and prevalence is about 1,500. 10-15% have a nonsense mutation (150-195

patients in the UK). Current options (corticosteroids) can delay but not prevent loss of

walking ability. Ataluren is the first therapy to target the underlying defect in nmDMD. It is

likely to be additional to current therapy in ambulant patients but could prolong

independence and delay complications. Likely to be expensive.




Table 1. Pipeline drugs

BNF 1. Gastrointestinal system

Golimumab injection

Simponi

MSD

Indication: Ulcerative colitis (UC), moderate to severe – second-line if inadequate response/ intolerance/ contra-indication to conventional therapy.

Current status: Recommended for approval in EU Jul 2013.

Licensed in US - see prescribing information.

Predicted UK licence extension:

2013

National guidance:

NICE: UC - management, infliximab - UC

subacute manifestations, acute exacerbations. Biologic drugs commissioning guide.

Reviews: NIHR HSC Sep 2011.

Target population: The incidence and prevalence of UC in the UK is about 10 and 240 per 100,000 people, respectively. 30–60% of people will have at least one relapse per year. About 80% of these are mild to moderate and about 20% are severe.

Sector: Secondary care.

Implications: Golimumab will be a second-line option with the advantage of s.c. administration vs. i.v. administration for infliximab. However, monthly administration is required vs. every 6-8 weeks for infliximab.

Financial: As a further treatment option it will be additional to current costs.

Likely commissioning route: CCG. PbR: Specified high cost drug.

Pharmacology: Anti-TNF monoclonal antibody given by monthly s.c. injection.

Efficacy: The published PURSUIT-SC study (n=774) compared induction treatment with golimumab (either 200mg or 400mg at week 0 and 100mg or 200mg at week 2) with placebo. The primary outcome of clinical response (defined as Mayo score of ≥30% and 3 points vs. baseline score, with a decrease in rectal bleeding subscore of ≥1 or a rectal bleeding subscore of 0 or 1) at week 6 was met by 52%, 55% and 30% of patients, respectively (p<0.01, NNT=4). In the published PURSUIT-M study 464 patients who had responded to induction therapy in PURSUIT-SC were randomised to golimumab 50mg, 100mg or placebo every 4 weeks to week 52. Clinical response was maintained through to week 54 in 47% (p=0.01, NNT=6), 50.6% (p<0.001, NNT=5) vs. 31.4%, respectively.

Safety: See medicines.org.uk.

Vedolizumab injection

Takeda

Indication:

Ulcerative colitis (UC), moderate to severe - second-line when resistant/ intolerant to conventional therapy and to TNF-alpha antagonists.

Current status:

Filed in EU Mar 2013.

Predicted UK launch:

2014

National guidance:

As for golimumab above.

Reviews: NIHR HSC Mar 2013.

Target population: As for golimumab above.


Implications: As first in a new class this could be an attractive option for patients with limited alternatives. It could compete with golimumab above as a second-line option but has the disadvantage of being an i.v. infusion.



Pharmacology: Monoclonal-antibody, alpha4-beta7 integrin antagonist (first-in-class), given as a 30 minute i.v. infusion.

Efficacy: In the published PIII GEMINI I study, patients were randomised to vedolizumab or placebo at weeks 0, 2, 6 and then at 4- or 8-week intervals for up to one year. The primary outcome was the proportion of patients with clinical response at week 6 (induction period) and clinical remission at week 52. At week 6, response rates were 47.1% with vedolizumab vs. 25.5% with placebo (p<0.01, NNT=5). Among initial responders re-randomised at 6 weeks, 52-week remission rates were 44.8% with 4 weekly vs. 41.8% with 8 weekly vedolizumab vs. 15.9% for placebo (p<0.001 for both, NNT=3 and 4).

Safety: Frequency of adverse events in trials was comparable to placebo.


http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion/human/000992/WC500146562.pdf


http://www.google.co.uk/url?sa=t&rct=j&q=Simponi+prescribing+data&source=web&cd=1&cad=rja&ved=0CC8QFjAA&url=http%3A%2F%2Fwww.simponi.com%2Fprescribing-information.pdf&ei=pQYJUujKIsithQf0_oD4BA&usg=AFQjCNGXjHvWn_7SDZPok3KfGIM0Z_hmyg&bvm=bv.50500085,d.ZG4

http://www.google.co.uk/url?sa=t&rct=j&q=Simponi+prescribing+data&source=web&cd=1&cad=rja&ved=0CC8QFjAA&url=http%3A%2F%2Fwww.simponi.com%2Fprescribing-information.pdf&ei=pQYJUujKIsithQf0_oD4BA&usg=AFQjCNGXjHvWn_7SDZPok3KfGIM0Z_hmyg&bvm=bv.50500085,d.ZG4

http://guidance.nice.org.uk/CG166

http://guidance.nice.org.uk/TA140/Guidance/pdf/English



http://www.nice.org.uk/usingguidance/commissioningguides/biologicaltherapies/home.jsp

http://www.nhsc-healthhorizons.org.uk/files/downloads/1652/2096.08032b57.Golimumab.pdf

http://www.ncbi.nlm.nih.gov/pubmed/23735746


http://www.medicines.org.uk/emc/


http://www.hsc.nihr.ac.uk/files/downloads/2034/2373.3b2fe5a1.Vedolizumabforulcerativecolitis_Mar13.pdf



Vedolizumab injection

Takeda

Indication:

Crohn’s disease, moderate

to severe - second-line when resistant/ intolerant to conventional therapy and to TNF-alpha antagonists.

Current status:

Filed in EU Mar 2013.


2014

National guidance:

NICE: Crohn’s disease: pathway, clinical

guideline; infliximab and adalimumab; Biologic drugs commissioning guide.


Target population: Estimates of UK

prevalence of Crohn’s disease range from 50 to 150 per 100,000 people; 20% may have severe active disease and up to 50% may be resistant to, or intolerant of, existing therapy, including TNF inhibitors.


Implications: As first in a new class vedolizumab could be an attractive

option for patients with limited alternatives.



Pharmacology: Monoclonal-antibody, alpha4-beta7 integrin antagonist (first-in-class), given as a 30 minute i.v. infusion.

Efficacy: In the published PIII GEMINI II study, patients were randomised to vedolizumab or placebo at weeks 0, 2, 6 and then at 4- or 8-week intervals for up to one year. The primary outcome was the proportion of patients in clinical remission at week 6 (induction period) and week 52. At week 6, remission rates were 14.5% with vedolizumab vs. 6.8% with placebo (p<0.03, NNT=13). Among initial responders re-randomised at 6 weeks, remission rates at 52 weeks were 36.4% with vedolizumab every 4 weeks vs. 39.0% for vedolizumab every 8 weeks vs. 21.6% for placebo (p<0.01 for both, NNT=7 and 6). In GEMINI III in 315 patients who failed anti-TNF therapy remission rates at week 6 were 15.2% vs. 12.1% for vedolizumab and placebo, respectively (p=ns).

Safety: Frequency of adverse events in trials was comparable to placebo.

Teduglutide injection

Revestive

NPS Pharma-ceuticals

Indication:

Short bowel syndrome (SBS).

Current status:

Licensed in EU Sep 2012 with orphan status – see prescribing information.


2014

National guidance:

NICE: Nutrition support in adults: clinical

guideline.

Reviews: No recent reviews.

Target population: The UK estimated

incidence of short bowel syndrome is 2 to 5 cases per million people.

Sector: Severe intestinal failure treatment is a specialised service.

Implications: Teduglutide would be the first drug specifically licensed for

SBS, the most common indication for home parenteral nutrition (PN). It may reduce PN volume requirements.

Financial: Likely to be expensive and additive to current options. The cost of teduglutide in the US is $295,000 a year. EU launch has been delayed by returning rights from Takeda to NPS Pharmaceuticals who recently established an office in Dublin in preparation for EU pricing negotiations. Teduglutide may initially be available on a named patient basis.


Pharmacology: Glucagon-like peptide-2 (GLP-2) analogue given by daily s.c injection.

Efficacy: In a published PIII study (n=86) teduglutide 0.05mg/kg was compared with placebo. Reduction in PN of ≥20% at weeks 20 to 24 was achieved by 63% vs. 30%, respectively (p=0.002, NNT=3). Patients completing this study were eligible to enter a 2-year follow-up study where all received teduglutide 0.05mg/kg. At a 6-month interim review, continued reductions in PN had been achieved and 3 patients no longer required PN. Another published PIII study (n=83) compared teduglutide to placebo. Teduglutide 0.10mg/kg did not meet the primary outcome of reduction of ≥20% in PN in weeks 16-24 (25% vs. 6%, p=ns). However, a post-hoc analysis of patients on teduglutide 0.05mg/kg did meet the primary outcome (46% vs. 6%, p<0.01, NNT=3). In a continuation study, of those who achieved ≥20% reduction of PN at week 20 and 24 in the initial study, 75% sustained this response after up to one year of continuous treatment.

Obeticholic acid oral

Intercept

Indication:

Cirrhosis, primary biliary - second line.

Pharmacology:

Modified bile acid; farnesoid X receptor agonist - first-in-class.

Current status:

PIII.


2015

Reviews: None.

Likely commissioning route: NHSE.

PbR: Likely HRG included.


http://pathways.nice.org.uk/pathways/crohns-disease



http://www.nice.org.uk/guidance/TA187

http://www.nice.org.uk/usingguidance/commissioningguides/biologicaltherapies/home.jsp

http://www.hsc.nihr.ac.uk/files/downloads/2035/2374.3bf2569b.VedolizumabforCrohns_Mar13.pdf


http://clinicaltrials.gov/ct2/show/NCT01224171


http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002345/WC500132926.pdf




http://www.specialisedservices.nhs.uk/service/severe-intestinal-failure/search:true







BNF 2. Cardiovascular system

Dabigatran oral

Pradaxa

Boehringer Ingelheim

Indication:

Venous thromboembolism (VTE) - treatment and secondary prevention (long-term).

Current status:

Filed in EU Jun 2013.


2014

National guidance:

NICE: VTE pathway, quality standard,

anticoagulation commissioning guide, guideline - thromboembolic diseases; VTE treatment and prevention: dabigatran due Oct 2014, rivaroxaban.

SIGN: VTE.


Target population: Annual incidence of pulmonary embolism (PE) and deep vein thrombosis (DVT) is about 40 and 100 per 100,000 people, respectively.

Sector: Initiated in secondary care.

Implications: Dabigatran will compete with rivaroxaban currently licensed for treatment and prevention of recurrent DVT and PE and with apixaban currently in PIII studies for this indication (see below). Differences in dosing frequency may be important for compliance.

Financial: Competition will continue to influence pricing strategies.


Pharmacology: Direct thrombin inhibitor.

Efficacy: Treatment. The published RE-COVER non-inferiority study (n=2,539) compared dabigatran (150mg twice daily) to warfarin (INR 2.0-3.0) for acute symptomatic VTE. The primary outcome was a composite of recurrent symptomatic VTE and deaths related to VTE, which was confirmed in 2.4% of patients on dabigatran and 2.1% of patients on warfarin (p<0.001 for non-inferiority). Major bleeding did not differ between the groups at 1.6% vs. 1.9%, respectively.

Secondary prevention. Two published PIII trials have compared dabigatran (150 mg twice daily) with warfarin (RE-MEDY, n=2,866) or placebo (RE-SONATE, n=1,353) in patients who had completed at least 3 months of treatment for VTE. In RE-MEDY, after a mean of 68 weeks treatment dabigatran was found to be non-inferior to warfarin for prevention of the primary outcome of recurrent symptomatic VTE or death associated with VTE (1.8% vs. 1.3%, p=0.01 for non-inferiority). Major bleeding was less common with dabigatran than warfarin (0.9% vs. 1.8%, p=0.06). In RE-SONATE, after a mean of 24 weeks treatment, recurrent VTE occurred in 0.4% vs. 5.6% of patients, respectively (p<0.001). Major or clinically relevant non-major bleeding was more common with dabigatran than placebo (5.3% vs. 1.8%, p=0.001, NNH=29).


Apixaban oral

Eliquis

Pfizer

Indication:

Venous thromboembolism (VTE) treatment - extended use.

Current status:

PIII.


2014

National guidance:

As for dabigatran above.

Reviews: None.

Target population: Annual incidence of pulmonary embolism (PE) and deep vein thrombosis (DVT) is about 40 and 100 per 100,000 people, respectively.


Implications: Rivaroxaban is now licensed for treatment and prevention of recurrent DVT and PE and dabigatran could have a similar licence soon (see above). Apixaban will be a competitor; differences in dosing frequency may be important for compliance.

Financial: Competition will influence pricing strategies.


Pharmacology: Factor Xa inhibitor.

Efficacy: The published PIII AMPLIFY trial (n=5,395) compared apixaban (10mg twice daily for 7 days, then 5mg twice daily for 6 months) with standard care (enoxaparin and warfarin). Apixaban was non-inferior to standard care for the primary outcome recurrent symptomatic VTE or death related to VTE (2.3% vs. 2.7%, p<0.001 for non-inferiority). In the published PIII AMPLIFY-EXT trial (n=2,486) apixaban was compared with placebo for 12 months. Recurrent VTE or death was more common with placebo (8.8%) than apixaban 2.5mg twice daily (1.7%) or apixaban 5.0mg twice daily (1.7%, p<0.001, NNT=14 for both comparisons).





http://pathways.nice.org.uk/pathways/venous-thromboembolism

http://guidance.nice.org.uk/QS29

http://www.nice.org.uk/usingguidance/commissioningguides/AnticoagulationTherapy.jsp


http://guidance.nice.org.uk/TA/WaveR/171

http://guidance.nice.org.uk/TA261

http://www.sign.ac.uk/guidelines/fulltext/122/index.html









Rivaroxaban oral

Xarelto

Bayer

Indication:

Acute coronary syndrome (ACS) - prevention of atherothrombotic events in patients with elevated cardiac biomarkers (combination with antiplatelet drugs).

Current status:

Licensed in the EU May 2013 – see prescribing information.


2014

National guidance:

NICE: ACS: Ticagrelor , unstable angina

and NSTEMI, secondary prevention post MI, prasugrel with percutaneous coronary intervention, rivaroxaban due Mar 2015.

SIGN: ACS

Reviews: NPC Mar 2012, NIHR HSC Apr 2011.

Target population: ACS refers to a group of conditions including ST segment elevation myocardial infarction (STEMI), non-STEMI and unstable angina. In England during 2011/12, there were 72,400 hospital admissions for angina and 50,708 for myocardial infarction.


Implications: Long term management of ACS includes the use of aspirin and another antiplatelet agent (clopidogrel, prasugrel or ticagrelor). Rivaroxaban 2.5mg twice daily is licensed for use in combination with aspirin alone or with aspirin plus clopidogrel or ticlopidine. Few patients over 75 years of age were included in the ATLAS study.

Financial: Cost will be in addition to existing therapy; price of 2.5mg tablets is currently uncertain.



Efficacy: The published PIII ATLAS ACS 2 TIMI 51 trial (n=15,526) compared rivaroxaban with placebo in patients

hospitalised with ACS, who were also receiving aspirin and a thienopyridine (clopidogrel or ticlodipine). The 2-year event rate for the primary outcome, a composite of death from cardiovascular (CV) causes, myocardial infarction or stroke, was reduced in patients on rivaroxaban 2.5mg or 5mg twice daily vs. placebo (8.9% vs.10.7%, HR 0.84, p=0.008). Rivaroxaban 2.5mg reduced CV death rate (p=0.002) and death from any cause (p=0.002); a survival benefit was not seen with 5mg.

Safety: See prescribing information. The rate of major bleeding unrelated to CABG was increased with rivaroxaban

compared to placebo in the above trial (2.1% vs. 0.6%, p<0.001), but the risk of fatal bleeding was similar.

Rivaroxaban oral

Xarelto

Bayer

Indication:

Prevention of stent thrombosis in acute

coronary syndrome (ACS).

Current status:

PIII in EU.

Not approved in US Jun 2013.


2014

National guidance:

NICE: ACS pathway, unstable angina &

NSTEMI, myocardial infarction with ST-segment elevation.

SIGN: ACS.

Reviews: None.

Target population: In 2011-12 there were 53,567 admissions in England for balloon angioplasty and insertion of stent into a coronary artery.


Implications: First of the new oral anticoagulants to seek a licence for this indication. Familiarity with the drug may increase willingness to use.

Financial: Rivaroxaban is added to standard therapy for ACS, so cost will also be additive.



Efficacy: A published, pre-specified sub-group analysis of a PIII trial (sub-group n=9,631) compared twice daily rivaroxaban (2.5mg or 5.0mg) with standard care (aspirin with or without a thienopyridine) in patients with ACS who had at least one stent inserted. There was no difference in the rate of definite stent thrombosis (1.0% vs.1.3%, p=ns). The pooled rate of definite or probable stent thrombosis was lower with rivaroxaban (1.5% vs. 1.9%, p=0.017).





http://publications.nice.org.uk/ticagrelor-for-the-treatment-of-acute-coronary-syndromes-ta236

http://publications.nice.org.uk/unstable-angina-and-nstemi-cg94

http://publications.nice.org.uk/unstable-angina-and-nstemi-cg94

http://publications.nice.org.uk/mi-secondary-prevention-cg48

http://publications.nice.org.uk/prasugrel-for-the-treatment-of-acute-coronary-syndromes-with-percutaneous-coronary-intervention-ta182

http://guidance.nice.org.uk/index.jsp?action=byId&o=13787

http://www.sign.ac.uk/pdf/sign93.pdf

http://www.npc.nhs.uk/rapidreview/?p=4954

http://www.nhsc-healthhorizons.org.uk/files/downloads/1561/2020.7dd8623a.RivaroxabanXarelto.pdf




http://pathways.nice.org.uk/pathways/acute-coronary-syndrome









Cangrelor injection

The Medicines Company

Indication:

Thrombosis prevention

(coronary) in percutaneous coronary intervention (PCI).

Current status:

PIII in EU.

Filed in US Jul 2013.


2014

National guidance:

None relevant.

Reviews: NIHR HSC Nov 2012.

Target population: 88,692 PCIs were carried out in the UK in 2011.


Implications: For patients undergoing PCI, current guidelines recommend antiplatelet therapy and antithrombin co-therapies. Cangrelor may be suitable for patients unable to take oral therapy or for those who require a rapidly reversible therapy.

Financial: Likely to displace current options but as an i.v. infusion is likely to be more expensive.


Pharmacology: Antiplatelet (P2Y12 antagonist) given by i.v. infusion. Half life 3-6 minutes; platelet function restored in less than 60 minutes.

Efficacy: A published pooled analysis of two PIII trials (n=13,049) compared cangrelor with clopidogrel in patients with non-ST-elevation acute coronary syndromes who underwent PCI. There was no difference in the primary outcome of death, MI or ischaemia-driven revascularisation (7.3% vs. 7.5%). A published PIII trial (n=11,145) compared cangrelor to clopidogrel alone. The primary outcome (a composite of death, myocardial infarction, ischaemia-driven revascularisation or stent thrombosis at 48 hours) occurred in 4.7% vs. 5.9%, of patients, respectively (p=0.005, NNT=84)

Safety: There was no difference between groups in the rates of severe bleeding.

Vorapaxar oral

MSD

Indication:

Secondary prevention of cardiovascular (CV) events in patients with a history of MI and no history of TIA or stroke.

Current status:

PIII with plans to file in EU in 2013.



2014

National guidance:

NICE: Myocardial infarction (MI) -

secondary prevention; Vascular disease – clopidogrel and dipyridamole

SIGN: Prevention of CV disease update

in progress.


Target population: Around 1.5 million people in the UK have had an MI (about 2,380 per 100,000).


Implications: Likely to be added to existing therapies but the associated bleeding risk could make it difficult to establish a place in therapy.

Financial: Likely to be considerably more expensive than current options.

Likely commissioning route: CCG. PbR: Likely HRG included.

Pharmacology: Thrombin receptor antagonist (PAR-1 inhibitor).

Efficacy: In a published PIII study 26,449 patients with prior MI, stroke or peripheral artery disease were randomised to vorapaxar or placebo in addition to standard treatment, including antiplatelet drugs. At 3 years, the primary outcome (death from CV causes, MI or stroke) occurred in 9.3% of the vorapaxar vs.10.5% of the placebo group (HR 0.87, p<0.01). In a published pre-specified analysis of the subgroup with prior MI (n=17,779) the primary outcome occurred in 8.1% vs. 9.7%, respectively (3 year estimates; HR 0.80, p<0.01).

Safety: Moderate/severe bleeding occurred in 4.2% vs. 2.5% of patients, respectively (p<0.001) and an increased risk of

intracerebral haemorrhage in 1.0% vs. 0.5%, respectively (p<0.01). In the MI subgroup, 3 year estimates for moderate/severe bleeding were 3.4% vs. 2.1%, respectively (HR 1.61, p<0.01).

Des-moteplase injection

Lundbeck

Indication:

Stroke, acute ischaemic,

within 9 hours of symptom onset.

Pharmacology:

Plasminogen activator.

Current status:

PIII.


2015


Likely commissioning route: CCG.

PbR: Likely specialist top-up as for alteplase.


http://www.hsc.nihr.ac.uk/topics/cangrelor-to-reduce-platelet-aggregation-and-throm/




http://www.nice.org.uk/cg048

http://www.nice.org.uk/guidance/TA210






http://www.nhsc-healthhorizons.org.uk/files/downloads/1620/2067.5fe81a4e.Desmoteplase.pdf


Lomitapide oral

Lojuxta

Aegerion Pharma-ceuticals

Indication:

Hypercholesterolaemia,

homozygous familial (HoFH).

Current status:

Licensed in EU Aug 2013.


2013

National guidance:

NICE: Familial hypercholesterolaemia:

guideline; Cardiovascular disease prevention: commissioning guide.

SIGN: Prevention of cardiovascular

disease - update in progress.


Target population: HoFH is rare, with an

incidence of about one case per million people.


Implications: Lomitapide may be an option for patients with HoFH with an

inadequate response to current therapy. Genetic confirmation of HoFH should be obtained prior to starting therapy. Treatment may reduce the requirement for LDL apheresis in some patients.

Financial: Likely to be very expensive, but may reduce need for LDL apheresis. US price is around $25,000/month.


Pharmacology: Microsomal triglyceride transfer protein inhibitor (first-in-class) given orally once daily.

Efficacy: In a published PIII open-label study (n=29) lomitapide combined with a low-fat diet was added to standard therapy, with or without apheresis. The mean reduction in LDL cholesterol (LDL-C) from baseline was 50% at 26 weeks (primary outcome), 44% at 56-weeks and 38% at 78-weeks (p<0.01 for all comparisons vs. baseline). Some patients were able to reduce or discontinue LDL apheresis.

Safety: Hepatotoxicity has been reported and regular liver function testing is advised. Gastrointestinal adverse effects are common.

Evolcumab injection

Amgen

Indication:

Hyperlipidaemia.

Pharmacology:

Monoclonal antibody -PCSK9 inhibitor.

Current status:

PIII.

Predicted launch:

2015



PbR: Likely specified high cost drug.

Alirocumab injection

Sanofi

Indication:

Hypercholesterolaemia –

third line.

Pharmacology:

Monoclonal antibody - PCSK9 inhibitor.

Current status:

PIII.


2016

Reviews: NIHR HSC Dec 2012.



Riociguat oral

Adempas

Bayer

Indication:

Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH)

Current status:

Filed in EU Feb 2013.

Recommended for approval in the US Aug 2013.


2014

National guidance:

None relevant.


Target population: 7,000 patients attended

specialist PH centres in the UK in 2012, of whom 88% had a final diagnosis. Among those with a diagnosis 47% had PAH and 19% CTEPH, equating to 2,895 and 1,170 patients, respectively.

Sector: National Pulmonary Hypertension Service (see commissioning policy statement).

Implications: Riociguat will be an additional option for PAH and CTEPH.

Current options include prostacyclins, endothelin antagonists and phosphodiesterase inhibitors. Riociguat will be the first treatment specifically licensed for CTEPH.

Financial: Likely to be expensive and as a further treatment option will be

additive to current costs.


Pharmacology: Guanylate cyclase stimulant (first-in-class).

Efficacy: PAH. The published 12-week, PIII PATENT-1 study compared individually titrated riociguat with placebo in 443 patients with symptomatic PAH. Riociguat improved the primary outcome of 6-minute walking distance (6-MWD) by 36 meters (p<0.01) vs. placebo. In patients that reached one year of treatment in the long-term extension trial PATENT-2 the improvement in 6-MWD was 48 meters.

CTEPH. The 16-week, published PIII CHEST-1 study compared individually titrated riociguat with placebo in 261 patients with CTEPH or persistent/recurrent PH after surgery. Riociguat improved the primary outcome of 6-minute walking distance by 46 meters (p<0.01) vs. placebo. After one year of treatment in the CHEST-2 extension trial the improvement in 6-MWD was 48 meters.

Safety: To date no serious adverse effects have been reported.



http://www.nice.org.uk/usingguidance/commissioningguides/integratedcommissioningforpreventionofcvd/CardiovascularDisease.jsp





http://www.hsc.nihr.ac.uk/files/downloads/2030/2369.4ce30d11.AMG145_Mar13.pdf


http://www.hsc.nihr.ac.uk/files/downloads/1973/2328.4eee025f.SAR236553_Nov12.pdf



http://www.england.nhs.uk/wp-content/uploads/2013/04/a11-ps-a.pdf

http://www.england.nhs.uk/wp-content/uploads/2013/04/a11-ps-a.pdf






Serelaxin injection

Novartis

Indication:

Acute heart failure (AHF) –

decompensated.

Pharmacology:

Recombinant human relaxin-2, a peptide hormone.

Current status:

Filed in EU Dec 2012.

Predicted launch:

Uncertain.

Reviews: NIHR HSC Jul 2012.



Defibrotide injection

Defitelio

Gentium

Indication:

Hepatic veno-occlusive disease (VOD) - treatment

in haematopoietic stem-cell transplant (HSCT).

Current status:

Recommended for approval in EU Jul 2013 with orphan status.


2013

National guidance:

None relevant.

Reviews: NIHR HSC Aug 2011, LNDG

due TBC.

Target population: VOD is a leading cause

of morbidity and mortality after HSCT. Without treatment 85% of those with severe VOD die within 100 days of HSCT.

Sector: Secondary or tertiary care.

Implications: Supportive care is the current treatment option. Defibrotide will

be the first specific therapy for VOD.

Financial: Likely to be expensive. Based on a dose of 25mg/kg/day, current named patient cost is around £40,000 for 21 days treatment.


Pharmacology: Cytokine modulator given every 6 hours for at least 21 days.

Efficacy: In a PIII trial (n=134) in patients with severe VOD and multi-organ failure, 24% in the defibrotide group achieved a

complete response at 100 days (primary outcome) vs. 9% in the historical control group (p<0.02, NNT=7). Mortality rate at day 100 (secondary outcome) was 62% vs. 75%, respectively, (p>0.05). An EMA analysis of US patient registry data showed that patients with severe VOD who received defibrotide plus standard care had better outcomes, including a higher survival rate after 100 days following transplantation, than those given standard care alone.

Safety: No safety concerns have been reported to date, with the frequency of adverse events comparable to control.

Clevidipine oral

Cleviprex

The Medicines Company

Indication:

Hypertension, perioperative.

Current status:

Licensed in UK Nov 2011 – see prescribing information.


2014

National guidance:

None relevant.


Target population: Perioperative

hypertension may affect 25% of hypertensive patients undergoing surgery.


Implications: Clevidipine is one of only two drugs (the other being esmolol)

specifically licensed for the management of perioperative hypertension.

Financial: Likely to be more expensive than available generic options.


Pharmacology: Ultra short-acting dihydropyridine calcium channel antagonist given by i.v. infusion.

Efficacy: Pooled results from three open-label PIII studies (ECLIPSE 1, 2 & 3) are published. Among patients undergoing cardiac surgery randomised to clevidipine, glyceryl trinitrate, sodium nitroprusside or nicardipine (n=1,512), there was no difference in primary outcome events (death, MI, stroke or renal dysfunction at 30 days) between the clevidipine group and the pooled comparator group.



http://www.nhsc-healthhorizons.org.uk/files/downloads/1882/2251.9795c893.SerelaxinRLX030_July2012.pdf


http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion_-_Initial_authorisation/human/002393/WC500146653.pdf


http://www.nhsc-healthhorizons.org.uk/topics/defibrotide-defitelio-for-hepatic-veno-occlusive-d/




http://www.medicines.org.uk/emc/medicine/28128/SPC/Cleviprex/

http://www.medicines.org.uk/emc/medicine/28128/SPC/Cleviprex/


http://www.medicines.org.uk/


BNF 3. Respiratory system

Indacaterol/ glycopyrron-ium inhaler

Ultibro Breezhaler

Novartis

Indication:

Chronic obstructive pulmonary disease (COPD).

Current status:

Recommended for approval in EU Jul 2013.


2013

National guidance:

NICE: COPD – clinical guideline,

commissioning guide, quality standard.

Reviews: NIHR HSC Aug 2011.

Target population: An estimated 3 million people in the UK are affected by COPD. The rate of COPD in the population is estimated at between 2% and 4%; the diagnosed prevalence is 1.5%.

Sector: Secondary and primary care.

Implications: The first combination inhaler to contain a long-acting muscarinic antagonist (LAMA) for use when maintenance long-acting beta agonist (LABA) is insufficient and an inhaled corticosteroid is not suitable.

Financial: Likely to be similar to other combination products.


Pharmacology: Once daily LABA and LAMA combination as a capsule for inhalation.

Efficacy: In the published PIII SHINE trial 2,144 patients were randomised to indacaterol/glycopyrronium, indacaterol, glycopyrronium, tiotropium or placebo. For the primary outcome of trough FEV1 at week 26, the difference between the combination and indacaterol alone was 0.07L, (p<0.01) and 0.09L vs. glycopyrronium (p<0.01). In the published PIII ILLUMINATE trial (n=523) indacaterol/ glycopyrronium was compared to salmeterol/fluticasone combination. At week 26, FEV1 (area under curve) at 12 hours was higher with indacaterol/glycopyrronium (difference 0.138L, p<0.0001).

Safety: In a 52-week safety study, ENLIGHTEN (n=339) the most frequent adverse event was COPD exacerbation (28.0%

vs. 25.7% in placebo group).

Umeclidinium inhaler

Espanda

GlaxoSmith-Kline

Indication:


Current status:

Filed in EU Apr 2013.


2014

National guidance:

NICE: As for indacaterol/

glycopyronnium above.

Reviews: None.

Target population: As for Indacaterol/

glycopyronnium above.


Implications: Umeclidinium will complete with aclidinium, glycopyrronium

and tiotropium. The place of long-acting muscarinic antagonists (LAMAs) is described in the NICE COPD guideline.

Financial: Likely to be similar to other long-acting bronchodilators.


Pharmacology: A once-daily LAMA formulated as a dry powder inhaler administered once daily.

Efficacy: Two on-going PIII trials of 600 patients each (one and two) involve the addition of once daily umeclidinium (62.5mcg or 125mcg) or placebo to twice daily fluticasone/salmeterol (250/50mcg) over 12 weeks. The primary outcome is change from baseline in trough FEV1 at day 85. A 12-week PIII trial with the same outcome has compared umeclidinium 62.5mcg or 125mcg to placebo in 206 patients. Significant improvements were shown in mean change from baseline in trough FEV1 for 62.5mcg (127ml) and 125mcg (152ml) vs. placebo.

Safety: A PIII 52-week study is evaluating safety and tolerability.

Umeclidinium/vilanterol inhaler

GlaxoSmith-Kline

Indication:


Current status:

Filed in EU Jan 2013.


2014

National guidance:

As for indacaterol/ glycopyronnium above.

Reviews: NIHR HSC Feb 2012.

Target population: As for indacaterol/ glycopyronnium above.


Implications: A long-acting muscarinic antagonist (LAMA) and long-acting beta agonist (LABA) combination is not yet available in a single inhaler.

Financial: Likely to be similar to other combination products.


Pharmacology: A once-daily dry powder inhaler containing a LAMA and a LABA.

Efficacy: In four 24-week studies the primary outcome was trough FEV1 at day 169. In a PIII study (n=871) the difference between tiotropium and umeclidinium/vilanterol (UMEC/VI) 125/25mcg was 74ml (p<0.01) and 60ml vs. UMEC/VI 62.5/25mcg (p=0.02). In another PIII study (n=846), both doses of UMEC/VI were more effective than tiotropium by 88 to 90ml (p<0.01). In a third PIII study (n=1,537) UMEC/VI 62.5/25mcg was more effective than placebo by 167ml (p<0.01) and in a fourth PIII study (n=1,493) UMEC/VI 125/25mcg was better than placebo by 238ml (p<0.01).

Safety: In the above studies, cardiovascular adverse events were seen in 6 to 11% of patients on UMEC/VI.




http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002679/smops/Positive/human_smop_000558.jsp&mid=WC0b01ac058001d127&source=homeMedSearch&category=human


http://publications.nice.org.uk/chronic-obstructive-pulmonary-disease-cg101

http://www.nice.org.uk/usingguidance/commissioningguides/copd/copd.jsp

http://publications.nice.org.uk/chronic-obstructive-pulmonary-disease-quality-standard-qs10

http://www.hsc.nihr.ac.uk/topics/indacaterol-glycopyrronium-qva-149-for-chronic-obs/


http://www.thelancet.com/journals/lanres/article/PIIS2213-2600(12)70052-8/abstract




http://clinicaltrials.gov/ct2/show/NCT01772134?term=01772134&rank=1






http://www.hsc.nihr.ac.uk/topics/umeclidinium-and-vilanterol-for-chronic-obstructiv/

http://clinicaltrials.gov/show/NCT01316913


http://clinicaltrials.gov/ct2/results?term=NCT01313650&Search=Search

http://clinicaltrials.gov/ct2/results?term=NCT01313637&Search=Search


Budesonide/ formoterol inhaler

Bufomix Easyhaler

Orion Pharma

Indication:

Asthma.

Current status:

Filed in the EU Apr 2013.


2014

National guidance:

NICE: Quality standard.

SIGN: British guideline on the

management of asthma.

Reviews: None.

Target population: At least 1 in 10 children and 1 in 12 adults have asthma in the UK.


Implications: Bufomix will compete with Seretide and Symbicort.

Financial: Likely to be similar to other dry powder inhalers (DPIs).


Pharmacology: Dry powder inhaler (DPI) containing a corticosteroid and long-acting beta agonist (LABA).

Efficacy: A PI/II study (n=87), has evaluated the bioequivalence of the Easyhaler to Symbicort Turbohaler.

Safety: For adverse effects of budesonide/formoterol DPI, see medicines.org.uk.

Masitinib oral

AB Science

Indication:

Asthma, severe persistent.

Pharmacology:

Tyrosine kinase inhibitor.

Current status:

PIII.


2015




Nalfurafine injection

Winfuran

Fresenius Medical Care

Indication:

Pruritus, uraemic dialysis-related.

Current status:

Filed in EU Aug 2012 with orphan status.


2013

National guidance:

None relevant.

Reviews: None.

Target population: In the EU uraemic

pruritus affects about 3.5 per million people. Data from 2003-2004 indicates about 50% of patients on haemodialysis in the UK have moderate to extreme pruritus.

Sector: Renal services are a specialised service.

Implications: No other treatments are specifically licensed for uraemic

pruritus. Options include gabapentin and UVB phototherapy.

Financial: Likely to be more expensive than off-label use of oral agents.


Pharmacology: Kappa opioid agonist.

Efficacy: A published meta-analysis reviewed data from 144 patients on haemodialysis with severe, uncontrolled pruritus. Patients received nalfurafine or placebo by i.v. infusion 3 times a week after haemodialysis. A 100-mm visual analogue scale was used to measure the “worst itching” during the previous 12 hours. At week 2, a mean difference of 9.53mm was found between nalfurafine and placebo (p<0.03). 36% on nalfurafine achieved ≥50% decrease from baseline in worst itching vs. 14% on placebo (p<0.03). Safety: The meta-analysis found adverse events to be similar to placebo.

Omalizumab injection

Xolair

Novartis

Indication:

Urticaria, chronic idiopathic

or spontaneous (CIU/CSU) - second line.

Current status:

PIII.


2014

National guidance:

None relevant.


Target population: In the UK, the point

prevalence of chronic urticaria is 0.1-0.51%, of which up to 50% of cases are idiopathic (50-250 per 100,000 people). First-line therapy is effective in <50% of patients.


Implications: Omalizumab will be a second-line option for CIU/CSU

refractory to H1-antihistamines. It will provide an alternative option to off-label leukotriene receptor- and H2-receptor antagonists.

Financial: Current cost of omalizumab is £256 for 150mg; there will be additional administration costs.


Pharmacology: Monoclonal antibody – IgE receptor antagonist given by s.c injection every four weeks.

Efficacy: A published PIII trial (n=323) compared omalizumab 75mg, 150mg, or 300mg (every 4 weeks for 12 weeks) with

placebo in symptomatic patients with CIU despite H1-antihistamine therapy. The primary outcome was change from baseline to week 12 in a weekly itch-severity score (ranging from 0 to 21). At week 12, the mean reduction from baseline was 5.9 in the 75mg group (p=0.46), 8.1 for 150mg (p=0.01) and 9.8 for 300mg (p<0.01) vs. 5.1 for placebo. In a published PIII trial in 336 patients with CIU/CSU the mean reduction in itch-severity score from baseline at week 12 was 8.6 in the 300mg group vs. 4.0 for placebo (p<0.01).







http://clinicaltrials.gov/ct2/show/NCT00964535?term=NCT00964535&rank=1



http://www.hsc.nihr.ac.uk/topics/masitinib-for-severe-asthma/


http://www.ema.europa.eu/docs/en_GB/document_library/Orphan_designation/2009/10/WC500005585.pdf

http://www.specialisedservices.nhs.uk/document/specialised-renal-services-adult

http://www.specialisedservices.nhs.uk/document/specialised-renal-services-adult



http://www.hsc.nihr.ac.uk/files/downloads/1938/2298.c478920f.Omalizumab_Sept12.pdf





Ataluren oral

Genzyme

Indication:

Cystic fibrosis (CF),

patients with nonsense mutation (nmCF).

Pharmacology:

CF transmembrane conductance regulator stimulant.

Current status:

PIII in EU with orphan status.


2015

Reviews: None.



Lumacaftor oral

Vertex

Indication:

Cystic fibrosis, in

combination with ivacaftor in homozygous F508del patients.

Pharmacology:

CF transmembrane conductance regulator stimulant.

Current status:

PIII in EU, fixed dose combination product also in PIII trials.

Breakthrough therapy and orphan drug status in US.


2015

Reviews: None.



BNF 4. Central nervous system

Loxapine inhalation

Adasuve

Grupo Ferrer

Indication:

Acute agitation associated with schizophrenia or bipolar disorder.

Current status:

Licensed in EU Feb 2013 – see prescribing information.


2014

National guidance:

NICE: Clinical guidelines: schizophrenia,

bipolar disorder. Commissioning guide: schizophrenia.

SIGN: Schizophrenia, bipolar disorder.

Reviews: RDTC Jun 2013, LNDG Feb 2013.

Target population: In England there are

about 755 people with schizophrenia and 865 with bipolar disorder per 100,000 people. More than 90% of people with either condition will experience agitation in their lifetime, with an average of 11 to 12 episodes of acute agitation each year.


Implications: Inhaled administration is less invasive than i.m. injection and

may be preferred by some patients.

Financial: Likely to be more expensive than oral and i.m. alternatives.


Pharmacology: Dopamine D2 and serotonin 5-HT2A antagonist given by single-dose inhaler.

Efficacy: Schizophrenia. A published PIII trial (n=344) compared up to 3 doses of loxapine 4.5 or 9.1mg with placebo in agitated in-patients with schizophrenia. At 2-hours post first dose the change from baseline in Positive and Negative Syndrome Scale–Excited Component (PANSS-EC) was -8.1, -8.6 and -5.5, respectively (both p<0.01 vs. placebo).

Bipolar. In a published PIII trial in in-patients with bipolar I associated agitation (n=314), change from baseline in PANSS-EC score 2 hours after the first dose was -8.1 with 4.5mg, -9.0 with 9.1mg and -4.9 with placebo (both p<0.01 vs. placebo).

Safety: See prescribing information. Severe respiratory effects (bronchospasm) are possible.

Lurasidone oral

Latuda

Takeda

Indication:

Schizophrenia.

Current status:

Filed in the EU Oct 2012.

Launched in US see prescribing information.


2013

National guidance:

NICE: Schizophrenia - Clinical guideline,

commissioning guide.

SIGN: Schizophrenia.

Reviews: NICE Evidence summary Apr

2013.

Target population: In England there are about 800 per 100,000 people with schizophrenia.


Implications: Lurasidone will be an additional treatment option alongside existing antipsychotics. A lower incidence of weight gain may be attractive.

Financial: Likely to be more costly than existing atypical antipsychotics.


Pharmacology: Dopamine and serotonin receptor antagonist.

Efficacy: In a published PIII trial, 478 hospitalised patients received lurasidone (40mg or 120mg), olanzapine or placebo. Improvement in the primary outcome of change from baseline to week 6 in the Positive and Negative Syndrome Scale (PANSS) total score was greater with lurasidone 40mg (-25.7, p=0.002), lurasidone 120mg (-23.6, p=0.022) and olanzapine (-28.7, p<0.001) vs. placebo (-16.0). Lurasidone and olanzapine were not directly compared.

Safety: In a published safety trial (n=621) the frequency of adverse events with lurasidone was similar to risperidone, but fewer patients experienced increased weight (9.3% vs. 19.8%).









http://www.nice.org.uk/usingguidance/commissioningguides/schizophrenia/schizophrenia.jsp



http://rdtc.nhs.uk/sites/default/files/publications/nde_127_loxapine_inhalation_powder.pdf

http://www.medicinesresources.nhs.uk/upload/Loxapine_Feb20132.pdf





http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/200603s015lbl.pdf



http://www.nice.org.uk/usingguidance/commissioningguides/schizophrenia/schizophrenia.jsp


http://publications.nice.org.uk/esnm15-schizophrenia-lurasidone-esnm15/overview




Liraglutide injection

Victoza

Novo Nordisk

Indication:

Obesity.

Current status:

PIII.


2014

National guidance:

NICE: Obesity guidelines.

SIGN: Obesity.


Target population: In 2011, 24% of men and 26% of women (>16 years) were classed obese (BMI ≥30kg/m

2); 41% of men and 33%

of women were overweight (BMI 25 to <30kg/m

2).

Sector: Initiated in secondary care with continued use in primary care.

Implications: It is likely liraglutide injection will be preferentially used in overweight patients with diabetes. It will have the advantage over exenatide which, although causes weight loss, is not specifically licensed for obesity. The liraglutide dose for obesity is much higher than for diabetes.

Financial: Based on a 3mg daily dose current cost of liraglutide is about £183/month vs. £32/month for orlistat 120mg 3 times a day.


Pharmacology: Glucagon-like peptide analogue given by daily s.c. injection.

Efficacy: A published PIII study (n=422) compared liraglutide 3mg with placebo over 56 weeks following a 12-week low-calorie dietary run-in. Mean reduction in body weight was -6.2% for liraglutide vs. -0.2% for placebo (p<0.01). A ≥5% reduction in body weight was achieved by 50.5% vs. 21.8% of patients, respectively (p<0.01). A 20-week published PII study (n=564) compared liraglutide 1.2, 1.8, 2.4 or 3mg with placebo and orlistat 360mg/day. Mean weight loss with liraglutide ranged from 4.8 - 7.2kg vs. 2.8kg with placebo and 4.1kg with orlistat (p=0.003 for liraglutide 2.4 mg vs. orlistat and p<0.0001 for liraglutide 3.0 mg vs. orlistat). In a published extension of this study, patients receiving liraglutide (2.4mg or 3mg pooled) for two years lost 3.0kg more than those on orlistat (p<0.01).


Dextro-methorphan/ quinidine oral

Nuedexta

Jenson

Indication:

Pseudobulbar affect (PBA).

Current status:

Licensed in EU Jun 2013 – see prescribing information.


2014

National guidance:

NICE: Pathways: stroke, dementia;

Clinical guidelines: multiple sclerosis, stroke rehabilitation, dementia, Parkinson’s disease; Quality standard: dementia

Reviews: None.

Target population: PBA can develop in several neurological diseases or following brain injury. The estimated prevalence of PBA is up to 500 per 100,000 people, of whom about 14 per 100,000 will have amyotrophic lateral sclerosis (ALS) or multiple sclerosis (MS).

Sector: Adult specialist neurosciences are a

specialised service.

Implications: First drug licensed for this indication. Confirmation of diagnosis is required before treatment as use in other emotional lability conditions would be off-label. This may increase referrals to specialist neurosciences. Although the indication is for treatment of PBA due to any cause efficacy has only been studied in those with ALS or MS.

Financial: Likely to be considerably more expensive than unlicensed alternatives (SSRIs, TCAs, levodopa, amantadine and thyrotropin-releasing hormone).


Pharmacology: Dextromethorphan is a sigma-1 receptor agonist and NMDA antagonist. Quinidine is a CYP2D6 inhibitor,

which increases plasma levels of dextromethorphan.

Efficacy: A published 12-week PIII trial (n=326) compared dextromethorphan plus quinidine (30/10mg (DMq-30) or 20/10mg (DMq-20) twice daily) with placebo in ALS and MS patients with clinically significant PBA. The primary outcome of PBA-episode daily rate was 46.9% lower for DMq-30 and 49.0% lower for DMq-20 vs. placebo (p<0.01 for both).

Safety: No safety concerns are reported to date, but patients with cardiovascular disorders were excluded from studies.


http://publications.nice.org.uk/obesity-cg43








http://pathways.nice.org.uk/pathways/stroke

http://pathways.nice.org.uk/pathways/dementia






http://www.specialisedservices.nhs.uk/document/specialised-neurosciences-services-adult



BNF 5. Infections

Tobramycin solution for inhalation

Vantobra

Pari Pharma

Indication:

Cystic fibrosis (CF)

associated respiratory tract infections.

Current status:

Filed in EU Nov 2012 with orphan status.


2013

National guidance:

NICE: CF (pseudomonas lung infection).

Reviews: None.

Target population: CF affects over 8,500 people in the UK. In 2008, 39.4% were found to be chronically infected with P. aeruginosa;

19.6% of these used nebulised tobramycin.

Sector: Secondary care, adult and paediatric specialist service.

Implications: The eFlow nebuliser system allows delivery of high concentration/low volume with shorter nebulisation time.

Financial: The current cost of 28-days therapy with Bramitob or TOBI nebuliser solutions is £1,187. Vantobra is likely to be competitive.


Pharmacology: Aminoglycoside antibiotic administered via the eFlow nebuliser delivery system.

Efficacy: A 28-day, PII study (n=78), compared Vantobra 100 (150mg/1.5mL) administered twice daily via an investigational eFlow nebuliser system with TOBI (tobramycin 300mg/5mL) delivered via the PARI LC PLUS nebuliser. The primary outcome was tobramycin serum level as a surrogate safety measure. However, inhalation time was also assessed with the average inhalation time being 4-4.5 minutes for Vantobra vs. 16-17 minutes for TOBI.

Safety: Maximum tobramycin serum levels were lower than recommended safety thresholds.

Bedaquiline oral

Situro

Janssen-Cilag

Indication:

Tuberculosis (TB), multi-

drug resistant (MDR).

Current status:

Filed in EU Aug 2012.



2013

National guidance:

NICE: Tuberculosis pathway.

WHO interim guidance on the use of bedaquiline Jun 2013.

Reviews: None.

Target population: Around 9,000 cases of TB are reported each year in the UK. Most occur in major cities, particularly London. In 2011, there were 431 reports of MDR-TB, a 26% increase from 2010.


Implications: Bedaquiline will be used in addition to second-line options. In the US it is only indicated when other options are not available. WHO recommend it should only be used when an effective regimen with four second-line drugs plus pyrazinamide is not possible or when there is evidence of resistance to any fluoroquinolone in addition to MDR-TB.

Financial: As add on therapy cost will be additional and is likely to be expensive. WHO conclude it would be cost effective in most settings.


Pharmacology: Oral diarylquinoline ATPase inhibitor, first-in-class. Administered by directly observed therapy for 24 weeks.

Efficacy: In a published PII study (n=47), bedaquiline (400mg daily for 2 weeks then 200mg 3 times a week for 6 weeks)

added to background second-line therapy reduced the time to conversion to a negative sputum culture (primary outcome) vs. placebo (p=0.003), and increased the number of patients with conversion (secondary outcome) at week 8 (48% vs. 9%, respectively, NNT=3). In a subsequent PII study (n=160) bedaquiline (24 weeks treatment) decreased time to culture conversion vs. placebo (83 vs. 125 days, respectively, HR 2.44, p<0.0001) and improved culture conversion rates at week 24 vs. placebo (79% vs. 58%, respectively, p=0.008, NNT=5). Using WHO-recommended treatment outcome definitions applied to final 120-week data, 58% vs. 32%, respectively, were defined as cured (p=0.003, NNT=4).

Safety: In the US there are warnings that an increased risk of death (NNH=11) was seen in one study. WHO recommend testing and monitoring for QT prolongation as well as strict conditions for use pending further data to assess risk vs. benefit.




http://www.janssenmd.com/pdf/sirturo/PI-Sirturo.pdf

http://www.janssenmd.com/pdf/sirturo/PI-Sirturo.pdf

http://pathways.nice.org.uk/pathways/tuberculosis/tuberculosis-overview

http://apps.who.int/iris/bitstream/10665/84879/1/9789241505482_eng.pdf

http://www.ncbi.nlm.nih.gov/pubmed/19494215?dopt=Abstract

http://clinicaltrials.gov/ct2/show/study/NCT00910871


Cobicistat oral

Tybost

Gilead

Indication:

HIV infection, enhancer of

the protease inhibitors atazanavir and darunavir.

Current status:



2013

National guidance:

British HIV Association (BHIVA) 2012.

Reviews: None.

Target population: In 2012, about 6,000 patients were diagnosed with HIV and about 96,000 were living with HIV with around 25% being undiagnosed.


Implications: Cobicistat will be the second enhancer available in the UK, ritonavir being the first. However, unlike ritonavir, cobicistat has no inherent antiretroviral activity.

Financial: Ritonavir cost ranges from about £20 to £78/month. Cost of

cobicistat is likely to be competitive.


Pharmacology: Specific inhibitor of CYP3A without antiretroviral activity.

Efficacy: In a published PII study, 79 patients received cobicistat or ritonavir as enhancers for atazanavir in combination with emtricitabine plus tenofovir. The primary outcome of HIV-1 RNA <50 copies/mL at week 24 was achieved by 84% on atazanavir/cobicistat vs. 86% on atazanavir/ritonavir, and was sustained to week 48 (82% vs. 86%, respectively). Pharmacokinetic analyses showed comparable cobicistat- and ritonavir-boosted atazanavir exposures. An ongoing non-inferiority PIII study (n=692) is assessing cobicistat vs. ritonavir in combination with atazanavir plus tenofovir plus emtricitabine. The primary outcome was achieved in 85% on atazanavir/cobicistat vs. 87% on atazanavir/ritonavir.

Safety: In patents on cobicistat, changes in e-GFR occurred, remained stable through to week 48 and were similar to that seen in patients receiving ritonavir.

Dolutegravir oral

ViiV healthcare UK

Indication:

HIV infection, in combination with other antiretroviral agents.

Current status:

Filed in the EU Dec 2012 and in US with priority review status.


2013

National guidance:

As for cobicistat above.

Reviews: None.

Target population: As for cobicistat above.


Implications: BHIVA guidelines suggest therapy-naïve patients start with two nucleoside reverse transcriptase inhibitors (NRTIs) plus one of the following: a ritonavir-boosted protease inhibitor (PI/r), an NNRTI (non-NRTI) or an integrase inhibitor. BHIVA do not recommend switching to an integrase inhibitor in patients with previous NRTI resistance mutations, historical/ existing mutations associated with NRTI resistance or past virological failure on NRTIs. Once daily dosing with dolutegravir may be an advantage over raltegravir twice daily.

Financial: Cost of raltegravir is £616/month. Elvitegravir is only available in a combination tablet (Stribald). Dolutegravir is likely to be competitive.


Pharmacology: Integrase inhibitor taken once daily.

Efficacy: The primary outcome in various PIII non-inferiority studies assessing dolutegravir plus optimised background

regimen (OBR) was the proportion of patients achieving HIV-1 RNA <50 copies/mL (virological suppression). In the published SPRING-2 study, 822 treatment-naïve patients received daily dolutegravir or twice daily raltegravir, plus OBR. At 48 weeks, 88% vs. 85%, respectively, achieved virological suppression, demonstrating non-inferiority. In the SINGLE study, 833 treatment-naïve patients received dolutegravir plus Kivexa, or Atripla. At 48 weeks, virological suppression was

achieved by 88% vs. 81%, respectively (p=0.003). In the SAILING study in 715 treatment-experienced, integrase-inhibitor naive patients interim 24-week data show virological suppression was achieved in 79% on dolutegravir vs. 70% on raltegravir (p=0.003). Virologic non-response was seen in 15% and 24%, respectively. In the open-label VIKING-3 study in183 treatment-experienced patients with resistance to raltegravir and/or elvitegravir, dolutegravir plus OBR led to a fall in mean HIV-RNA levels by 1.4 log10 copies/mL after 7 days and 63% of patients had virological suppression at 24 weeks.

Safety: Dolutegravir has a similar safety profile to raltegravir.




http://www.bhiva.org/TreatmentofHIV1_2012.aspx


http://www.clinicaltrials.gov/ct2/show/NCT01108510?term=NCT01108510&rank=1


http://www.medicines.org.uk/emc/medicine/27810/SPC/Stribild+150+mg+150+mg+200+mg+245+mg+film-coated+tablets






Sofosbuvir oral

Gilead

Indication:

Hepatitis C viral infection (HCV), genotype 1 to 6 infection.

Current status:

Filed in EU Apr 2013 and in US with accelerated approval and priority review status.


2014

National guidance:

NICE: HCV- PEG/RBV, HCV genotype 1

- telapravir, boceprevir.

SIGN: Hepatitis C.


Target population: There are an estimated

173,000 chronically infected HCV patients in England and Wales; only 91,000 of these are diagnosed. Chronic HCV was the primary cause of 2,967 hospital admissions in England in 2010/11, with 2,688 bed days.


Implications: HCV is a major cause of liver transplantation. Patients with

genotype 1 are treated with triple therapy. Sofosbuvir is another option with efficacy shown in HCV genotypes 1-6. It could reduce treatment duration with the advantage of reduced dosing frequency vs. available options.

Financial: Monthly cost of boceprevir is £2,800 and telaprevir is £7,466. Sofosbuvir is likely to be competitive.


Pharmacology: Once daily nucleotide NS5B inhibitor.

Efficacy: The primary outcome of all PIII studies is the proportion of patients achieving a sustained virologic response at 12 weeks (SVR12) after the end of therapy. In the published open-label NEUTRINO study, 90% of 327 treatment-naïve patients with HCV genotypes 1, 4, 5 or 6 treated with sofosbuvir plus peginterferon alfa 2a plus ribavirin (PEG/RBV) achieved a SVR12. In the published FISSION non-inferiority study, 499 patients with genotype 2 or 3 were treated with either sofosbuvir/RBV given for 12 weeks or PEG/RBV given for 24 weeks. SVR12 was 67% in both groups. In the sofosbuvir/RBV group, response rates in patients with genotype 3 were lower than in those with genotype 2 (56% vs. 97%, respectively). In the published PIII POSITRON study in 278 patients with genotypes 2 or 3 for whom treatment with peginterferon was not an option, the SVR12 was 78% in the sofosbuvir/RBV group vs. 0% for placebo (p<0.001). In the published PIII FUSION study in 201 patients who had not had a response to prior interferon treatment, patients received sofosbuvir/RBV for 12 or 16 weeks. The SVR12 was 50% and 73% (p<0.001), respectively. In both studies, response rates were lower in patients with genotype 3 than genotype 2. Sofosbuvir is also in PIII trials in patients co-infected with HIV.

Safety: Adverse events were less frequent with sofosbuvir than with peginterferon. Common adverse effects include headache, fatigue, nausea, and insomnia.

Simeprevir oral

Janssen-Cilag

Indication:

Hepatitis C virus infection (HCV), genotype 1 or 4 in adults with compensated liver disease who are treatment naïve or have failed interferon.

Current status:



2014

National guidance:

As for sofosbuvir above.

Reviews: NIHR HSC - treatment naïve Sep 2012, failed interferon Sep 2012.

Target population: As for sofosbuvir above.

Sector: Secondary care initiated.

Implications: Other oral protease inhibitors for genotype 1 infection are taken twice or three times a day.

Financial: As for sofosbuvir above.


Pharmacology: Once daily NS3/4A protease inhibitor.

Efficacy: The primary outcome of all the following PIII studies is the number of patients achieving a sustained virologic

response at 12 weeks (SVR12) after the end of therapy.

Treatment naïve: In CONCERTO-1, 183 patients received peginterferon alfa-2a plus ribavirin (PEG/RBV) for up to 24 or 48 weeks plus simeprevir or placebo for 12 weeks. SVR12 was achieved by 89% vs. 62%, respectively. In CONCERTO-4, 79 patients received PEG/RBV plus simeprevir for 12 weeks followed by response-guided treatment. SVR12 was 92%. In QUEST-1 (n=394) and QUEST-2 (n=391) patients received simeprevir or placebo for 12 weeks plus interferon-based therapy for 24 or 48 weeks. 80% and 81% of those on simeprevir achieved SVR12, respectively.

Failed interferon: In CONCERTO-2,106 previous non-responders received simeprevir plus PEG/RBV for 12 or 24 weeks, followed by response-guided treatment. SVR12 was achieved by 53 vs. 36% of patients after 12 or 24 weeks. In CONCERTO-3, 49 relapsed patients received simeprevir plus PEG/RBV for 12 weeks, plus PEG/RBV for up to 36 weeks. SVR12 was achieved by 96% of patients. In CONCERTO-4, 79 patients received simeprevir plus PEG/RBV for 12 weeks followed by response-guided treatment. SVR12 in patients who had previously relapsed on interferon-based treatment was 100% and 39% in prior non-responders. In PROMISE, 393 previously relapsed patients received simeprevir or placebo with PEG/RBV for 12 weeks then PEG or RBV for 12 or 36 weeks. 79% of the simeprevir group achieved SVR12. On-going trials include a PIII trial in patients with concomitant HIV-1 infection and the RESTORE trial in those with genotype 4 infection.

Safety: In the PROMISE study, simeprevir was associated with influenza-like illness, rash and itching.



http://www.nice.org.uk/TA252



http://www.hsc.nihr.ac.uk/topics/sofosbuvir-for-chronic-hepatitis-c-infection-with








http://www.hsc.nihr.ac.uk/topics/simeprevir-for-hepatitis-c-andndash-first-line/

http://www.hsc.nihr.ac.uk/topics/simeprevir-for-chronic-hepatitis-c-infection/












Sofosbuvir/ ledipasvir oral

Gilead

Indication:

Hepatitis C viral infection,

genotype 1.

Pharmacology:

Ledipasvir is a NS5A protein inhibitor and sofosbuvir is a nucleotide NS5B inhibitor.

Current status:

PIII.


2015

Reviews: None.



Asunaprevir/ daclatasvir oral

Bristol Myers Squibb

Indication:

Hepatitis C virus infection,

genotype 1.

Pharmacology:

Asunaprevir is a NS3 protease inhibitor and daclatasvir is a NS5A inhibitor.

Current status:

PIII.


2015

Reviews: None.



ABT450/ ritonavir/ ABT267/ ABT333 oral

AbbVie Ltd

Indication:

Hepatitis C virus infection,

genotype 1.

Pharmacology:

ABT 450 is a NS3/4A inhibitor, ABT 267 is a NS5A inhibitor, ABT 333 is a non-nucleoside inhibitor.

Current status:

PIII.


2015

Reviews: None.



Actoxumab/ bezlotoxumab injection

MSD

Indication:

Clostridium difficile

infections, prevention of recurrence.

Pharmacology:

Monoclonal antibodies against C difficile-producing toxin A (actoxumab) and toxin B (bezlotoxumab).

Current status:

PIII.


2016

Reviews: None.


(children and young people) or CCG (adults).











BNF 6. Endocrine system

Alogliptin oral

Vipidia

Alogliptin/ metformin Vipdomet oral

Takeda

Indication:

Diabetes, type 2 (T2DM).

Current status:


Launched in US - see prescribing information.


2013

National guidance:

NICE: Diabetes: pathway, quality

standard.

SIGN: Management of diabetes.

Reviews: NICE-MPC May 2013.

Target population: Estimated UK prevalence of diagnosed diabetes was 2.9 million people in 2011; 85% have T2DM and about 72% are receiving medication. It is thought a further 850,000 are undiagnosed.

Sector: Primary care.

Implications: Vipdomet will be the fifth DPP-4 inhibitor/metformin combination available in the UK.

Financial: The 28-day cost for other DPP-4 inhibitors alone and in combination is £30-35. Alogliptin combinations will have to be competitive.


Pharmacology: Oral dipeptidyl peptidase-4 (DPP-4) inhibitor.

Efficacy: Unless stated otherwise, the primary outcome for all trials is mean change in HbA1c from baseline to week 26. Adding alogliptin 12.5mg or 25mg to metformin (n=527) resulted in changes in HbA1c of -0.6% (both doses) vs. -0.1% with placebo (p<0.001). In a PIII study patients received either alogliptin 25mg daily, 12.5mg twice daily, metformin 500mg or 1g twice daily, or a combination of both. Change in HbA1c was greater with combination (p<0.001) than with either monotherapy. Results from the 2-year ENDURE study (n>2,600) with alogliptin or glipizide plus metformin showed HbA1c reductions at week 104 were -0.68% and -0.72% for alogliptin 12.5 and 25mg, respectively, vs. glipizide (-0.59%). In a study (n=390) alogliptin 12.5mg or 25mg (added to insulin therapy ± metformin) was compared with placebo. HbA1c reductions were -0.63%, -0.71% and -0.13%, respectively (p<0.001). In a 52-week study (n=803) alogliptin 25mg or pioglitazone 15mg were added to metformin (≥1500mg) plus pioglitazone 30mg therapy. HbA1c change from baseline was -0.7% vs. 0.29%, respectively (p<0.001). In 441 elderly patients alogliptin was compared with glipizide in patients who were treatment-naïve or only taking one antidiabetic medication. The mean change in HbA1c at week 52 was -0.14% vs. -0.095%, respectively. The EXAMINE study (n=5,400) will assess cardiovascular outcomes of alogliptin vs. placebo, in addition to standard of care, in subjects with T2DM and acute coronary syndrome. Final results are expected in 2014.

Alogliptin may also be available in combination with pioglitazone although this is a little used treatment option in the UK.

Safety: Incidence of hypoglycaemia with alogliptin was similar to that seen with other therapies, but lower than that seen with sulphonylureas in elderly patients (5.4% vs. 26%). There have been reports of pancreatitis in patients taking alogliptin.

Canagliflozin oral

Invokana

Canagliflozin/metformin oral

Janssen-Cilag

Indication:

Diabetes, type 2.

Current status:

Filed in EU Jun 2012 and Mar 2013 (combination with metformin).

Launched in US –see prescribing information.


2013 and 2014 (comb-ination)

National guidance:

As for alogliptin above, canagliflozin due Jun 2014, dapagliflozin.

Reviews: NIHR HSC Apr 2011.

Target population: As for alogliptin above.


Implications: NICE have approved dapagliflozin for dual therapy with metformin in certain circumstances but not as triple therapy with metformin and sulphonylureas. Canagliflozin is another option.

Financial: Canagliflozin will compete with dapagliflozin at £37 per month.


Pharmacology: Sodium-glucose co-transporter 2 (SGLT2) inhibitor.

Efficacy: In the published CANTATA-M monotherapy study (n=584), HbA1c changes at week 26 with canagliflozin 100mg and 300mg were -0.77% and -1.03%, and were sustained to week 52 (-0.81% and -1.1%, respectively). Dual therapy regimens: In the published CANTATA-SU study (n=1,450), for lowering of HbA1c at 52 weeks, canagliflozin 100mg was non-inferior to glimepiride; canagliflozin 300 mg was superior (difference -0.12%). In CANTATA-D (n=1,284) canagliflozin, placebo or sitagliptin were added to metformin for 26 weeks, then all patients on placebo were switched to sitagliptin for a further 26 weeks. At week 52, both doses of canagliflozin were non-inferior to sitagliptin at lowering HbA1c, and canagliflozin 300mg was superior. Triple therapy regimens: In the 26-week PIII CANTATA-MSU (n=469) study HbA1c changes were -0.13% with placebo, -0.85% with canagliflozin 100mg and -1.06% with 300mg (p<0.001). In the published CANTATA-D2 study (n=755) canagliflozin showed a greater reduction in HbA1c at week 52 vs. sitagliptin (-1.03 vs. -0.66%). Canagliflozin also showed improvement in weight reduction and blood pressure vs. sitagliptin (p<0.001). In the CANTATA-MP study (n=340), canagliflozin was added to metformin and pioglitazone. The 26-week HbA1c changes were -0.89% (100mg) and -1.03% (300mg) (p<0.001), which were sustained to week 52 (-0.98% and -1.07% respectively). In CANVAS, which is due to complete in 2018, the effects of canagliflozin on cardiovascular events are being compared with placebo (n=4,330). Canagliflozin has been used with metformin in a number of the above studies, this data plus bioequivalence studies will be used in the licence application for the canagliflozin/metformin combination.

Safety: Higher rates of genital and urinary tract infections with canagliflozin reflect increases in urinary glucose excretion.




http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/landing/smop_search.jsp&mid=WC0b01ac058001d127&source=homeMedSearch&category=human&keyword=alogliptin&isNewQuery=true

http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/landing/smop_search.jsp&mid=WC0b01ac058001d127&source=homeMedSearch&category=human&keyword=alogliptin&isNewQuery=true

http://general.takedapharm.com/content/file/pi.pdf?applicationcode=66B0B942-E82B-46AD-886A-F4AA59F5F33C&FileTypeCode=NESINAPI

http://general.takedapharm.com/content/file/pi.pdf?applicationcode=66B0B942-E82B-46AD-886A-F4AA59F5F33C&FileTypeCode=NESINAPI

http://pathways.nice.org.uk/pathways/diabetes

http://www.nice.org.uk/guidance/qualitystandards/diabetesinadults/diabetesinadultsqualitystandard.jsp

http://www.nice.org.uk/guidance/qualitystandards/diabetesinadults/diabetesinadultsqualitystandard.jsp


http://www.nice.org.uk/mpc/evidencesummariesnewmedicines/ESNM20.jsp


http://clinicaltrials.gov/ct2/show/results/NCT01023581?sect=X46015



http://www.ncbi.nlm.nih.gov/pubmed/?term=Alogliptin+as+a+third+oral+antidiabetic+drug+in+patients+with+type+2+diabetes+and+inadequate+glycaemic+control+on+metformin+and+pioglitazone%3A+a+52-week%2C+randomized%2C+double-blind%2C+active-controlled%2C+parallel-group+study

http://clinicaltrials.gov/ct2/show/results/NCT00707993?term=NCT00707993&rank=1&sect=Xne6015

http://clinicaltrials.gov/ct2/show/record/NCT00968708?term=NCT00968708&rank=1





http://www.invokanahcp.com/prescribing-information.pdf

http://www.invokanahcp.com/prescribing-information.pdf


http://publications.nice.org.uk/dapagliflozin-in-combination-therapy-for-treating-type-2-diabetes-ta288

http://www.nhsc-healthhorizons.org.uk/topics/canagliflozin-for-type-2-diabetes-mellitus

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3593184/



http://clinicaltrials.gov/ct2/show/NCT01106625?term=nct01106625&rank=1


http://clinicaltrials.gov/ct2/show/results/NCT01106690?term=cantata+MP&rank=1&sect=X6015



Dapagliflozin/metformin oral

AstraZeneca/ Bristol Myers Squibb

Indication:

Diabetes, type 2.

Current status:



2013

National guidance:

NICE: As for alogliptin above,

dapagliflozin.

Reviews: NIHR HSC May 2011.

Target population: As for alogliptin above.


Implications: NICE has approved use of dapagliflozin as dual therapy with metformin in certain circumstances. The combination product may be more convenient for patients stabilised on the two drugs taken separately.

Financial: Currently UK cost for 28 days treatment with various metformin formulations ranges from around £1.50 to £12; dapagliflozin costs about £37/month. The combination product will have to compete with this.


Pharmacology: SGLT2-inhibitor with a biguanide in a once daily formulation.

Efficacy: Dapagliflozin is licensed for use in combination with other glucose-lowering medicines, such as metformin, when

these, together with diet and exercise, do not provide adequate glycaemic control. Bioequivalence studies comparing fixed-dose combination products with individual components have been undertaken.


Exenatide implant

Intarcia therapeutics

Indication:

Diabetes, type 2.

Pharmacology:

Long-acting analogue of glucagon-like peptide 1 (GLP-1) delivered via DUROS device over 3-12 months.

Current status:

PIII trials in EU and US.


2016

Reviews: None.


PbR: HRG included.

Insulin degludec/ insulin aspart injection

Ryzodeg

Novo Nordisk

Indication:

Diabetes, type 1 (T1DM)

and type 2 (T2DM).

Current status:

Licensed in EU Jan 2013. Company plan to launch early 2014.


2014

National guidance:

As for alogliptin above.

Reviews: NIHR HSC - T1DM, T2DM, Jan 2011.

Target population: As for alogliptin above. About 15% of adults and children with diabetes have T1DM.

Sector: Primary and secondary care.

Implications: In T2DM NICE recommends insulin (starting with human NPH insulin or a long-acting insulin analogue) for patients with HbA1c not controlled with metformin plus sulfonylurea. Ryzodeg will be another option

for those not controlled on oral therapy or basal insulin regimens.

Financial: Cost of 1,500 units of NovoMix 30 is about £30 and of Humulin M3 £15-22. Cost of 1,500 units insulin degludec is £72. Ryzodeg is likely to be more expensive than currently available insulin combinations.


Pharmacology: Long-acting basal insulin [degludec, 70%] plus short-acting bolus insulin [aspart, 30%] (IDegAsp).

Efficacy: Unless stated otherwise, in all studies, the primary outcome was HBA1c change at 26 weeks.

T1DM. In the published BOOST-T1 study (n=548) IDegAsp given once-daily with any meal with insulin aspart (IAsp) at remaining meals was non-inferior to once-daily insulin detemir with IAsp at all meals.

T2DM. In BOOST-START 1 (n=530) and BOOST-INTESIFY-BASAL (n=465) IDegAsp demonstrated non-inferiority vs. insulin glargine (IGlar). In the published BOOST: Intensify All trial (n=296), at 26 weeks, mean HbA1c was 7% with IDegAsp vs. 7.3% with IGlar (difference -0.28%, p<0.01).

Safety: See medicines.org.uk. This has not been approved in the US pending further cardiovascular outcomes data.

Insulin inhalation

Afrezza

MannKind Corporation

Indication:

Diabetes, types 1 and 2.

Pharmacology:

Dry-powder formulation of insulin, rapid acting.

Current status:

PIII trials in EU and US.


2015



PbR: Likely HRG Included.



http://publications.nice.org.uk/dapagliflozin-in-combination-therapy-for-treating-type-2-diabetes-ta288

http://www.hsc.nihr.ac.uk/files/downloads/1582/2039.c6b9a607.Dapagliflozin.pdf





http://www.nhsc-healthhorizons.org.uk/topics/insulin-degludec-insulin-aspart-degludecplus-t1

http://www.nhsc-healthhorizons.org.uk/topics/insulin-degludec-insulin-aspart-degludecplus-t2









Bazedoxifene/conjugated estrogens oral

Duavive

Pfizer

Indication:

Postmenopausal osteoporosis and menopausal symptoms.

Current status:

Filed in EU Jul 2012.


2014

National guidance:

NICE: Osteoporosis pathway.

SIGN: Management of osteoporosis.

Reviews: None.

Target population: It is estimated that more than 2 million women have osteoporosis in England and Wales. After the menopause, the prevalence of osteoporosis increases markedly with age, from about 2% at 50 years of age rising to more than 25% at 80 years.


Implications: NICE suggests first-line treatment for primary prevention of postmenopausal osteoporosis is a bisphosphonate. Raloxifene (a SERM) is not recommended for primary prevention of osteoporotic fractures but can be used for secondary prevention. Many preparations are available for menopausal symptoms. Bazedoxifene plus conjugated oestrogens (BZA/CE) is another option and, as a single tablet, could be attractive.

Financial: Current 28-day treatment costs range from £1.10 (alendronate

70mg/week) to £17.06 (raloxifene 60mg/day) and £25.60 (strontium ranelate 2g/day). Conjugated oestrogens for HRT cost around £3-6 for 3 months treatment. BZA/CE is likely to be competitive.


Pharmacology: Selective oestrogen receptor modulators (SERM) plus oestrogen receptor agonist.

Efficacy: Five PIII Selective Estrogen Menopause and Response to Therapy (SMART) studies have been undertaken, the

results of four are fully published. Endometrial safety and changes in bone mineral density (BMD) are assessed in SMART-1 (n=3,397), SMART-4 (n=1,061) and SMART-5 (n=1,843). In SMART-1, over 24 months, BZA/CE was associated with low rates (<1%) of endometrial hyperplasia and endometrial thicknesses that were similar to placebo. BMD increases seen in all three studies were significantly greater with BZA/CE vs. placebo and in SMART-1, were greater with most doses of BZA/CE vs. raloxifene. In SMART-1 and SMART-2 (n=332) studies, the incidence of hot flushes by week 12 was reduced by 50-85% with BZE/CE vs. 17-50% with placebo (p<0.01). BZA/CE was used in SMART 3 (n=664) to treat vulvar/vaginal atrophy. BZA/CE increased superficial, and decreased parabasal, cells vs. placebo (p<0.01). Vaginal pH and dryness improved with BZA/CE vs. placebo (p≤0.05).

Safety: BZA/CE is associated with low rates (<1%) of endometrial hyperplasia and endometrial thicknesses.

Pasireotide LAR injection

Signifor

Novartis

Indication:

Acromegaly.

Current status:



2014

National guidance: None.


Target population: The UK incidence of acromegaly is about 3 per million; about 3,000 have the condition.


Implications: Pasireotide will compete with other somatostatin analogues, pegvisomant and dopamine agonists.

Financial: Current depot therapy includes lanreotide 30mg (£645/month) or octreotide 20mg (£776/ month) for initial therapy, dose and/or frequency adjusted according to response.


Pharmacology: Somatostatin analogue in a long-acting release (LAR) i.m. injection given every 4 weeks.

Efficacy: In the PIII PASPORT-ACROMEGALY study (n=358), pasireotide LAR was compared with octreotide LAR both

given by monthly i.m. injection. At 12 months, 31.3% on pasireotide LAR vs. 19.2% on octreotide LAR (p=0.007) achieved a biochemical response (growth hormone level <2.5mcg/L and normal insulin like growth factor-1). Those who did not initially achieve biochemical control could switch to the other treatment in a 6-month extension phase; 81 switched to pasireotide LAR and 38 to octreotide LAR. A biochemical response was achieved by 21.0% and 2.6%, respectively. A PIII study assessing pasireotide vs. octreotide or lanreotide is ongoing.

Safety: See medicines.org.uk for short-acting formulation. Hyperglycaemia is more common with pasireotide than octreotide.




http://pathways.nice.org.uk/pathways/osteoporosis




http://posterdocument.com/assets/posters/poster-490_4fdf1657c3609.pdf









Tolvaptan oral

Samsca

Otsuka Pharma-ceuticals

Indication:

Autosomal-dominant polycystic kidney disease (ADPKD)

Current status:

PIII in EU.

Not recommended for approval in US Aug 2013.


2014

National guidance:

NICE: Chronic kidney disease pathway.

SIGN: Diagnosis and management of

chronic kidney disease.


Target population: ADPKD has a prevalence of 100-1,300 per 100,000 people (at least 60,000 in the UK). In 2007 polycystic kidney disease accounted for 12.7% of patients receiving renal transplants.


Implications: There are currently no therapies that modify the disease course and slow the rate of decline in renal function. Current management options include anti-hypertensives, dialysis and renal transplantation.

Financial: Based on current prices, tolvaptan 60mg/day will cost over £4,100/month.

Likely commissioning route: Uncertain -depending on statge of renal failure. PbR: Specified high cost drug.

Pharmacology: Selective vasopressin V2-receptor antagonist.

Efficacy: In the published PIII TEMPO 3:4 trial (n=1,445) patients received tolvaptan at the highest of three dose regimens

tolerated or placebo. At 3 years, the increase in total kidney volume in the tolvaptan group was 2.8% per year vs. 5.5% per year for placebo (p<0.001). Secondary outcome measures including a composite of time to clinical progression (defined as worsening kidney function, kidney pain, hypertension, and albuminuria) and rate of kidney-function decline favoured tolvaptan (p=0.01 and p<0.001, respectively).

Safety: See medicines.org.uk. In the TEMPO 3:4 trial more patients on tolvaptan had raised liver enzymes. The MHRA has issued a safety warning.

BNF 7. Obstetrics, gynaecology, and urinary-tract disorders

Botulinum A toxin (onabotulinum-toxin A) injection

Botox

Allergan

Indication:

Overactive bladder (OAB), idiopathic in adults who have an inadequate response/are intolerant of antimuscarinic medication.

Current status:

Filed in UK, date uncertain. Recommended for approval in EU (but not UK) Dec 2012.



2013

National guidance:

NICE: Lower urinary tract symptoms in

men - pathway, quality standard due Sep 2013; Urinary incontinence in women – guideline, update due Sep 2013, commissioning guide.

SIGN: Urinary incontinence.

Reviews: NICE-MPC Sep 2012.

Target population: The estimated population with OAB for whom antimuscarinic treatment does not give an adequate response is around 0.265%, equating to around 106,000 adults in England.


Implications: NICE guidance suggests that botulinum toxin is an option in patients able and willing to self-catheterise, for whom standard therapy with lifestyle changes, bladder retraining and anticholinergic drugs has failed and who might otherwise have been considered for surgical intervention or neuromodulation.

Financial: The current NHS cost of Botox is £138.20 for a 100-unit vial; the cost per patient will be £276.40/year if given twice. This does not include the cost of the procedure.


Pharmacology: Purified neurotoxin complex presented as a single 1,000 unit injection administered as 20 individual 5 unit

injections into the detrusor muscle. The effects of a single injection can last for between 3-10 months.

Efficacy: In a published 12-week PIII trial (n=557) in the EMBARK programme, botulinum A toxin 100 units reduced the primary outcome of daily urinary incontinence episodes vs. placebo (-2.65 vs. -0.87, p<0.001) and 22.9% vs. 6.5% of patients became completely continent (NNT=6). More patients on botulinum A toxin reported a positive response on the treatment benefit scale (primary outcome) vs. placebo (60.8% vs. 29.2%, respectively, p<0.001). Similar results have been noted in another PIII study (n=548) in the EMBARK programme. An on-going, long-term follow-up study (n=750) has completed enrolment. The published UK RELAX study (n=240) reported that 31% of women were continent at 6 months after one botulinum 200 unit injection vs. 12% on placebo (NNT= 5).

Safety: In the PIII trials, 18% of patients had urinary tract infections, 9% had dysuria and 6.5% had urinary retention. NNH

(urinary tract infection/ requirement for self catheterisation) was 5 for botulinum and 8 for placebo.


http://pathways.nice.org.uk/pathways/chronic-kidney-disease



http://www.hsc.nihr.ac.uk/topics/tolvaptan-for-autosomal-dominant-polycystic-kidney



http://www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate/CON282737





http://www.allergan.com/assets/pdf/botox_pi.pdf

http://www.allergan.com/assets/pdf/botox_pi.pdf

http://pathways.nice.org.uk/pathways/lower-urinary-tract-symptoms-in-men

http://guidance.nice.org.uk/QSD/40

http://publications.nice.org.uk/urinary-incontinence-cg40/other-versions-of-this-guideline#full-guideline

http://guidance.nice.org.uk/CG/WaveR/101

http://www.nice.org.uk/usingguidance/commissioningguides/uiwomen/UrinaryContinenceService.jsp


http://publications.nice.org.uk/idiopathic-overactive-bladder-syndrome-botulinum-toxin-a-esnm2






Collagenase clostridium histolyticum injection

Xiapex

Auxilium

Indication:

Peyronie’s disease (PsD).

Current status:

PIII in EU.

Filed in US in Nov 2012.


2014

National guidance:

NICE: Extracorporeal shock waves for

PsD.

EAU Guidelines on Penile Curvature 2012.

Reviews: None.

Target population: PsD affects around 1% of men; it will improve or resolve spontaneously in about 13%. The average age of onset is in the fifth decade with many cases undiagnosed.


Implications: Current therapy incudes oral potassium para-aminobenzoate, intralesional interferon-alpha or verapamil, and surgery.

Financial: Xiapex 900 microgram currently costs £650; much more than interferon-alpha.


Pharmacology: Collagenase stimulant injected into penile plaque twice weekly every 6 weeks for up to 4 treatment cycles, each injection accompanied by penile modelling.

Efficacy: A post-hoc meta-analysis of two identical 52-week PIII studies IMPRESS I and II has been published, each

enrolling over 400 men. Those treated with collagenase had a 34% mean improvement in penile curvature vs. 18% in those on placebo (representing a mean change -17.0 vs. -9.3 degrees, respectively). The mean change in Peyronie’s disease symptom bother score was improved with collagenase treatment (-2.8 vs. -1.8, p=0.004).

Safety: Local treatment site reactions are common and include injection site haematoma, pain and swelling. Across

IMPRESS I and II, 3 cases of corporal rupture and 3 serious penile haematomas occurred.

BNF 8. Malignant disease and immunosuppression

Brain cancer vaccine injection

DCVax-L

Northwest Bio-therapeutics

Indication:

Glioblastoma multiforme, first-line adjuvant therapy.

Pharmacology:

Immunostimulant vaccine manufactured using the patient’s dendritic cells and resected tumour tissue.

Current status:

PIII with orphan status.


2015



PbR: Chemotherapy is locally negotiated.

Afatinib oral

Giotrif


Indication:

Head and neck cancer, squamous cell – locally advanced, recurrent or metastatic - second-line.

Pharmacology:

Tyrosine kinase inhibitor blocking EGFR and HER2.

Current status:

PIII.


2015




Sorafenib oral

Nexavar

Bayer

Indication:

Thyroid cancer, differentiated (DTC) – advanced, radioactive-iodine refractory.

Current status:

Filed in EU and US Jul 2013 with priority review in the US.


2014

National guidance:

None relevant.


Target population: UK incidence of thyroid cancer is 3.5 per 100,000; DTC (papillary and follicular) accounts for 80%. 5-20% of patients develop local or regional recurrences and 10-15% have distant metastases.


Implications: Options for recurrent or metastatic disease include surgery, radioactive iodine and radiotherapy. Sorafenib will be the first drug licensed for progressive disease.

Financial: This is additional therapy that currently costs £2,980 a month. Median treatment duration in a PII trial was 16.5 months.

Likely commissioning route: NHSE. PbR: Chemotherapy is locally

negotiated.

Pharmacology: Blocks Raf and tyrosine kinases, vascular endothelial and platelet derived growth factor receptors.

Efficacy: In the published PIII DECISION study (n=417), median PFS was 10.8 months with sorafenib vs. 5.8 months with

placebo (HR 0.58, p<0.0001). Median overall survival (OS) had not been reached in either arm. A partial response (PR) was seen in 12.2% and 0.5% of sorafenib and placebo patients, respectively (p<0.0001); 42% and 33% had stable disease (SD) lasting at least 6 months, respectively. In a published PII study (n=31), 59% had a clinical response (25% a PR and 34% SD); 22% had progressive disease. In published long-term results, median PFS was 18 months and median OS was 34.5 months. In a published PII study (n=19), the radiological response rate was 18% and OS 79% at 12 months.





http://publications.nice.org.uk/extracorporeal-shockwave-therapy-for-peyronies-disease-ipg29

http://publications.nice.org.uk/extracorporeal-shockwave-therapy-for-peyronies-disease-ipg29

http://www.uroweb.org/gls/EU/Hatzimouratidis%20K%20et%20al%20Eur%20Urol%202012%2062(3)543%20EAU%20Guidelines%20on%20penile%20curvature.pdf

http://www.ncbi.nlm.nih.gov/pubmed?term=((peyronie%5BTitle%5D)%20AND%20collagenase%5BTitle%5D)%20AND%20IMPRESS




http://www.hsc.nihr.ac.uk/files/downloads/2021/2360.4a9d1211.Afatinib_Mar13.pdf








Lenvatinib oral

Eisai

Indication:

Thyroid cancer,

differentiated (DTC) – advanced, radioactive-iodine refractory.

Current status:



2014

National guidance:

As for sorafenib above.

Reviews: None.

Target population: As for sorafenib above.


Implications: Options for recurrent or metastatic disease include surgery, radioactive iodine and radiotherapy. A competitor to twice-daily sorafenib.

Financial: Likely to be similarly priced to sorafenib (£2,980/month).


Pharmacology: A once-daily, multi-targeted kinase inhibitor of VEGFR1-3, FGFR1-4 and RET tyrosine kinases.

Efficacy: Data from a PII trial (n=58) show an objective clinical response rate of 50%; the rate in patients who received prior VEGFR-directed treatment (n=17) was 41%, in those with no prior VEGFR-directed treatment it was 54%. Median PFS was 12.6 months after a minimum follow-up of 8 months. Results from the placebo-controlled PIII SELECT trial (n=360) are expected in 2013. A PII trial enrolling 104 patients with DTC and medullary TC is expected to complete in Oct 2013.

Safety: In a PII trial, 10% of patients experienced grade 3 diarrhoea, hypertension and proteinuria. Toxicities were manageable by dose reduction in 35% of patients. 23% withdrew from the study due to adverse events.

Cabozantinib oral

Cometriq

Exelixis

Indication:

Thyroid cancer, medullary

(MTC).

Current status:

Filed in EU Dec 2012 with orphan status.



2013

National guidance:

None relevant.


Target population: MTC is rare, accounting for 5-8% of all thyroid cancers (about 0.2 per 100,000 people).


Implications: First-line therapy is thyroidectomy. Cabozantinib may slow disease progression in patients who cannot be managed by surgery alone and will be an alternative to vandetanib.

Financial: Likely to be expensive but may offset other treatment costs. An alternative to vandetanib which costs £5,000 per month.


negotiated.

Pharmacology: Tyrosine kinase inhibitor that blocks RET, MET, VEGFR-1, -2 and -3, KIT, TRKB, FLT-3, AXL and TIE-2.

Efficacy: In the published PIII EXAM trial (n=330) progression-free survival (PFS) was 11.2 months with cabozantinib vs. 4.0

months with placebo (HR 0.28, p<0.0001). One-year PFS was 47.3% and 7.2%, respectively; overall response rates were 28% and 0%, respectively (p<0.0001). In a published PI study (n=35), 29% had a partial response to cabozantinib, and 49% had tumour shrinkage of 30% or more. At two years, 30% were progression-free.

Safety: Cabozantinib has been associated with perforations, fistulas, haemoptysis and gastrointestinal haemorrhage.

Afatinib oral

Giotrif


Indication:

Non-small cell lung cancer (NSCLC), advanced with EGFR mutation.

Current status:




2013

National guidance:

NICE: Lung cancer - pathway, quality

standard; NSCLC - afatinib due May 2014.

SIGN: Lung cancer, update due 2013.


Target population: UK incidence of advanced NSCLC is 45 per 100,000 people; 25% are able to have first-line therapy. Epidermal growth factor receptor (EGFR) is overexpressed in 10-15% of tumours.


Implications: Afatinib will compete with first generation EGFR inhibitors, erlotinib and gefitinib. It is a less complicated and less toxic alternative to i.v. chemotherapy in selected patients.

Financial: PASs are in place for erlotinib and gefitinib for NSCLC. Monthly

list price is £1,600 and £2,000, respectively.


Pharmacology: Tyrosine kinase inhibitor irreversibly blocking epidermal growth factor receptors, including HER2.

Efficacy: In the published global PIII LUX-Lung 3 trial (n=345) comparing first-line afatinib with cisplatin and pemetrexed, median progression-free survival (PFS) was 11.1 vs. 6.9 months, respectively (HR 0.58, p=0.001). In 308 patients with EGFR mutation, median PFS was 13.6 months for afatinib vs. 6.9 months for chemotherapy (0.47, p=0.001). The objective response rate was 56% for afatinib vs. 23% in the control group (p<0.0001). Afatinib also delayed time to deterioration of cancer-related symptoms of cough (0.6, p=0.007) and dyspnoea (0.68, p<0.01). The PIII LUX-Lung 6 trial compared afatinib with cisplatin and gemcitabine in 364 Asian patients; median PFS was 11.0 vs. 5.6 months, respectively (0.28, p<0.0001).

Safety: Common adverse effects are diarrhoea, rash, mucositis and paronychia.





http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/203756lbl.pdf


http://www.nhsc-healthhorizons.org.uk/files/downloads/1762/2175.f4a3e84f.Cabozantinib.pdf




http://www.ema.europa.eu/ema/pages/includes/document/open_document.jsp?webContentId=WC500146640




http://pathways.nice.org.uk/pathways/lung-cancer



http://guidance.nice.org.uk/TA/Wave0/664






Belagenpu-matucel-L injection

Lucanix

NovaRx Corporation

Indication:

Non-small cell lung cancer

– second-line.

Pharmacology:

Antisense-DNA vaccine.

Current status:

PIII.

Granted fast track status in US.


2015

Reviews: None.



Afatinib oral

Giotrif


Indication:

Non-small cell lung cancer – second-line plus.

Pharmacology:

Tyrosine kinase inhibitor blocking EGFR and HER2.

Current status:

PIII.


2015

Reviews: None.



Dacomitinib oral

Pfizer

Indication:

Non-small cell lung cancer, advanced – second-line plus.

Pharmacology:

Pan-HER tyrosine kinase inhibitor.

Current status:

PIII.


2015




Ganetespib injection

Synta

Indication:

Non-small cell lung cancer (NSCLC), advanced – second-line plus.

Pharmacology:

A second-generation heat shock protein-90 inhibitor.

Current status:

PIII.


2015

Reviews: None.



Eribulin injection

Halaven

Eisai

Indication:

Non-small cell lung cancer,

advanced – third-line.

Pharmacology:

Synthetic analogue of halichondrin B, with tubulin-based antimitotic activity.

Current status:

PIII.


2015




LDK378 oral

Novartis

Indication:

Non-small cell lung cancer, ALK-positive, locally advanced or metastatic – second-line.

Pharmacology:

ALK inhibitor.

Current status:

PII.

Granted breakthrough therapy status in US.


2015



PbR: Chemotherapy is locally

negotiated.





http://www.hsc.nihr.ac.uk/files/downloads/1960/2316.64aaa7ac.Dacomitinib_Nov12.pdf



http://www.hsc.nihr.ac.uk/files/downloads/2074/2402.282aeac6.Eribulinmesilate.pdf


http://www.hsc.nihr.ac.uk/files/downloads/2024/2363.daa124be.LDK378_Mar13.pdf


Enobosarm oral

Ostarine

GTXi

Indication:

Non-small cell lung cancer (NSCLC), advanced – prevention and treatment of cachexia.

Current status:

PIII in EU.

PIII in US with fast track status.


2014

National guidance:

NICE: Lung cancer pathway, quality

standard.

SIGN: Lung cancer, update due 2013.


Target population: Cancer-related cachexia (loss of skeletal muscle mass and progressive functional impairment) occurs in 50% of cancer patients and causes at least 20% of deaths. The UK incidence of advanced NSCLC is 45 per 100,000 people; 25% receive first-line chemotherapy.


Implications: Therapeutic options are limited for patients with cachexia, but include nutritional support, short-term corticosteroids and progestogens. Enobosarm is intended to be given to patients receiving first-line chemotherapy and may improve quality of life.

Financial: Costs will be additive to current therapy.


Pharmacology: A first-in-class, non-steroidal selective androgen receptor modulator (SARM).

Efficacy: In a published PII trial (n=100; 31 with NSCLC), median total lean body mass (LBM) at 4 months increased from

baseline with enobosarm 1mg and 3mg (1.5kg and 1.0kg, respectively; both p<0.05) but not with placebo (0.02kg; p=0.88). Absolute changes from baseline in mean stair climb power (SCP) with enobosarm 1mg, 3mg and placebo were 18.0%, 21.7% and 4.8%, respectively. Although not designed to assess survival, the survival hazard ratios for patients on enobosarm 1mg or 3mg vs. placebo were 0.80 and 0.70, respectively. Initial data from two PIII trials (both n=325) show enobosarm failed to meet criteria for the co-primary outcome of LBM and SCP; POWER1 involves patients on first-line platinum plus taxane chemotherapy, and POWER2 involves patients on first-line platinum plus non-taxane chemotherapy. Although the effect of enobosarm vs. placebo on SCP was inconsistent, LBM was significantly increased at all assessment times (p=0.0003 and p=0.0227 at day 84 for POWER1 and POWER2, respectively). Survival and quality of life results are awaited.

Safety: Transient changes in liver function tests have been reported.

Anamorelin oral

Helsinn

Indication:

Anorexia/cachexia associated with non-small cell lung cancer.

Pharmacology:

Ghrelin receptor agonist.

Current status:

PIII.


2015

Reviews: None.



Trastuzumab emtansine injection

Kadcyla

Roche

Indication:

Breast cancer (BC),

advanced, HER2-positive – second/ third-line.

Current status:

Filed in EU Sep 2012.



2013

National guidance:

NICE: BC pathways - early/locally

advanced, advanced and familial, BC quality standard; trastuzumab emtansine due Aug 2014.

SIGN: Breast cancer.

Reviews: NIHR HSC Jan 2011.

Target population: The incidence of BC in the UK is about 80 per 100,000 people. About 40% develop metastatic disease; 25% of these are HER2-positive which has a worse prognosis. About 70% of patients do not respond to first-line trastuzumab and the rest develop resistance within the first year.


Implications: This will compete with other second-line options including biological therapies, chemotherapies and hormonal therapies.

Financial: Cost unknown but will displace other expensive treatments. US cost is $9,800 a month.


Pharmacology: First-in-class trastuzumab emtasine (T-DM1) is an antibody conjugate of trastuzumab and an anti-mitotic

agent, maytansinoid DM1. Given by 3-weekly i.v. infusion.

Efficacy: The published EMILIA study enrolled 991 patients with BC that progressed after first-line trastuzumab and a taxane. Median progression-free survival (PFS) was 9.6 months for T-DM1 vs. 6.4 months for lapatinib and capecitabine (LC) (HR 0.65, p<0.001). Median overall survival at the second interim analysis was 30.9 months vs. 25.1 months, respectively (0.68, p<0.001). Objective response rates were 43.6% for T-DM1 and 30.8% for LC. 1-year and 2-year survival rates with T-DM1 were 85% and 65%; with LC they were 78% and 52%, respectively. The PIII TH3RESA study is comparing T-DM1 with treatment of choice in 606 women who have received at least 2 prior HER2 regimens. Results are due in 2015.

Safety: Compared with LC, T-DM1 more commonly causes thrombocytopenia and raised liver enzymes, but less often

causes diarrhoea, vomiting and hand-foot syndrome. Liver function and left ventricular ejection fraction require monitoring.






http://www.hsc.nihr.ac.uk/files/downloads/1962/2318.6a41c7bb.Enobosarm_Nov12.pdf


http://www.clinicaltrials.gov/ct2/show/NCT01355484







http://pathways.nice.org.uk/pathways/early-and-locally-advanced-breast-cancer

http://pathways.nice.org.uk/pathways/early-and-locally-advanced-breast-cancer

http://pathways.nice.org.uk/pathways/advanced-breast-cancer

http://pathways.nice.org.uk/pathways/familial-breast-cancer

http://www.nice.org.uk/guidance/qualitystandards/breastcancer/home.jsp



http://www.nhsc-healthhorizons.org.uk/files/downloads/1051/1557.c48d2fd1f5ce098adf8f6db790fe739e.pdf




Trastuzumab emtansine injection

Kadcyla

Roche

Indication:

Breast cancer (BC),

advanced, HER2-positive – first-line in combination with pertuzumab.

Current status:

PIII.


2014

National guidance:

As for trastuzumab emtansine above.

Reviews: NIHR HSC Jun 2012.

Target population: As for trastuzumab emtansine above.


Implications: This could prevent the need for first-line chemotherapy and could result in a delay in disease progression and improved quality of life.

Financial: Cost unknown but would displace trastuzumab plus taxane

therapy. US cost is $9,800 a month.


Pharmacology: As above.

Efficacy: The PIII MARIANNE study is assessing progression-free survival (PFS) in 1,092 patients given first-line trastuzumab emtansine, either alone or in combination with pertuzumab vs. trastuzumab plus taxane. Results are expected in 2014. In a published PII trial (n=137), the objective response rate with T-DM1 was 64.2% vs. 58.0% with trastuzumab plus docetaxel. Compared with the control group, there was a 41% reduction in risk of disease progression or death with T-DM1, with median PFS of 9.2 months vs.14.2 months, respectively (HR 0.59).

Safety: T-DM1 caused fewer grade ≥3 adverse effects (46% vs. 91%) and adverse effects leading to discontinuations (7% vs. 41%) than trastuzumab plus taxane. Liver function and left ventricular ejection fraction require monitoring.

Trastuzumab/ hyaluronidaseinjection

Herceptin SC

Roche

Indication:

Breast cancer (BC), early and metastatic HER2-positive (all BC indications for which trastuzumab is currently indicated).

Current status:

Licensed in EU Sep 2013.


2013

National guidance:


Reviews: NIHR HSC Jan 2011, NICE-MPC Mar 2013.

Target population: As for trastuzumab

emtansine above.


Implications: Compared to the i.v. formulation, s.c. trastuzumab will reduce

preparation and administration time and would facilitate homecare delivery. This s.c. formulation is presented as a fixed dose formulation unlike the i.v. formulation that is dosed according to body weight. Biosimilar formulations of i.v. trastuzumab are in development (see page 70).

Financial: Cost unknown but may reduce overall costs and clinic time.


Pharmacology: Anti-HER2 monoclonal antibody co-formulated with recombinant human hyaluronidase to facilitate absorption of trastuzumab through subcutaneous tissue. Given by s.c. injection every 3 weeks.

Efficacy: The published PIII HannaH study compared the pharmacokinetics and efficacy of s.c and i.v. trastuzumab in 596 women with early HER2-postive BC. The s.c. formulation was non-inferior to the i.v. formulation; serum trough plasma concentrations before surgery were at least as high (69.0 and 51.8 microgram/mL, respectively) and efficacy as determined by pathological complete response was similar in both groups (45.4% and 40.7%, respectively).

Safety: Adverse effects are consistent with those of i.v. trastuzumab. See medicines.org.uk.

Bevacizumab injection

Avastin

Roche

Indication:

Breast cancer (BC), early HER2-positive – adjuvant therapy.

Current status:

PIII.


2014

National guidance:



Target population: As for trastuzumab emtansine above. Around 95% of patients present with localised disease and are eligible for surgery. 15-20% are HER2-positive and have a worse prognosis; nearly all require adjuvant treatment with trastuzumab, which lowers risk of recurrence by 25-50% and risk of death by 17-33%.


Implications: Despite treatment with trastuzumab, many women develop recurrent or metastatic disease. The addition of bevacizumab may improve response rates and delay progression.

Financial: Costs will be additive to chemotherapy and trastuzumab. Current

cost of one year’s treatment with bevacizumab for a 65kg woman is about £40,000.


Pharmacology: Vascular endothelial growth factor antagonist, given by i.v. infusion every 3 weeks.

Efficacy: The PIII BETH study is investigating whether giving bevacizumab for one year in addition to chemotherapy

(docetaxel/carboplatin or 5-fluorouracil, epirubicin and cyclophosphamide) plus trastuzumab improves invasive disease-free survival in 3,509 women who have undergone surgery. Interim results are expected in 2013.




http://www.hsc.nihr.ac.uk/files/downloads/1841/2228.fc11020e.Trastuzumab_June12.pdf






http://www.nhsc-healthhorizons.org.uk/files/downloads/1052/1558.3c8869bc49189f6393ee111d4cd627c5.pdf

http://publications.nice.org.uk/esnm13-early-and-metastatic-her2-positive-breast-cancer-subcutaneous-trastuzumab-esnm13

http://publications.nice.org.uk/esnm13-early-and-metastatic-her2-positive-breast-cancer-subcutaneous-trastuzumab-esnm13




http://www.hsc.nihr.ac.uk/files/downloads/1786/2193.11ebf62f.Bevacizumab.pdf




Everolimus oral

Afinitor

Novartis

Indication:

Breast cancer (BC),

advanced HER2-positive – first-line.

Current status:

PIII.


2014/2015

National guidance:





Implications: About 70% of patients are resistant to trastuzumab. Adding everolimus may improve response rates and delay need for second-line chemotherapy. Oral everolimus will compete with i.v. pertuzumab.

Financial: Costs will be additive to trastuzumab and chemotherapy. Current

cost of everolimus 10mg daily is £2,970 per month, and the costs of a 420mg dose of pertuzumab given three-weekly is £2,400 (excluding loading dose and administration costs).


Pharmacology: mTOR inhibitor.

Efficacy: The PIII BOLERO-1 trial (n=717) is assessing addition of first-line everolimus to trastuzumab and paclitaxel.

Results are imminent. This study was initiated following published PI trial results. Disease was controlled for more than 6 months in 74% of 27 women with prior resistance to trastuzumab given everolimus in addition to paclitaxel and trastuzumab. Overall response rate was 44% and progression-free survival (PFS) was 8.5 months. A pooled analysis of PII data from 47 women with trastuzumab resistance showed adding everolimus to trastuzumab produced partial responses in 7 patients and persistent stable disease (lasting 6 months or longer) in 9 patients. Median PFS was 4.1 months.


Everolimus oral

Afinitor

Novartis

Indication:

Breast cancer (BC), advanced HER2-positive – second- or third-line with trastuzumab.

Current status:

PIII.


2014

National guidance:





Implications: Current options for patients resistant to trastuzumab produce low response rates and short durations of response. Everolimus is an alternative to lapatinib for overcoming trastuzumab resistance.

Financial: Costs will be additive to trastuzumab and chemotherapy. Current

cost of everolimus 5mg daily is £2,250/month, and lapatinib1g daily is £1,300/ month.


Pharmacology: mTOR inhibitor.

Efficacy: Final results of the placebo-controlled PIII BOLERO-3 trial (n=569) showed that adding everolimus 5mg daily to trastuzumab and vinorelbine reduced risk of disease progression by 22% (HR 0.78, p<0.01). Median time to progression was 7.0 months in the everolimus group and 5.8 months in the placebo group. All patients were resistant to trastuzumab-containing regimens and 27% were pre-treated with a lapatinib-containing regimen. Overall survival data are not yet mature.


Sorafenib oral

Nexavar

Bayer

Indication:

Breast cancer, locally advanced metastatic HER2 negative, with capecitabine – second-line.

Pharmacology:

VEGFR, PDGFR and RAF inhibitor.

Current status:

PIII.


2015




Palbociclib oral

Pfizer

Indication:

Breast cancer, advanced or metastatic – first-line.

Pharmacology:

Cyclin-dependent kinase inhibitor.

Current status:

PII.

Granted breakthrough therapy status in US.


2015

Reviews: None.




http://www.nhsc-healthhorizons.org.uk/files/downloads/1787/2194.52714e18.Everolimus.pdf




http://medicines.org.uk/


http://www.nhsc-healthhorizons.org.uk/files/downloads/1752/2166.db4b57e4.EverolimusAfinitor.pdf




http://www.nhsc-healthhorizons.org.uk/files/downloads/1632/2077.b2aabeb2.Sorafenibwithcapecitabine_breastcancer.pdf



Regorafenib oral

Stivarga

Bayer

Indication:

Gastrointestinal stromal tumours (GIST), metastatic – third-line.

Current status:

PIII.

Launched in US -see prescribing information.


2014

National guidance:

NICE: GIST - imatinib, sunitinib; not

recommended – higher-dose imatinib (after imatinib 400mg failure).

Reviews: None.

Target population: The incidence of metastatic GIST is 4 per million people. About two thirds of patients do not respond, or develop resistance, to first-line imatinib. Sunitinib is a second-line option.


Implications: Regorafenib will provide another option for patients who have failed imatinib and sunitinib.

Financial: It will be additive to other therapies. UK cost unknown but is

$9,350/month in the US. A PAS is in place in the UK for sunitinib in GIST.


Pharmacology: Multi-targeted inhibitor of angiogenic, stromal and oncogenic kinase receptors, taken once daily for 3 weeks of every 4-week cycle.

Efficacy: In the published PIII GRID study 199 patients whose disease progressed despite at least 2 prior treatments received regorafenib or placebo, in addition to best supportive care. Median progression-free survival (PFS) was 4.8 months for regorafenib vs. 0.9 months for placebo (HR 0.27, p<0.0001). PFS rates at 3 and 6 months were 60% and 38% with regorafenib vs. 11% and 0% with placebo. The disease control rate (defined as the rate of partial response (PR) plus stable disease (SD) lasting for ≥12 weeks) was 53% vs. 9%, respectively (p<0.0001). In a published PII study (n=33), the clinical benefit rate (defined as complete or PR, and SD ≥16 weeks) was 79%. Four patients achieved PR, and 22 exhibited SD ≥16 weeks. Median PFS was 10.0 months.

Safety: Severe and sometimes fatal hepatotoxicity has been reported.

Masitinib oral

Kinaction

AB Science

Indication:

Pancreatic cancer, advanced – first-line in combination with chemotherapy.

Current status:

Filed in EU Oct 2012 with orphan status.


2013

National guidance:

NICE: Pancreatic cancer – gemcitabine;

masitinib due TBC.


Target population: UK incidence of pancreatic cancer is 13 per 100,000 people; 90% have advanced disease at diagnosis and 3% survive 5 years.


Implications: Masitinib may extend life in patients with a bleak prognosis and few therapeutic options. It will be given in addition to gemcitabine, which is recommended by NICE for patients with a Karnofsky score of ≥50.

Financial: Cost of masitinib will be additive to current therapies. A test for

the prognostic genetic biomarker is being developed.


Pharmacology: Tyrosine kinase inhibitor which targets c-kit, platelet-derived growth factor receptors and fibroblast growth factor receptor 3.

Efficacy: In a PIII trial (n=348), the primary outcome of improved overall survival (OS) was not met in patients given masitinib vs. placebo, both in combination with gemcitabine (p=ns). However, masitinib increased median OS in two subgroups. In patients with a genetic biomarker (GBM) indicative of aggressive disease, median OS was 11.0 with masitinib vs. 5.0 months with placebo (0.29, p=0.00004); OS rates at 12 and 18 months were respectively, 41.4% and 18.5% for masitinib vs. 11.1% and 4.2% for placebo. In patients without the GBM, median OS in the placebo arm was 14.3 months. In patients with pain at baseline (VAS score >20mm on a 100mm scale) median OS was 8.1 months with masitinib vs. 5.4 months with placebo (0.61, p=0.01); OS rates at 12 and 18 months were respectively, 32.2% and 18.2% for masitinib vs. 17.8% and 7.8% for placebo. In patients without pain, median OS was 15.4 months for placebo.

Safety: Common adverse events in a published trial include nausea, vomiting, rash, oedema, and haematological effects.





http://publications.nice.org.uk/imatinib-for-the-treatment-of-unresectable-andor-metastatic-gastro-intestinal-stromal-tumours-ta86/guidance

http://publications.nice.org.uk/sunitinib-for-the-treatment-of-gastrointestinal-stromal-tumours-ta179






http://publications.nice.org.uk/guidance-on-the-use-of-gemcitabine-for-the-treatment-of-pancreatic-cancer-ta25


http://www.nhsc-healthhorizons.org.uk/files/downloads/1692/2134.c1079a5c.Masitinibwithgemcitabine.pdf




Doxorubicin heat-sensitive liposomes injection

ThermoDox

Celsion

Indication:

Hepatocellular carcinoma (HCC), inoperable – first-line.

Current status:


PIII in US with orphan and fast track status.


2014

National guidance:

NICE: HCC - radiofrequency ablation,

microwave ablation, sorafenib not recommended.


Target population: UK incidence of HCC is 6 per 100,000 people. Potentially curative options are surgery (suitable for <25%) and microwave or radiofrequency ablation (RFA). 90% present with unresectable disease and 2-year survival rates are 8-50%; chemo-embolisation (chemotherapy delivered via the hepatic artery) is an option for some but systemic chemotherapy has limited benefits.


Implications: For patients with limited treatment options, ThermoDox offers the possibility of greater efficacy and fewer systemic adverse effects than standard chemotherapy because of the combined effects of targeted cytotoxicity and ablation. Sorafenib is licensed for advanced HCC but not recommended by NICE. Mitozantrone is also used in the palliation of non-resectable primary hepatocellular carcinoma.

Financial: Likely to be more expensive than standard options.


Pharmacology: A heat-activated liposomal formulation of doxorubicin, which is released when the tumour site is heated by microwave or radiofrequency ablation (RFA) to 39-42

oC. Given by 30 minute infusion, started 15 minutes prior to ablation.

Efficacy: In the PIII HEAT trial (n=700), ThermoDox in combination with RFA vs. RFA alone did not improve progression-free survival (PFS). However, post-hoc analysis showed ThermoDox improved PFS and overall survival in 300 patients who had optimal RFA lasting ≥45 minutes, regardless of HCC lesion size.

Safety: Pre-medication is required to minimise infusion-related reactions.

Ramucirumab injection

Eli Lilly

Indication:

Hepatocellular carcinoma (HCC), advanced – second-line.

Pharmacology: Vascular endothelial growth factor receptor-2 antagonist.

Current status:



2015

Reviews: None.



Sorafenib oral

Nexavar

Bayer

Indication:

Hepatocellular carcinoma - adjuvant therapy.

Pharmacology:

VEGFR, PDGFR and RAF inhibitor.

Current status:

PIII with orphan status in EU and US and fast track in US.


2015




negotiated.

Regorafenib oral

Stivarga

Bayer

Indication:

Colorectal cancer (CRC), metastatic disease – third- or fourth-line.

Current status:

Recommended for approval in EU Jun 2013.



2013

National guidance:

NICE: CRC: pathway, quality standard;

regorafenib (suspended); not recommended - bevacizumab, cetuximab, panitumumab.

SIGN: CRC.


Target population: UK incidence of CRC is

67 per 100,000 people. 20-55% of patients present with metastatic disease. Management is mainly palliative with surgery and chemo/radiotherapy for symptom control.


Implications: For patients with no further treatment options, regorafenib may

delay disease progression and improve quality of life.

Financial: Regorafenib will be additive to other therapies. UK cost is unknown but US cost is $9,350/month. A PAS is in place for cetuximab as first-line therapy for CRC in the UK.


Pharmacology: Multi-targeted inhibitor of angiogenic, stromal and oncogenic kinase receptors, taken once daily for 3 weeks

of every 4-week cycle.

Efficacy: The published PIII CORRECT study, in 753 adults with metastatic CRC that had progressed after receiving all approved drugs for CRC, was stopped early after meeting its primary outcome. Median overall survival was 6.4 months in patients randomised to regorafenib plus best supportive care (BSC) vs. 5.0 months for placebo plus BSC (HR 0.77, p=0.0052). Median progression-free survival was 1.9 vs. 1.7 months, respectively (0.49, p<0.0001). The on-going expanded-access PIII CONSIGN study is designed to collect safety data.

Safety: Severe and sometimes fatal hepatotoxicity has been reported.




http://www.nice.org.uk/IPG2

http://publications.nice.org.uk/microwave-ablation-of-hepatocellular-carcinoma-ipg214

http://publications.nice.org.uk/sorafenib-for-the-treatment-of-advanced-hepatocellular-carcinoma-ta189

http://www.nhsc-healthhorizons.org.uk/files/downloads/1690/2132.ef5e9c57.HeatactivatedliposomeencapsulateddoxorubicinThermoDox.pdf




http://www.nhsc-healthhorizons.org.uk/files/downloads/1631/2076.ad9851a4.Sorafenib_hepatocellularcarcinoma.pdf






http://pathways.nice.org.uk/pathways/colorectal-cancer


http://guidance.nice.org.uk/TAG/358

http://publications.nice.org.uk/cetuximab-bevacizumab-and-panitumumab-for-the-treatment-of-metastatic-colorectal-cancer-after-ta242

http://publications.nice.org.uk/cetuximab-bevacizumab-and-panitumumab-for-the-treatment-of-metastatic-colorectal-cancer-after-ta242


http://www.nhsc-healthhorizons.org.uk/files/downloads/1630/2075.58eb294f.Regorafenib.pdf





Sorafenib oral

Nexavar

Bayer

Indication:

Renal cell carcinoma (RCC) - adjuvant therapy.

Current status:



2014/2015

National guidance:

NICE: Urological cancer; pazopanib,

sunitinib (first-line advanced); not recommended – bevacizumab, sorafenib, sunitinib (second-line) and temsirolimus.

Reviews: None.

Target population: UK incidence of RCC is

12 per 100,000 people. Patients with stage 1 (39%) and 2 (16%) RCC, and some with stage 3 (26%), are candidates for surgery. Five-year survival ranges from 40-90% in stage 1-3 disease, and 10% in stage 4.


Implications: RCC recurs in 30% of patients undergoing nephrectomy for

localised disease. Sorafenib may delay development of metastatic disease, which responds to targeted therapies, such as sorafenib and sunitinib, but not to chemotherapy.

Financial: Cost of sorafenib 400mg twice daily is £2,980/month.


negotiated.

Pharmacology: Blocks Raf and tyrosine kinases, vascular endothelial and platelet derived growth factor receptors.

Efficacy: Adjuvant sorafenib in patients who have undergone partial or radical nephrectomy, at high or intermediate risk of relapse, is being studied in two PIII trials. SORCE is a placebo-controlled trial in 1,656 patients treated for 1 or 3 years; ASSURE (n=1,923) will compare sorafenib with sunitinib or placebo for 1 year. Results are expected in 2013 and 2016, respectively. In a published trial, overall recurrence rate was 15.0% in patients receiving sorafenib (n=20), 17.4% in patients given sunitinib (n=23) and 38.7% in those receiving no adjuvant therapy (n=388, p<0.05 vs. treatment groups). Disease-free survival was 18.9 months, 16.9 months and 13.3 months, respectively (p<0.05 vs. treatment groups).


Apaziquone intravesical

Neoquin

Spectrum

Indication:

Bladder cancer, non-

muscle invasive (NMIBC), in patients at low or intermediate risk of progression.

Current status:

PIII in EU.

PIII in the US with fast track status.


2014/2015

National guidance:

NICE: Urological cancer, bladder cancer

due 2014.

SIGN: Bladder cancer.

Reviews: None.

Target population: UK incidence of NMIBC is about 13 per 100,000 people. After surgery, intravesical chemotherapy reduces risk of recurrence at 1 year by up to 44% (depending on the number of doses).


Implications: Apaziquone will be an alternative to intravesical mitomycin, epirubin and doxorubicin in patients at low or intermediate risk of progression. BCG vaccine is used in high-risk patients.

Financial: Apaziquone may displace current options.


Pharmacology: An indoloquinone mitomycin analogue prodrug metabolised to an alkylating agent by the DT-diaphorase enzyme, which is over-expressed by bladder cancer cells.

Efficacy: Two PIII trials (SPI-611 and SPI-612) each recruiting 800 patients have investigated use of a single dose of

apaziquone following transurethral resection of bladder tumours. Individually they did not meet their primary outcomes but pooled analysis showed apaziquone reduced the rate of tumour recurrence at 2 years (p=0.017). In a published PII study of 46 patients who underwent surgical excision of all but one superficial lesion, 67% had complete histological disappearance of the remaining lesion 2-4 weeks after 6 once-weekly instillations of apaziquone. After 24 months, 50% of responders were recurrence-free, with a median response duration of 18 months. Overall recurrence-free survival was 39%. Two ongoing placebo-controlled PIII studies (SPI-1011 and SPI-1012) are investigating 6-weekly instillations.

Safety: Adverse effects include cystitis, dysuria, haematuria and abdominal pain.


http://guidance.nice.org.uk/CSGUC

http://publications.nice.org.uk/pazopanib-for-the-first-line-treatment-of-advanced-renal-cell-carcinoma-ta215

http://publications.nice.org.uk/sunitinib-for-the-first-line-treatment-of-advanced-andor-metastatic-renal-cell-carcinoma-ta169

http://publications.nice.org.uk/bevacizumab-first-line-sorafenib-first--and-second-line-sunitinib-second-line-and-ta178








http://guidance.nice.org.uk/CSGUC

http://guidance.nice.org.uk/CG/Wave0/600








Sipuleucel-T injection

Provenge

Dendreon

Indication:

Prostate cancer (PC),

metastatic castration-resistant – first-line.

Current status:


Launched in US – see prescribing information.


2013

National guidance:

NICE: PC pathway; docetaxel,

sipuleucel-T due Feb 2014.


Target population: In the UK, the incidence

of PC is 134 per 100,000 men. 55-65% develop metastatic disease and over 90% become resistant to standard hormonal therapy (castration-resistant).


Implications: Sipuleucel-T will compete with docetaxel and first-line

abiraterone acetate. It may prolong survival and have improved tolerability over existing therapies.

Financial: Cost in the US is $93,000 for 3 doses.


Pharmacology: First personalised therapeutic vaccine that stimulates a T-cell response against prostatic acid phosphatase, an antigen expressed in most PCs but not in non-prostate tissue. Given by i.v. infusion every 2 weeks for 3 doses.

Efficacy: In published PIII trials, patients had leukapheresis followed 3 days later by infusion of sipuleucel-T or control (autologous peripheral blood mononuclear cells that had not been activated). In the IMPACT study (n=512), median overall survival (OS) was 25.8 months for sipuleucel-T vs. 21.7 months for control (HR 0.78, p=0.03). Median time to objective disease progression (TTP) was 14.6 weeks vs. 14.4 weeks, respectively (p=ns). In the D9901 study (n=127), median TTP for sipuleucel-T was 11.7 weeks vs. 10.0 weeks for placebo (1.45, p=0.052) and median OS was 25.9 months and 21.4 months, respectively (1.7, p=0.01). In a meta-analysis of 3 trials (n=737), median OS of patients who received sipuleucel-T vs. the control group was longer (0.73, p=0.001) but median TTP was not (p=ns).

Safety: Pre-medication is required to prevent acute infusion reactions (commonly chills, fever and fatigue).

Ipilimumab injection

Yervoy


Indication:

Prostate cancer (PC), metastatic castration-resistant – second-line.

Current status:

PIII.


2014

National guidance:

NICE: PC pathway; abiraterone,

docetaxel, enzalutamide due Feb 14; not recommended – cabazitaxel.


Target population: UK incidence of PC is 134 per 100,000 men. 55-65% develop metastases and >90% become resistant to hormonal therapy (castration-resistant). About 40% of these men receive first-line therapy (NICE recommends docetaxel), and of these about 75% may receive second-line therapy (24 per 100,000 men).


Implications: Second-line treatments include abiraterone, cabazitaxel and enzalutamide. Ipilimumab may provide an additional treatment option for patients with a poor prognosis.

Financial: Ipilimumab costs £52,500 per dose for a 70kg person. A PAS is in place for second-line abiraterone.


Pharmacology: Anti-CTLA-4 monoclonal antibody given by i.v. infusion every 3 weeks for 4 doses, then 3-monthly.

Efficacy: A placebo-controlled PIII trial is assessing the effect of ipilimumab monotherapy following radiotherapy on overall survival in 800 men previously treated with docetaxel. Data are due soon. In a PII trial (n=24), decreases in serum prostate-specific antigen (PSA) levels of >50% were seen in 12.5% of patients treated with ipilimumab. One patient had a confirmed response lasting 246 days, one had a response of ≥79 days, and a third had an unconfirmed response.


Custirsen injection

OncoGenex

Indication:

Prostate cancer, metastatic castration-resistant, first/second-line.

Pharmacology:

Clusterin inhibitor.

Current status:

PIII in EU.

PIII in US with fast track status.


2015

Reviews: None.



negotiated.




http://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/UCM210031.pdf

http://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/UCM210031.pdf

http://pathways.nice.org.uk/pathways/prostate-cancer

http://publications.nice.org.uk/docetaxel-for-the-treatment-of-hormone-refractory-metastatic-prostate-cancer-ta101


http://www.nhsc-healthhorizons.org.uk/files/downloads/1565/2024.b293d3d0.SipuleucelTProvenge.pdf






http://publications.nice.org.uk/abiraterone-for-castration-resistant-metastatic-prostate-cancer-previously-treated-with-a-ta259

http://publications.nice.org.uk/docetaxel-for-the-treatment-of-hormone-refractory-metastatic-prostate-cancer-ta101


http://publications.nice.org.uk/cabazitaxel-for-hormone-refractory-metastatic-prostate-cancer-previously-treated-with-a-ta255

http://www.nhsc-healthhorizons.org.uk/files/downloads/1691/2133.d5a594f1.IpilimumabYervoy.pdf






Cabozantinib oral

Cometriq

Exelixis

Indication:

Prostate cancer,

castration-resistant – third-line.

Pharmacology:

MET, RET and VEGFR2 inhibitor.

Current status:

PIII.


2015

Reviews: None



Radium-223 chloride injection

Alpharadin

Bayer

Indication:

Prostate cancer (PC), castration-resistant (patients with bone metastases).

Current status:


Licensed in US after priority review. See US prescribing information.


2013

National guidance:

NICE: PC pathway, denosumab

(metastases in PC) due TBC, radium-223 due Feb 2014, denosumab (in solid tumours other than prostate).


Target population: UK incidence of PC is 134 per 100,000 men. 55-65% develop metastases and >90% become resistant to standard hormonal therapy (castration-resistant). Over 90% with advanced disease develop bone metastases which can lead to fractures, uncontrollable bone pain and spinal cord compression.


Implications: Radium-233 could improve quality of life and delay disease progression. It is potentially an alternative/additive option to palliative therapies.

Financial: Cost is unknown but may displace other therapies.


Pharmacology: A first-in-class radiopharmaceutical that targets bone metastases. Given i.v. monthly for up to 6 cycles.

Efficacy: The published PIII ALSYMPCA study (n=921) was stopped early after meeting its primary outcome. Median overall survival (OS) was 14.9 months in the radium-223 group vs. 11.3 months for placebo (HR 0.7, p<0.0001). Radium-223 delayed median time to first skeletal-related event vs. placebo (15.6 vs. 9.8 months, respectively, HR 0.66, p<0.001). In a published PII study (n=64), median change in alkaline phosphatase was -65.6% in the radium-223 group vs. 9.3% in the placebo group (p<0.001); median OS was 16.3 months vs. 11.6 months (p=0.066). In a published PII study (n=100), pain was significantly reduced at 8 weeks in 56% of men given a single dose of radium-223.

Safety: Most common adverse effects are nausea, diarrhoea, vomiting, peripheral oedema and anaemia.

Pazopanib oral

Votrient

GlaxoSmith-Kline

Indication:

Ovarian cancer (OC) – maintenance after first-line chemotherapy.

Current status:

Filed in EU Aug 2013.


2014

National guidance:

NICE: OC pathway, quality standard;

first-line – paclitaxel; not recommended – bevacizumab.

SIGN: Ovarian cancer.


Target population: UK incidence of OC is

21 per 100,000 people. Most women have advanced disease and 75% receive first-line platinum chemotherapy; between 70 and 80% respond (11-13 per 100,000). Of these 55-75% relapse within 2 years.


Implications: Pazopanib will be used in addition to current therapies but

may delay need for second-line chemotherapy.

Financial: Cost of pazopanib 800mg daily is £2,200/month.


Pharmacology: Multi-targeted tyrosine kinase receptor inhibitor.

Efficacy: In a PIII trial (n=940) assessing the effect of pazopanib monotherapy for 2 years in OC (91% advanced disease), that has not progressed after first-line chemotherapy, median progression-free survival (PFS) was 17.9 months with pazopanib vs. 12.3 months with placebo (HR 0.77, p=0.0021). Overall survival data are immature. In a published PII trial (n=36) with pazopanib monotherapy, 31% of patients achieved the primary outcome of ≥50% decrease in cancer antigen-125 levels. Stable disease was seen in 56% of patients, with median duration of 80 days. At 6 months, 17% remained progression-free.












http://publications.nice.org.uk/denosumab-for-the-prevention-of-skeletal-related-events-in-adults-with-bone-metastases-from-solid-ta265





http://pathways.nice.org.uk/pathways/ovarian-cancer

http://www.nice.org.uk/guidance/qualitystandards/ovariancancer/home.jsp

http://publications.nice.org.uk/guidance-on-the-use-of-paclitaxel-in-the-treatment-of-ovarian-cancer-ta55

http://publications.nice.org.uk/bevacizumab-in-combination-with-paclitaxel-and-carboplatin-for-first-line-treatment-of-advanced-ta284


http://www.nhsc-healthhorizons.org.uk/files/downloads/1558/2017.048feb4e.PazopanibVotrient.pdf





Paclitaxel injection

Paclical

Oasmia

Indication:

Ovarian cancer (OC),

platinum-sensitive or partially platinum-sensitive – second- or third-line.

Current status:



2014

National guidance:

NICE: As for pazopanib above plus OC

recurrent, advanced – paclitaxel, pegylated liposomal doxorubicin and topotecan; not recommended – bevacizumab, trabectedin.



Target population: As for pazopanib above.


Implications: Compared to current formulations, Paclical may cause fewer adverse effects, requires no pre-medication and may allow higher doses.

Financial: Cost unknown but will displace other taxanes. Cost of currently available paclitaxel is £3,600 for six cycles (body surface area of 1.7m

2).


negotiated.

Pharmacology: A new formulation of paclitaxel encapsulated to increase its water solubility, removing the need for solvents

which can cause hypersensitivity reactions. Given by i.v infusion every 3 weeks for 6 cycles.

Efficacy: The PIII OAS-07OVA trial is comparing Paclical (250mg/m2) with Taxol (175mg/m

2), both in combination with

carboplatin, in 790 women with OC who have relapsed more than 6 months after first- or second-line chemotherapy. The final patient was treated in early 2013. Interim analysis indicates Paclical reduces levels of the biomarker, cancer antigen-125 (CA-125), to similar levels as Taxol.

Safety: Requires no pre-medication.

Vintafolide injection

Vynfinit

MSD

Indication:

Ovarian cancer (OC), advanced platinum-resistant, folate receptor (FR)-positive – second-line.

Current status:

Filed in EU Nov 2012 with orphan status.


2014

National guidance:

NICE: As for paclitaxel above plus

vintafolide due Jul 2014.



Target population: As for pazopanib above. Between 90 and 100% of tumours are FR-positive.


Implications: Vintafolide added to doxorubicin will provide a more targeted treatment for patients whose disease recurs within 6 months of chemotherapy. They are unlikely to respond to further platinum therapy and have few options, with 10-40% responding to non-platinum agents.

Financial: Likely to be expensive. Cost of the radiopharmaceutical diagnostic test technetium Tc99m etarfolatide is unknown.


Pharmacology: Vinca alkaloid conjugated to a folate molecule. It enters tumour cells via the folate receptor, which is over-expressed by most OC tumour cells. Given as an i.v. infusion in combination with pegylated liposomal doxorubicin (PLD).

Efficacy: The PII PRECEDENT study involved 162 women who had relapsed within 6 months of platinum chemotherapy. Progression-free survival (PFS) was 21.7 weeks in those on vintafolide plus PLD and 11.7 weeks in those on PLD alone (HR 0.63, p=0.03). PFS in patients with at least one FR-positive tumour site was 24.6 weeks in the vintafolide plus PLD group vs. 7.6 weeks in the PLD only group (0.6, p=0.04); in patients in whom all tumour sites were FR-positive it was 24.0 vs. 6.6 weeks, respectively (0.4, p<0.02). The PIII PROCEED trial (n=640) is similar in design with results due in 2014.

Safety: Adverse effects include neutropenia, anaemia, fatigue and hand/foot syndrome.

Bevacizumab injection

Avastin

Roche

Indication:

Ovarian cancer (OC), advanced platinum-resistant – second-line in combination.

Current status:

PIII.


2014

National guidance:

NICE: As for vintafolide above.



Target population: As for pazopanib above. Most patients receive platinum chemotherapy a second or third time before developing resistance.


Implications: Bevacizumab will be used in addition to current chemotherapies and may delay disease progression.

Financial: Current cost of 10 doses (15mg/kg) for a 65kg woman is £23,000.


negotiated.

Pharmacology: Vascular endothelial growth factor antagonist given by i.v. infusion every 3 weeks.

Efficacy: In the PIII AURELIA trial, 361 women were randomised to chemotherapy (liposomal doxorubicin, paclitaxel or

topotecan) alone or with bevacizumab (10mg/kg every 2 weeks or 15mg/kg every 3 weeks) until progression. Median progression-free survival (PFS) was 6.7 months in the bevacizumab group and 3.4 months in the control group (HR 0.48, p<0.001). The objective response rate was 30.9% vs. 12.6%, respectively (p=0.001).

Safety: See medicines.org.uk. Gastrointestinal perforations and fistulas occurred in 2% of women receiving bevacizumab

plus chemotherapy and in none of the control group.


http://publications.nice.org.uk/paclitaxel-pegylated-liposomal-doxorubicin-hydrochloride-and-topotecan-for-second-line-or-ta91



http://publications.nice.org.uk/bevacizumab-in-combination-with-gemcitabine-and-carboplatin-for-treating-the-first-recurrence-of-ta285

http://publications.nice.org.uk/trabectedin-for-the-treatment-of-relapsed-ovarian-cancer-ta222


http://www.nhsc-healthhorizons.org.uk/files/downloads/1693/2135.ccea1945.PaclitaxelPaclical.pdf





http://www.nhsc-healthhorizons.org.uk/files/downloads/1688/2130.9bd33474.EC145.pdf





http://www.hsc.nihr.ac.uk/files/downloads/1988/2337.95d74634.Bevacizumab_Jan13.pdf




Olaparib oral

AstraZeneca

Indication:

Ovarian cancer, relapsed,

platinum-sensitive, gBRCAm positive.

Pharmacology:

PARP enzyme inhibitor.

Current status:

PII with orphan status in EU.


2015




Trebananib injection

Amgen

Indication:

Epithelial ovarian, fallopian tube or primary peritoneal cancer, recurrent disease.

Pharmacology:

Angiopoietin-1 and 2 inhibitor.

Current status:

PIII.


2015




Eribulin injection

Halaven

Eisai

Indication:

Soft tissue sarcoma, advanced – third-line.

Pharmacology:

Synthetic analogue of halichondrin B, with tubulin-based antimitotic activity.

Current status:

PIII with orphan status in US.


2015

Reviews: None.




Yervoy


Indication:

Malignant melanoma, resected high-risk stage III – first-line adjuvant therapy.

Current status:

PIII.


2014

National guidance:

NICE: Skin tumours, melanoma due Apr

2015.

SIGN: Cutaneous melanoma.


Target population: UK incidence of malignant melanoma is about 21 per 100,000 people, and is doubling every 10-20 years. 7% of 15-64 year olds present with advanced (III/IV) disease compared with 20% aged ≥65.


Implications: There is currently no standard adjuvant therapy. Interferon is of uncertain benefit and causes significant toxicity. Ipilimumab given after surgery may prevent melanoma recurrence.

Financial: Ipilimumab costs £52,500 per dose for a 70kg person.



Efficacy: A placebo-controlled PIII study is investigating the efficacy of ipilimumab in 950 adults with confirmed lymph node metastases, who have undergone complete resection of stage III melanoma. The primary outcome is recurrence-free survival and initial results are expected in 2013 or 2014. In a published PII trial (n=75), 56% of patients with stage III or IV melanoma given adjuvant ipilimumab were relapse-free and 86% alive at 2 years. An on-going PIII study is comparing adjuvant ipilimumab with high-dose interferon alfa-2b.



http://www.hsc.nihr.ac.uk/files/downloads/2075/2403.b418bc7c.Olaparib.pdf


http://www.hsc.nihr.ac.uk/files/downloads/1991/2340.06352fc0.Trebananib_Jan13.pdf



http://guidance.nice.org.uk/CSGSTIM



http://www.hsc.nihr.ac.uk/files/downloads/1838/2225.89ffe025.Ipilimumab_June12.pdf






Dabrafenib oral

Tafinlar

GlaxoSmith-Kline

Indication:

Malignant melanoma,

unresectable or metastatic BRAF

V600E-positive – first-

line.

Current status:


Licensed in US -see prescribing information.


2013

National guidance:

NICE: As for ipilimumab above plus

dabrafenib due TBC, vemurafenib, ipilimumab (first-line) due Jun 2014.



Target population: As for ipilimumab above. About 50% are BRAF

V600-positive (80-90%

V600E and 10-20% V600K) which is associated with increased tumour aggressiveness.


Implications: Dabrafenib will compete with vemurafenib, providing an alternative to i.v. dacarbazine which has a low response rate. A test is needed to identify BRAF

V600E-positive patients.

Financial: Likely to be similarly priced to vemurafenib (£7,000 per month).


Pharmacology: BRAFV600E

kinase inhibitor taken twice daily.

Efficacy: In the published BREAK-3 trial, 250 adults with previously untreated, stage IV or unresectable stage III BRAFV600E

-positive melanoma were randomised to dabrafenib or 3-weekly cycles of i.v. dacarbazine. Median PFS was 5.1 months for dabrafenib vs. 2.7 months for dacarbazine; dabrafenib reduced risk of disease progression or death by 70% (HR 0.30, p<0.0001). There was no difference in overall survival (HR 0.61) but data are immature. 50% of patients on dabrafenib had a confirmed objective response vs. 6% on dacarbazine.

Safety: Photosensitivity, which is common with vemurafenib, occurs rarely with dabrafenib.


Yervoy


Indication:

Malignant melanoma, unresectable or metastatic – first-line with dacarbazine.

Current status:

PIII in EU.



2014/2015

National guidance:


vemurafenib, ipilimumab (first-line) due Jun 2014, dabrafenib due TBC.



Target population: As for ipilimumab above.


Implications: A therapeutic option for patients whose tumours do not have

BRAF mutations, which may improve response rates and survival when added to current first-line standard of care (dacarbazine).

Financial: Ipilimumab costs £52,500 per dose for a 70kg person.


negotiated.


Efficacy: In the published 024 study, 502 patients were randomised to receive dacarbazine with or without ipilimumab.

Median overall survival (OS) in the ipilimumab plus dacarbazine group was 11.2 months vs. 9.1 months in the dacarbazine alone group (HR 0.72, p<0.001). OS rates at 1 year were 47.3% vs. 36.3%, at 2 years were 28.5% vs. 17.9%, and at 3 years were 20.8% vs. 12.2%, respectively (0.72, p<0.001). There was a 24% reduction in risk of progression in the ipilimumab plus dacarbazine group vs. the dacarbazine group (0.76, p=0.006).






http://www.nice.org.uk/nicemedia/live/14005/61877/61877.pdf

http://guidance.nice.org.uk/TA/WaveCRS2/49


http://www.nhsc-healthhorizons.org.uk/files/downloads/1629/2074.674f3130.GSK2118436.pdf












Trametinib oral

Mekinist

GlaxoSmith-Kline

Indication:

Malignant melanoma,

unresectable or metastatic BRAF

V600-positive – first-or

second-line monotherapy and first-line in combination with dabrafenib.

Current status:

Filed in EU Feb 2013. Monotherapy is licensed in US -see prescribing information. Combination therapy filed in US Jul 2013.


2014

National guidance:


ipilimumab (second-line), vemurafenib, dabrafenib due TBC, ipilimumab (first-line) due Jun 2014.


Reviews: NIHR HSC (monotherapy) Aug 2011, NIHR HSC (combination therapy) Sep 2012.

Target population: As for dabrafenib above. About 50% of patients progress within about 6 months of starting a BRAF or MEK inhibitor.


Implications: Trametinib, like dabrafenib and vemurafenib, are alternatives to i.v. dacarbazine which has a response rate of 5-15% and improves progression-free survival (PFS) by only a few months. A test is needed to identify BRAF

V600-positive patients. Combination therapy offers the possibility

of improved survival and better tolerability.

Financial: US cost of trametinib is $8,700/month.


negotiated.

Pharmacology: A mitogen-activated extracellular signal regulated kinase-1 (MEK) inhibitor taken once daily. Use in

combination with twice-daily dabrafenib overcomes resistance to BRAF inhibition associated with reactivation of MEK.

Efficacy: Results from the published PIII METRIC study (n=322) show trametinib monotherapy increased PFS and overall survival (OS) at 6 months vs. chemotherapy (dacarbazine or paclitaxel). Median PFS was 4.8 months vs. 1.5 months, respectively (HR 0.45, p<0.001); respective OS rates were 81% and 67% (0.54, p=0.01, NNT 7). A published PII study showed patients previously treated with a BRAF inhibitor (n=40) were unresponsive to trametinib monotherapy, unlike BRAF inhibitor-naïve patients (n=57); median PFS was 1.8 months and 4.0 months, respectively. In a published PII trial (n=162) of dabrafenib-trametinib combination therapy, median PFS was 9.4 months vs. 5.8 months in patients given dabrafenib alone (0.39, p<0.001); objective response rates were 76% and 54%, respectively (p=0.03). 41% of patients were alive and progression-free at 1 year vs. 9% (p<0.001, NNT 3). PIII trials are comparing trametinib plus dabrafenib with vemurafenib (COMBI-v; n=694) or dabrafenib (COMBI-d; n=340) alone; initial results are expected in 2014.

Safety: Dose-limiting skin adverse effects occur less frequently with combination therapy, but the rate of pyrexia is higher.

Talimogene laherparepvec injection

Amgen

Indication:

Malignant melanoma,

unresectable or metastatic.

Pharmacology:

Oncolytic virus immunostimulant.

Current status:

PIII.


2015




Cobimetinib

oral

Roche

Indication:

Malignant melanoma, metastatic, BRAF positive, with vemurafenib – first-line.

Pharmacology:

MEK inhibitor.

Current status:

PIII.


2015

Reviews: None.

Likely commissioning route: NHSE


Erismodegib oral

Novartis

Indication:

Basal cell carcinoma, locally advanced or metastatic.

Pharmacology:

Smoothened (Smo) inhibitor.

Current status:

PII.


2015









http://publications.nice.org.uk/ipilimumab-for-previously-treated-advanced-unresectable-or-metastatic-melanoma-ta268





http://www.nhsc-healthhorizons.org.uk/files/downloads/1628/2073.1b7c02e2.GSK1120212.pdf

http://www.hsc.nihr.ac.uk/files/downloads/1924/2284.e96e4020.Trametinib_Sept12.pdf










http://www.hsc.nihr.ac.uk/files/downloads/1989/2338.97d616b8.Erismodegib_Jan13.pdf


Rituximab injection

MabThera

Roche

Indication:

Non-Hodgkin's lymphoma (NHL) - s.c. formulation.

Current status:



2013

National guidance:

NICE: NHL - rituximab (follicular, first-

line), rituximab (follicular maintenance). Reviews: None.

Target population: All patients with NHL for whom i.v. rituximab is currently indicated. Those with poor venous access may be initial candidates.


Implications: Availability of s.c. formulation could reduce outpatient preparation and administration time and may facilitate homecare delivery. Biosimilar i.v. formulations of rituximab are likely to be available in 2015.

Financial: Likely to be the same cost as the current i.v. formulation but future

availability of biosimilar i.v. formulations may affect pricing strategy.


Pharmacology: Anti-CD20 monoclonal antibody plus recombinant human hyaluronidase for s.c. administration.

Efficacy: The PIII SABRINA open-label study assessed s.c. vs. i.v. administration of rituximab in 530 patients with follicular NHL receiving induction and maintenance therapy. The stage 1 primary outcome of non-inferiority of the Ctrough,SC:Ctrough,IV ratio at cycle 7 of induction was met and analysis showed similar investigator-assessed overall response rates (84.4% for i.v. vs. 90.5% for s.c.). Stage 2 of the trial is on-going and will assess overall survival.

Safety: See medicines.org.uk. Injection site reactions are possible.

Benda-mustine injection

Levact

Napp

Indication:

Non-Hodgkin’s lymphoma (NHL), advanced low-

grade - first-line with rituximab.

Current status:

Filed in EU.

Filed in US Dec 2011 but additional data requested in Oct 2012.


2013

National guidance:

NICE: As for rituximab above plus NHL-

bendamustine first-line due Jul 2014.

Reviews: LCNDG Apr 2013.

Target population: The UK incidence of NHL is about 20 per 100,000 people and about 40% present with indolent (low-grade) disease, usually advanced (stage III or IV).


Implications: Bendamustine could be used instead of standard chemotherapy regimens which have more adverse effects.

Financial: Bendamustine is currently licensed for second-line use in NHL.

Cost of a 12-dose course is about £6,500.


Pharmacology: An alkylating agent with antimetabolite activity, given by i.v. infusion for up to six cycles.

Efficacy: In the published PIII non-inferiority StiL trial, 549 patients newly diagnosed with stage III or IV indolent or mantle-cell lymphoma were randomised to bendamustine or standard therapy. At median follow-up of 45 months, median PFS was 69.5 months for bendamustine vs. 31.2 months for standard therapy (HR 0.58, p<0.0001). In the ongoing PIII BRIGHT study (n=477) bendamustine was non-inferior to standard therapy for complete response rate (31% vs. 25%, p<0.03).

Safety: See medicines.org.uk. In the StiL trial bendamustine resulted in lower rates of alopecia, haematological toxicity, infections, peripheral neuropathy and stomatitis than standard therapy (all p<0.003) but skin reactions were more common.

Dasiprotimut-T injection

BiovaxID

Biovest International

Indication:

Non-Hodgkin’s lymphoma (NHL), low-grade follicular disease.

Current status:

PIII with orphan status and plans to file in EU in 2013. Available on compassionate use basis. Fast track status in US.


2014

National guidance:

As for rituximab above.


Target population: The UK incidence of follicular NHL is 5-7 per 100,000 and most present with stage III or IV disease. These patients are considered for chemotherapy and will be eligible for this vaccine if they have prolonged remission.


Implications: The company believes dasiprotimut-T may eliminate the risk of rituximab resistance and increase utility of other therapies. A subgroup of patients with the IgM isotype may be more responsive to treatment; US authorities have requested additional data to confirm this.

Financial: Additive to current options after first-line treatment but may delay need for other therapies.

Likely commissioning route: NHSE. PbR: Uncertain.

Pharmacology: An autologous vaccine consisting of a conjugated lymphoma-associated antigen given about 6 months after chemotherapy. Five s.c. injections are given over a 6 month period. Booster vaccination may be required after 3 years.

Efficacy: In the prematurely closed PIII BV301 trial 117 patients who maintained a complete response to initial chemotherapy were given dasiprotimut-T or control vaccine. Median disease-free survival was 30.6 vs. 17 months, respectively (p<0.05). At 36 months, 61% of patients on dasiprotimut-T were disease-free vs. 37% of control patients (NNT=4). These data, together with data from two long-term PII trials will be used in the EU licence application. In another PIII study, in 35 IgM-positive patients given dasiprotimut-T made with IgM isotype, 5-year tumour-free rates were 42% vs.11% in patients receiving control vaccine (NNT=3). Median time to relapse was 52.9 vs. 28.7 months, respectively (HR 0.34, p=0.002).

Safety: To date no serious adverse effects have been reported.


http://publications.nice.org.uk/rituximab-for-the-first-line-treatment-of-stage-iii-iv-follicular-lymphoma-ta243

http://publications.nice.org.uk/rituximab-for-the-first-line-treatment-of-stage-iii-iv-follicular-lymphoma-ta243



http://www.emc.medicines.org.uk/




http://www.medicinesresources.nhs.uk/upload/documents/Communities/London_CNDG/Bendamustine%20with%20rituximab.pdf


http://clinicaltrials.gov/ct2/show/NCT00877006?term=BRIGHT&intr=bendamustine&rank=1

http://emc.medicines.org.uk/



Bortezomib injection

Velcade

Janssen-Cilag

Indication:

Multiple myeloma (MM),

relapsed or progressive disease - combined with dexamethasone or pegylated doxorubicin.

Current status:

Filed in EU Oct 2012.


2013

National guidance:

NICE: MM - bortezomib (monotherapy,

relapsed), lenalidomide (after at least one prior therapy).


Target population: The UK incidence of MM is about 8 per 100,000 and prevalence is about 16 per 100,000 people. Of these, 39% have relapsed MM and of these 65% will have received 2 or more prior therapies. Patients typically relapse 3 or 4 times before developing treatment resistance.


Implications: Current options in this setting include bortezomib monotherapy and lenalidomide plus dexamethasone. This licence extension will provide further options with the possibility of delaying disease progression further.

Financial: Cost of 32 doses (8 cycles) is about £24,000.


Pharmacology: A proteasome inhibitor given by i.v. injection.

Efficacy: In a published PIII study bortezomib plus pegylated liposomal doxorubicin (PLD) was compared with bortezomib monotherapy in 646 patients. Interim data show the primary outcome of median time to progression was 6.5 months for bortezomib vs. 9.3 months with PLD plus bortezomib (HR 1.82, p<0.001). The 15-month survival rate was 65% vs. 76%, respectively (p=0.03) and overall response rate was 41% vs. 44%, respectively (p=ns).


Carfilzomib injection

Kyprolis

Onyx

Indication:

Multiple myeloma (MM), relapsed and refractory – third-line.

Current status:

PIII in EU with orphan status and plans to file 2013.



2014

National guidance:

NICE: As for bortezomib above.


Target population: As for pomalidomide above. The majority of patients are expected to receive third-line therapy.


Implications: US indication is monotherapy use in relapsed MM after at least 2 prior therapies; this is likely to be the initial indication in the EU. There is currently no standard third-line option in the UK.

Financial: US cost is $10,000 per cycle for an average patient, making it the most expensive drug in the US for MM.


Pharmacology: Second generation selective and irreversible proteasome inhibitor, first-in-class.

Efficacy: The US licence is based on a published PII single-arm study in 266 patients with a median of 5 prior therapies, including bortezomib, lenalidomide, and thalidomide. The overall response rate was 23.7%. Median overall survival, a secondary outcome, was 15.6 months. The ongoing PIII FOCUS study compares carfilzomib with best supportive care after treatment with at least 3 prior therapies. The primary outcome is overall survival. Comparative studies with bortezomib (ENDEAVOR) and in combination with lenalidomide and dexamethasone (ASPIRE) are ongoing.

Safety: Adverse effects are similar to other proteasome inhibitors but low rates of peripheral neuropathy have been reported.

Daratumumab injection

Janssen-Cilag

Indication:

Multiple myeloma, recurrent/ refractory – second-line.

Pharmacology:

Humanised anti-CD38 monoclonal antibody.

Current status:

PII.

Granted fast track and breakthrough therapy status in US.


2015

Reviews: None.



Omacetaxine meppe-succinate injection

Synribo

Teva

Indication:

Chronic myelogenous leukaemia (CML), after failure of two tyrosine kinase inhibitors.

Pharmacology:

Protein synthesis inhibitor.

Current status:

PIII in EU with orphan status. Launched in US– see prescribing information.


Uncertain.

Reviews: None.




http://publications.nice.org.uk/bortezomib-monotherapy-for-relapsed-multiple-myeloma-ta129

http://publications.nice.org.uk/lenalidomide-for-the-treatment-of-multiple-myeloma-in-people-who-have-received-at-least-one-prior-ta171

http://www.hsc.nihr.ac.uk/files/downloads/1922/2282.f30a8593.Bortezomib_relapsedmultiplemyeloma_Sept12.pdf


http://www.emc.medicines.org.uk/




http://www.hsc.nihr.ac.uk/files/downloads/1951/2283.3d321f0d.OnyxPharmaCarfilzomibforrelapsedandorrefractoryMM2.pdf












Vosaroxin injection

Sunesis

Indication:

Acute myeloid leukaemia,

first relapse or refractory, with cytarabine.

Pharmacology:

Anticancer quinolone derivative.

Current status:

PIII with orphan status in EU and US.


2016




Obinutuzu-mab injection

Gazyva

Roche

Indication:

Chronic lymphocytic leukaemia (CLL), first-line

in patients with co-morbidities unable to have standard therapy.

Current status:

Filed in EU Apr 2013 with orphan status.

Filed in US with breakthrough therapy status.


2014

National guidance:

NICE: CLL - Bendamustine, fludarabine,

rituximab.


Target population: UK annual incidence of CLL is 4.2 per 100,000 people, increasing to over 30 per 100,000 in those over 80 years of age.


Implications: An alternative for patients with co-morbidities who cannot have FCR (fludarabine, cyclophosphamide, rituximab). Current options include chlorambucil or bendamustine (both with/without rituximab) or reduced dose FCR. It will compete with ofatumumab below.

Financial: Alternative monthly treatment costs: chlorambucil £56, bendamustine £966, rituximab £1,572.


negotiated.

Pharmacology: Humanised anti-CD20 monoclonal antibody given by i.v. infusion.

Efficacy: In an interim analysis (n=589) of the on-going PIII CLL11 trial investigating obinutuzumab plus chlorambucil vs.

rituximab plus chlorambucil vs. chlorambucil alone in 781 patients, median progression-free survival (PFS) was 23 months for obinutuzumab and chlorambucil vs. 10.9 months for chlorambucil alone (p<0.01). The primary outcome of improved PFS with obinutuzumab plus chlorambucil vs. rituximab plus chlorambucil has been met; data will be released in Dec 2013.

Safety: Adverse events are similar to other anti-CD20 monoclonal antibodies.

Ofatumumab injection

Arzerra

GlaxoSmith-Kline

Indication:

Chronic lymphocytic leukaemia (CLL), first-line in patient with co-morbidities unable to have standard therapy.

Current status:



2014

National guidance:

As for obintuzumab above.


Target population: As for obintuzumab

above.


Implications: As for obinutuzumab above with which it will compete.

Financial: As for obinutuzumab above and cost for ofatumumab 100mg is £1,820/month.


Pharmacology: Humanised anti-CD20 monoclonal antibody given by i.v. infusion.

Efficacy: In the on-going PIII COMPLEMENT-1 trial (n=447) median progression-free survival was 22.4 months for

ofatumumab and chlorambucil vs. 13.1 months for chlorambucil alone (HR 0.57, p<0.01). More data are due to be released in Sept 2013.


Idelalisib oral

Gilead Sciences

Indication:

Chronic lymphocytic leukaemia - second-line.

Pharmacology:

Phosphatidylinositol 3-kinase delta (PI3K-delta) inhibitor.

Current status:

PIII.


2015

Reviews: None.



Ibrutinib oral

Janssen-Cilag

Indication:

Mantle cell lymphoma, refractory/relapsed – second-line.

Pharmacology:

Bruton’s tyrosine kinase inhibitor - first-in-class.

Current status:

PIII with orphan status in EU.

Filed in US Jul 2013 with orphan and breakthrough therapy status.


2015

Reviews: None.



negotiated.


http://www.nhsc-healthhorizons.org.uk/files/downloads/1843/2230.9292e45c.Vosaroxin_June12.pdf



http://publications.nice.org.uk/bendamustine-for-the-first-line-treatment-of-chronic-lymphocytic-leukaemia-ta216

http://publications.nice.org.uk/fludarabine-monotherapy-for-the-first-line-treatment-of-chronic-lymphocytic-leukaemia-ta119

http://publications.nice.org.uk/rituximab-for-the-first-line-treatment-of-chronic-lymphocytic-leukaemia-ta174

http://www.hsc.nihr.ac.uk/files/downloads/1840/2227.38bd267e.Obinutuzumab_June12.pdf


http://www.ukmi.nhs.uk/applications/ndo/record_view.asp?newDrugID=5235

http://www.hsc.nihr.ac.uk/files/downloads/1768/2172.4e411be3.OfatumumabArzerra.pdf






Ibrutinib oral

Janssen-Cilag

Indication:

Chronic lymphocytic leukaemia (CLL), relapsed/ refractory - second line.

Pharmacology:

Bruton’s tyrosine kinase inhibitor – first-in-class.

Current status:

PIII in EU.



2015




Chlormethine topical

Valchlor

Ceptaris Therapeutics

Indication:

Cutaneous T-cell lymphoma (CTCL),

mycosis fungoides (MF).

Current status:

PII with orphan status in EU. Licensed in US with orphan and fast track status.


2014

National guidance:

NICE: Skin tumours

Reviews: None.

Target population: The UK incidence of CTCL is 4 per million people. MF accounts for about 72% of CTCL. 71% of patients present with early stage disease; disease progression occurs in 34%.


Implications: First-line options for early stage MF include topical therapy, radiotherapy and phototherapy. Unlicensed topical formulations of chlormethine have been used for many years but are cumbersome to prepare and use and global supply shortages have limited availability of raw ingredient. A solution licensed in France was discontinued in 2012.

Financial: As the first licensed topical formulation of chlormethine it is likely to be expensive.


negotiated.

Pharmacology: Nitrogen mustard, an alkylating agent, formulated as a 0.02% gel applied daily.

Efficacy: In a published PII study (n=260) chlormethine 0.02% gel was compared with a 0.02% ointment formulation applied

daily for up to 12 months. The primary outcome (response rate based on composite assessment of index lesion severity) was achieved by 59% and 48% of patients, respectively, demonstrating non-inferiority.

Safety: In the above study, 20% of patients on gel and 17% on ointment withdrew due to drug-related skin irritation.

Rigosertib injection

Estybon

Baxter

Indication: Myelodysplastic syndromes, refractory/relapsed.

Pharmacology:

Phosphatidylinositol 3-kinase (PI3K) and polo-like kinase (PLK) inhibitor.

Current status:

PIII with orphan status in EU and US.


2015

Reviews: None.



Alemtuzumab injection

Lemtrada

Genzyme

Indication:

Multiple sclerosis (MS, relapsing-remitting (RRMS) active disease defined by clinical or imaging features.

Current status:



2013

National guidance:

NICE: Multiple sclerosis (update due

Oct 2014), fingolimod, natalizumab, beta interferon and glatiramer, alemtuzumab due Apr 2014, dimethyl fumarate due Jan 2014, laquinimod due Feb 2014, teriflunomide due Jan 2014.


Target population: In a population of 100,000, 110 people will have MS and 39 will have RRMS. 31% of these are on, or will have received, disease modifying agents. In 2011-12, there were 33,566 hospital admissions due to MS in England.


Implications: This is a new class of drug for MS and as a single annual treatment may be attractive. Use is likely to be in the second-line setting.

Financial: Cost of Lemtrada may be similar to other options; beta-interferon costs up to £10,500 per year and fingolimod is around £19,500/year (PAS in place). There may be additional monitoring costs.


Pharmacology: Monoclonal CD52 antibody given by i.v. infusion daily for 5 days as a first annual treatment course, and as a 3 day course in the second year. An on-going extension study will help define a subsequent treatment regimen.

Efficacy: Two published PIII studies, CARE-MS 1 in 581 patients with early, active RRMS who had received no prior therapy, and CARE_MS II in 840 patients who had relapsed on prior therapy, compared alemtuzumab to high dose s.c. interferon beta-1a. Both studies met the primary outcome of relapse rate at 2 years (a 55% and 49% reduction vs. interferon, respectively, p<0.0001). CARE-MS II also met the co-primary outcome of time to 6-month sustained accumulation of disability (42% reduction vs. interferon, p=0.008), but CARE-MS I did not. Interim results from the first year of the PIII extension to the CARE-MS I & II studies suggest less than 20% of patients received a third course of alemtuzumab and 67% and 55% in the studies, respectively, remained relapse-free through to year 3.

Safety: Over 3 years, 30% of patients in the CARE studies on alemtuzumab developed autoimmune thyroid disease, 1% immune thrombocytopenia and 0.3% nephropathy. Regular monitoring for autoimmune disease may be required.


http://www.hsc.nihr.ac.uk/files/downloads/2114/2436.2a2d89c8.Ibrutinib_July13.pdf



http://guidance.nice.org.uk/CSGSTIM




http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/003718/smops/Positive/human_smop_000544.jsp&mid=WC0b01ac058001d127



http://guidance.nice.org.uk/CG/WaveR/115

http://publications.nice.org.uk/fingolimod-for-the-treatment-of-highly-active-relapsingremitting-multiple-sclerosis-ta254

http://publications.nice.org.uk/natalizumab-for-the-treatment-of-adults-with-highly-active-relapsingremitting-multiple-sclerosis-ta127

http://www.nice.org.uk/guidance/index.jsp?action=byID&r=true&o=11441

http://www.nice.org.uk/guidance/index.jsp?action=byID&r=true&o=11441









Peginterferon beta-1a injection

Plegridy

Biogen Idec

Indication:

Multiple sclerosis (MS),

relapsing-remitting disease (RRMS).

Current status:

Filed in the EU Jul 2013.


2014

National guidance:

As for alemtuzumab above.


Target population: As for alemtuzumab above.


Implications: Interferon is currently the most frequently used disease modifying agent to treat RRMS. Interferon beta-1a (Rebif) is given by s.c. injection 3 times a week. A less frequent administration schedule will be attractive to users, but it will have to complete with oral options.

Financial: Likely to be more expensive than non-pegylated interferon.


Pharmacology: A PEGylated form of recombinant human interferon-beta-1a given s.c. every 2 or 4 weeks.

Efficacy: The PIII ADVANCE study (n=1,516) reported a reduction in annual relapse rate at 1 year of 36% and 28% with peginterferon beta-1a given every 2 or 4 weeks, respectively (p<0.001 and p<0.02 vs. placebo). Secondary outcomes including 12-week confirmed disability progression were also met. After 1 year, patients on placebo were re-randomised to one of the peginterferon beta-1a arms for a further year. Patients then have the option of enrolling in an open-label extension study ATTAIN and followed for up to 4 years.

Safety: No unexpected safety issues reported.

Laquinimod oral

Teva

Indication:

Multiple sclerosis (MS), relapsing remitting (RRMS), first or second-line therapy.

Current status:

Filed in EU Jul 2012.

More data needed for US licensing.


2013

National guidance:





Implications: Around 30% of patients with RRMS are on, or have received, disease modifying agents; 74% on interferons and 26% on glatiramer. NICE estimated that fingolimod, the first licensed oral preparation for RRMS, could take up to 15% of the interferon share of the market.

Financial: Beta-interferon costs up to £10,500/year and fingolimod costs about £19,500/year based on list price (PAS in place). There may be price competition as more oral agents become available.


Pharmacology: SAIK compound, an immune defence regulator.

Efficacy: In the published 2-year PIII ALLEGRO study (n=1,106), laquinimod 0.6mg daily reduced the mean annualised

relapse rate (ARR) vs. placebo (0.3 vs. 0.39, p=0.002) and reduced the risk of disability progression (11.1% vs. 15.7%, HR 0.64, p=0.01). The mean cumulative numbers of lesions on MRI scan were lower in the laquinimod group. In the PIII BRAVO study, laquinimod did not reduce the ARR vs. placebo whereas beta-interferon did. The on-going PIII CONCERTO study (n=1,800) is evaluating effect of laquinimod 0.6mg and 1.2mg daily on confirmed disability progression at 24 months.

Safety: Adverse events include headaches, nasopharyngitis and back pain. Increases in liver enzymes are reported.



http://www.hsc.nihr.ac.uk/files/downloads/1934/2294.ae42efe8.BIIB017_Sept12.pdf




http://www.nhsc-healthhorizons.org.uk/topics/laquinimod-for-multiple-sclerosis-relapsing-remitt/






Teriflunomideoral

Aubagio

Sanofi

Indication:


relapsing remitting disease (RRMS) – monotherapy.

Current status:




2013

National guidance:





Implications: Another oral option for the treatment of RRMS, at a cost likely to be lower than oral fingolimod.

Financial: In the US, teriflunomide costs slightly less than interferon beta-1a and about 30% less than fingolimod. There is a UK PAS for fingolimod.


Pharmacology: The active metabolite of leflunomide, teriflunomide is a dehydrogenase inhibitor.

Efficacy: In the published 2-year PIII TEMSO study (n=1,088), the annualised relapse rate (ARR) was 0.37 for patients on either 7mg or 14mg terflunomide daily vs. 0.54 for placebo (p<0.001). In the TOWER study (n=1,169), the ARR was 0.32 for teriflunomide 14mg vs. 0.50 for placebo (p<0.0001) and there was a 31.5% reduction (p=0.04 vs. placebo) in the risk of 12-week sustained accumulation of disability (SAD). Although the reduction in ARR in the 7mg group (0.39) was statistically significance vs. placebo, the 12-week SAD was not. In the PIII TENERE trial, the risk of treatment failure (primary outcome, defined as a confirmed relapse, or discontinuation of treatment for any reason) was similar among the 324 patients randomised to teriflunomide 7mg or 14mg or to beta-interferon (48.6%, 37.8% and 42.3%, respectively).

Safety: As an active metabolite of leflunomide adverse effects of teriflunomide are anticipated to be similar. See medicines.org.uk.

Dimethyl fumarate oral

Tecfidera

Biogen Idec

Indication:

Multiple sclerosis (MS), relapsing-remitting disease (RRMS) – monotherapy.

Current status:

Recommended for approval in EU Mar 2013.



2013

National guidance:





Implications: The majority of patients on disease modifying agents are treated with beta-interferon which is not tolerated by many. Effective oral preparations may make treatment more convenient and acceptable, increasing the proportion of patients treated.

Financial: In the US the price for Tecfidera is between that for teriflunomide and fingolimod. There is a UK PAS in place for fingolimod.


Pharmacology: A derivative of fumaric acid with dual immunosuppressive and cytoprotective actions.

Efficacy: Two PIII studies, DEFINE (n=1,237) and CONFIRM (n=1,417) have been published. In DEFINE, 27% and 26% of

patients on dimethyl fumarate 240mg 2 and 3 times a day, respectively, relapsed over 2 years vs. 46% on placebo (p<0.001). The annualised relapse rates (ARR) were 0.17, 0.19 and 0.36, respectively. In CONFIRM, the ARRs for the corresponding groups were 0.22, 0.20 and 0.40 (p<0.001 vs. placebo), and in the glatiramer arm, 0.29 (p<0.01 vs. placebo). In a post-hoc analysis, 3- times daily dimethyl fumarate was more effective than glatiramer in reducing the ARR (p<0.05). Active treatment was associated with a reduction in disability progression vs. placebo (34-38% p=0.01) in DEFINE but not CONFIRM. There were fewer new gadolinium enhancing lesions with active treatment in both studies.

Safety: Flushing and gastrointestinal effects are the most frequent adverse events.

Daclizumab injection

Zenapax

Biogen

Indication:

Multiple sclerosis,

relapsing-remitting.

Pharmacology:

Interleukin 2 receptor antagonist, humanised monoclonal antibody that binds to CD25.

Current status:

PIII.


2015

Reviews: None.



Fingolimod oral

Gilenya

Novartis

Indication:

Multiple sclerosis, primary

progressive.

Pharmacology:

Oral sphingosine-1 phosphate receptor modulator.

Current status:

PIII.


2015








http://www.nhsc-healthhorizons.org.uk/files/downloads/1639/2084.171805f0.Teriflunomide.pdf










http://www.tecfidera.com/pdfs/full-prescribing-information.pdf

http://www.tecfidera.com/pdfs/full-prescribing-information.pdf

http://www.nhsc-healthhorizons.org.uk/topics/dimethyl-fumarate-for-relapsing-remitting-multiple/







Teriflunomide oral

Aubagio

Sanofi

Indication:


clinically isolated syndrome (CIS).

Current status:

PIII.


2014

National guidance:


Reviews: None.

Target population: 85% of cases of MS are heralded by a clinically isolated syndrome (CIS) of demyelination, but people who experience a CIS have a less than 50% risk of developing MS within five years. Use of disease modifying drugs after a CIS is only recommended if there is also MRI evidence showing high likelihood of developing MS.


Implications: Interferons and glatiramer are licensed to treat CIS and although they have been shown to reduce conversion rates to MS over 2-3 years, only a marginally significant gain in terms of disability has been demonstrated over 3 to 5 years. Teriflunomide will provide an oral treatment option.

Financial: In the US, teriflunomide costs less than interferon beta-1a.


Pharmacology: The active metabolite of leflunomide, teriflunomide is a dehydrogenase inhibitor.

Efficacy: In the PIII TOPIC trial (n=618) patients on teriflunomide 7mg and 14mg daily had a mean reduction in risk of

conversion to clinically definite MS over 2 years of 37% and 43%, respectively vs. placebo (p=0.03 and p=0.009). The average duration of teriflunomide exposure was around 16 months.

Safety: As an active metabolite of leflunomide adverse effects of teriflunomide are anticipated to be similar. See medicines.org.uk.

BNF 9. Nutrition and blood

Eltrombopag oral

Revolade

GlaxoSmith-Kline

Indication:

Thrombocytopenia (TCP), associated with hepatitis C infection.

Current status:




2013

National guidance:

NICE: TCP- eltrombopag.

SIGN: Management of hepatitis C.

Reviews: None.

Target population: About 216,000 people in the UK are infected with hepatitis C (340 per 100,000). In a systematic review, prevalence of hepatitis C associated TCP was 0.16- 45.4%. More than half of the studies reported a TCP prevalence of ≥24%.


Implications: Eltrombopag will be used where thrombocytopenia prevents starting, or limits the ability to maintain, optimal interferon-based therapy.

Financial: Eltrombopag costs between £770 and £3,080/month (25mg to 100mg/day).

Likely commissioning route: Uncertain – depending on complexity of patient. PbR: Specified high cost drug.

Pharmacology: Thrombopoietin receptor agonist given orally in doses determined by platelet count.

Efficacy: Two PIII studies, ENABLE 1 (n=715) and ENABLE 2 (n=805) treated patients with open-label eltrombopag for 9 weeks. Patients who achieved a platelet count that enabled antiviral therapy to be started were randomised to continued eltrombopag or placebo, plus peginterferon alfa and ribavirin for 24 or 48 weeks depending on genotype. The primary outcome was the proportion of patients who achieved a sustained virological response 24 weeks after antiviral therapy had finished. This was achieved by 23% vs. 14% of eltrombopag and placebo groups, respectively (p<0.01) in ENABLE 1 and 19% vs.13% (p=0.02) in ENABLE 2. Non-responders could take part in ENABLE-ALL.

Safety: See medicines.org.uk. The ocular safety of eltrombopag has been investigated in the long-term LENS study.

Elosulfase alfa injection

Vimizim

BioMarin

Indication:

Mucopolysaccharidosis IVA (Morquio A syndrome).

Current status:

Filed in EU Apr 2013 with orphan status and accelerated assessment.


2014

National guidance:

None relevant.


Target population: Mucopolysaccharidosis

type IVA affects less than 15 in 100,000 people in the EU.

Sector: Lysosomal storage disorders are specialised services.

Implications: There are no licensed treatments for this condition.

Financial: Cost is likely to be expensive and similar to other treatments for mucopolysaccharidosis diseases (galsulfase, idursulfase, laronidase).


Pharmacology: GALNS enzyme replacement therapy, given by a 4-hour i.v. infusion.

Efficacy: A PIII trial randomised 176 patients to elosulfase alfa weekly, every other week or placebo. The study met the primary outcome with a mean increase of 22.5 metres in six-minute walk distance vs. placebo at 24 weeks in subjects on weekly treatment (p<0.02). Treatment given every 2 weeks did not differ from placebo.

Safety: Long-term safety and efficacy are being assessed in an open-label extension study and a 240 week study.


















http://www.hsc.nihr.ac.uk/topics/recombinant-human-n-acetylgalactosamine-6-sulfatas/

http://www.specialisedservices.nhs.uk/service/lysosomal-storage-disorders/search:true

http://clinicaltrials.gov/ct2/show/NCT01275066?term=bmn110&rank=2


http://clinicaltrials.gov/ct2/show/NCT01415427?term=bmn110&rank=3&submit_fld_opt=


Alipogene tiparvovec injection

Glybera

Chiesi

Indication:

Lipoprotein lipase deficiency, familial, in adults with pancreatitis despite dietary restrictions.

Current status:

Licensed in EU Oct 2012 with orphan status –see prescribing information.


2013 via a restricted access programme

National guidance:

None relevant.


Target population: An estimated 30 - 50

people in the UK may be eligible for treatment in the next 5 years.


Implications: Dietary restriction is currently the only management option.

Diagnosis has to be confirmed by genetic testing. Patients must adhere to a lipid-restricted diet and need short-term (12 weeks) immunosuppression with ciclosporin and mycophenolate mofetil. The product contains genetically-modified organisms requiring use of biosafety procedures.

Financial: Likely to be expensive.


Pharmacology: Single treatment gene therapy given by i.m. injection at multiple-sites in a single session. It is delivered

frozen in a patient-specific pack containing the correct amount of vials per patient, calculated according to weight.

Efficacy: In a published PII/III study (n=14), alipogene was administered as multiple injections into leg muscles on a single occasion under spinal anaesthesia. All patients maintained a low fat diet. 50% achieved the primary outcome of at least 40% reduction in triglycerides vs. baseline 3 to 12 weeks after dosing. In a published PII/III study, 5 patients received 1 x 10

12

gc/kg. 14 weeks after injection, mean total plasma triglyceride levels fell by about 60% (p<0.01 vs. controls). All patients in the above trials have entered continuation studies lasting several years.

Safety: In the PII/III study of 14 patients, 12 (86%) had injection site events.

Sodium phenyl-butyrate oral granules

Pheburane

Lucane Pharma

Indication:

Urea cycle disorders.

Current status:

Licensed in EU Aug 2013 - see prescribing information.


2013

National guidance:

None relevant.

Reviews: SMC due Nov 2013.

Target population: In the EU less than 2 per

million people are affected.

Sector: Urea cycle disorders are a specialised service.

Implications: Sodium phenylbutyrate Ammonaps (940mg/g) granules are already available. Pheburane contains less sodium phenylbutyrate per gram (483mg/g) due to a coating used to mask the unpleasant taste. This tasteless formulation is designed to improve compliance.

Financial: Cost of Ammonaps is £860 for 250g sodium phenylbutyrate. Likelihood for better compliance may increase the price of Pheburane.


Pharmacology: A conjugated metabolite is excreted in the urine, leading to reduced nitrogen and ammonia levels.

Efficacy: A bioequivalence study between Pheburane 483 mg/g granules and Ammonaps 940mg/g granules was submitted in the licence application. As Ammonaps is the reference product, no new clinical studies are needed.

Safety: See medicines.org.uk for Ammonaps, and prescribing information for Phenburane.

Sebelipase alfa injection

Synageva BioPharma

Indication:

Lysosomal acid lipase deficiency.

Pharmacology:

Recombinant human lysosomal acid lipase.

Current status:

PIII with orphan status in EU and US and breakthrough therapy status in US.


2015















http://www.specialisedservices.nhs.uk/library/26/Specialised_Services_for_Metabolic_Disorders_all_ages.pdf





http://www.hsc.nihr.ac.uk/topics/sebelipase-alfa-for-lysosomal-acid-lipase-deficien/


BNF 10. Musculoskeletal and joint diseases

Canakinumab injection

Ilaris

Novartis

Indication:

Juvenile idiopathic arthritis (JIA), systemic disease in patients aged ≥ 2 years with inadequate response to NSAIDs and systemic corticosteroids.

Current status:

Recommended for approval in EU Jul 2013 with orphan status. Launched in US - see prescribing information.


2013

National guidance:

NICE: JIA - etanercept, tocilizumab


Target population: NICE estimate the target population for tocilizumab in JIA is around 372 individuals in England.


Implications: Likely to be a competitor to tocilizumab, with more convenient administration (s.c. vs. i.v.) but much higher price.

Financial: Monthly cost for 30kg child of canakinumab is nearly £10,000 (single dose of 4mg/kg) assuming no vial sharing vs. about £700 for tocilizumab (two doses of 8mg/kg); a PAS is in place for tocilizumab for JIA.


Pharmacology: Interleukin-1 beta inhibitor, given by s.c. injection. In the US it is given every 4 weeks.

Efficacy: Two PIII trials published together (β-SPECIFIC 1 and 2) examined single dose (β-SPECIFIC 1, n=84) and longer-term (β-SPECIFIC 2, n=177) efficacy in patients aged 2 to 19 years. In β-SPECIFIC 1, the primary outcome (an adapted JIA ACR 30 response) was achieved by 84% patients on canakinumab, vs. 10% on placebo (p<0.001) by day 15. The β-SPECIFIC 2 study started with an open-label phase; those who responded and achieved steroid tapering by 32 weeks (n=100) were randomised to a placebo-controlled withdrawal phase. Risk of flare was lower for those on canakinumab vs. those switched to placebo; 74% on canakinumab had no flare vs. 25% in the placebo group (HR 0.36, p=0.003, NNT=2).

Safety: See medicines.org.uk. In clinical trials, there were 7 cases of macrophage activation syndrome.

Golimumab injection

Simponi

MSD

Indication:

Juvenile idiopathic arthritis (JIA), polyarticular, poor response to methotrexate.

Current status:

PIII.


2014

National guidance:

As for canakinumab above.

Reviews: None.

Target population: NICE estimate around 600 children with polyarticular JIA would be eligible for etanercept, of whom over 300 would be maintained on it long-term.


Implications: A competitor to etanercept with the advantage of once-monthly dosing vs. twice-monthly dosing for etanercept.

Financial: Golimumab is currently more expensive than etanercept and the etanercept patent expires in 2015; biosimilar formulations are in development. A PAS is in place for golimumab use in adults with arthritis and for tocilizumab for systemic JIA.


Pharmacology: A monoclonal TNF-alpha inhibitor, given by monthly s.c. injection.

Efficacy: In the PIII GO-KIDS study, 173 patients with JIA aged under 16 at diagnosis, at least 5 involved joints, and poor response to methotrexate were randomised to monthly golimumab 30mg/m

2 or placebo after a 16-week open-label run-in to

identify those showing at least 30% response to golimumab. Primary outcome is disease flare between weeks 16 to 48 with results due in 2013.


Masitinib oral

AB Science

Indication:

Rheumatoid arthritis not

responding to standard therapy.

Pharmacology:

Protein kinase inhibitor.

Current status:

PIII.


2015

Reviews: None.



Secukinumab injection

Novartis

Indication:

Rheumatoid arthritis, when TNF-alpha inhibitors are ineffective or not tolerated.

Pharmacology:

Monoclonal interleukin IL-17A inhibitor.

Current status:

PIII.


2015







http://www.pharma.us.novartis.com/cs/www.pharma.us.novartis.com/product/pi/pdf/ilaris.pdf

http://www.pharma.us.novartis.com/cs/www.pharma.us.novartis.com/product/pi/pdf/ilaris.pdf




http://www.nejm.org/doi/full/10.1056/NEJMoa1205099





http://www.clinicaltrials.gov/ct2/show/study/NCT01230827




http://www.hsc.nihr.ac.uk/topics/secukinumab-for-moderate-to-severe-active-rheumato/


Ustekinumab injection

Stelara

Janssen-Cilag

Indication:

Psoriatic arthritis (PsA),

active disease when response to DMARDS is inadequate.

Current status:



2013

National guidance:

NICE: Psoriasis pathway, PsA

subsection; PsA - etanercept, infliximab and adalimumab, golimumab, ustekinumab (due May 2014).

SIGN: Psoriasis and PsA.

Reviews: NIHR HSC Sept 2012.

Target population: UK prevalence of severe

PsA is uncertain. NICE suggest 1,248 people per year in England will respond to and continue TNF-alpha inhibitor therapy.


Implications: This will provide an alternative to TNF-alpha inhibitors; trial

evidence suggests it may be useful in patients unresponsive to this group.

Financial: Annual cost is similar to that of the TNF-alpha inhibitors for patients weighing <100kg; a PAS is in place for patients with psoriasis who weigh >100kg.


Pharmacology: Monoclonal antibody, inhibiting interleukins IL-12 and IL-23 given by s.c. injection every 12 weeks.

Efficacy: In two PIII trials, PSUMMIT 1 (n=615) and PSUMMIT 2 (n=312) the primary outcome was ACR20 response (20%

improvement in signs and symptoms) after 24 weeks. Patients received ustekinumab 45mg, 90mg, or placebo at 0, 4, then every 12 weeks. PSUMMIT 1 excluded patients with prior use of TNF-alpha inhibitors, PSUMMIT 2 did not. In PSUMMIT 1, more patients on ustekinumab (42.4% on 45mg, 49.5% on 90mg) achieved ACR20 vs. 22.8% on placebo (p<0.0001 for both comparisons, NNT=5 and 4, respectively). In PSUMMIT 2, 43.7%, 43.8% and 20.2%, respectively achieved ACR20 (p<0.001, NNT=4 for both). In anti-TNF-experienced patients 37-41% achieved ACR20 vs. 59-73% in naïve patients.


Apremilast oral

Celgene

Indication:

Psoriatic arthritis (PsA) - where other options are ineffective/contra-indicated.

Licence application also to include plaque psoriasis.

Current status:

PIII with plans to file in EU second half of 2013.

Filed in US May 2013.


2014

National guidance:

As for ustekinumab above.


Target population: As for ustekinumab above.

Sector: Primacy care (after initiation in

secondary care).

Implications: Apremilast is likely to be used after conventional systemic therapies, but as an oral preparation, it may be used before parenteral biological therapies.

Financial: Production costs, and therefore price, are likely to be lower than for biological (PAS for golimumab). Administration costs will be lower.

Likely commissioning route: CCG. PbR: Likely specified high-cost drug.

Pharmacology: Phosphodiesterase-4 inhibitor.

Efficacy: In PIII trials (PALACE 1, n=504; PALACE 2, n=495; and PALACE 3, n=495) adults with active PsA who failed existing therapy were randomised to apremilast 20mg, 30mg, or placebo. Primary outcome was ACR20 (20% improvement in signs and symptoms) after 16 weeks. In PALACE 1, response rate for 20mg was 31.3% (p<0.05 vs. placebo, NNT=8); 30mg, 41.0% (p<0.0001, NNT=5) and placebo 19.4%. Results in PALACE 2 and 3 are similar. All studies are on-going with total planned durations of 4.5 years. Results of a PII study are published.

Safety: In a pooled analysis of PALACE 1, 2, and 3, adverse effects included diarrhoea, nausea, headache and upper respiratory tract infections. Incidence of serious adverse events was similar in active and placebo groups.


Novartis

Indication:

Psoriatic arthritis, after failure of conventional DMARD.

Pharmacology:


Current status:

PIII.


2015





Novartis

Indication:

Ankylosing spondylitis,

second or third-line.

Pharmacology:


Current status:

PIII.


2015







http://pathways.nice.org.uk/pathways/psoriasis

http://pathways.nice.org.uk/pathways/psoriasis#content=close&path=view%3A/pathways/psoriasis/systemic-biological-therapy-for-psoriasis-and-psoriatic-arthritis.xml






http://www.hsc.nihr.ac.uk/topics/ustekinumab-stelara-for-psoriatic-arthritis/

http://guidance.nice.org.uk/TA199/CostingStatement/pdf/English






http://www.hsc.nihr.ac.uk/topics/apremilast-for-psoriatic-arthritis/







http://www.hsc.nihr.ac.uk/topics/secukinumab-for-active-and-progressive-psoriatic-a/


http://www.hsc.nihr.ac.uk/topics/secukinumab-for-ankylosing-spondylitis-andndash-se/


Pegloticase injection

Krystexxa

Savient

Indication:

Gout prophylaxis, where

xanthine oxidase inhibitors have failed or are contra-indicated.

Current status:

Licensed in EU Jan 2013 – see prescribing information.


2013

National guidance:

NICE: Pegloticase Jun 2013.


Target population: The manufacturer estimates about 2,700 people in England and Wales may be eligible; NICE estimates that the guidance would affect about 8 people per 100,000 in England.


Implications: NICE does not currently recommend pegloticase as, although effective at lowering urate levels, it is not cost-effective at the £30,000 per QALY threshold and can cause serious adverse reactions. It would be a competitor to canakinumab (also not recommended by NICE).

Financial: Pegloticase cost is £1,770 per vial (about £23,000 for 6 months therapy) and would require fortnightly day case admission as infusion plus minimum observation period for severe allergic reactions is 3.5 hours. Canakinumab cost is about £1,000 per dose (max. 2 doses in 6 months).


Pharmacology: A polyethylene glycol conjugate of recombinant uricase given by a 2-hour i.v. infusion every 2 weeks.

Efficacy: The published PIII GOUT1 and 2 studies randomised 225 patients to pegloticase bi-weekly or monthly, or placebo, for 6 months. The primary outcome, plasma uric acid <6.0mg/dL 80% of the time at 3 and 6 months, was met in GOUT1 by 47% of patients (bi- weekly, p<0.001) and 20% (monthly, p<0.05) and in GOUT2 by 38% (p=0.001) and 49% (p<0.001), respectively.

Safety: Anaphylaxis (including anaphylactic shock) in about 6.5% of patients and infusion reactions (26%) are reported; premedication with antihistamines and corticosteroids is mandated in prescribing information.

Lesinurad oral

AstraZeneca

Indication:

Gout, second-line.

Pharmacology:

Selective urate transporter-1 inhibitor.

Current status:

PIII.


2015




Odanacatib oral

MSD

Indication:

Osteoporosis in men when

bisphosphonates contra-indicated or not successful.

Pharmacology:

Selective cathepsin-K inhibitor.

Current status:

PIII.


2015




Ataluren oral

Translarna

PTC Therapeutics

Indication:

Duchenne muscular dystrophy, nonsense-

mutation (nmDMD).

Current status:

Filed in EU Dec 2012 with orphan status.


2013

National guidance:

None relevant.


Target population: DMD affects 1 in 3,600

to 6,000 male births in the UK; about 100 boys are diagnosed annually and UK prevalence is about 1,500. Around 10-15% have a nonsense mutation (nm), corresponding to 150-195 patients in the UK who may be eligible.


Implications: Current options (corticosteroids) can delay but not prevent

loss of walking ability. Ataluren is the first therapy to target the underlying defect in nmDMD, but will benefit only a small proportion of all DMD patients. It is likely to be additional to current therapy in ambulant patients but could prolong independence and delay complications.



Pharmacology: Dystrophin synthesis stimulant, mechanism of action is uncertain.

Efficacy: Licence application is based on a PII trial in boys (n=174) with nm Duchenne or Becker MD, aged ≥5 years treated with 40mg/kg or 80mg/kg ataluren daily or placebo. At week 48, mean change from baseline in the primary outcome of 6-minute walk distance failed to reach statistical significance for both doses. However, post-hoc secondary analyses suggest there may be a benefit with the lower dose. A larger PIII study (n=220 target) is in progress.

Safety: Ataluren was well tolerated in trials.


http://www.emea.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002208/human_med_001591.jsp






http://www.emea.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002208/WC500138318.pdf


http://www.hsc.nihr.ac.uk/topics/lesinurad-for-gout/


http://www.hsc.nihr.ac.uk/topics/odanacatib-for-male-osteoporosis-andndash-first-an/


http://clinicaltrials.gov/ct2/show/study/NCT00592553?term=ataluren&rank=11

http://clinicaltrials.gov/ct2/show/NCT01826487?term=ataluren&rank=6


Idebenone oral

Sovrima

Takeda

Indication:

Duchenne muscular dystrophy (DMD).

Current status:



2014

National guidance:

None relevant.

Reviews: None.

Target population: As for ataluren above. Patients are living longer due to intensive symptomatic respiratory and cardiac support.


Implications: Unlike ataluren above, if licensed, idebenone would potentially be suitable for all affected patients with DMD.



Pharmacology: Coenzyme Q10 analogue that enhances mitochondrial respiratory chain function.

Efficacy: The on-going PIII DELOS study compares idebenone 900mg daily with placebo in 260 boys aged 10 to 18 years.

The primary outcome is percentage change in predicted peak expiratory flow as a measure of respiratory function, over 52 weeks. Trial completion is expected late 2013. The PII DELPHI trial (n=21) results have been published. Idebenone 450mg daily did not show a significant difference from placebo at 12 months in the primary outcome of effect on peak systolic radial strain in the left ventricular inferolateral wall, the region of the heart that is earliest and most severely affected in DMD. Patients completing DELPHI entered the open-label DELPHI-extension study and received 450mg or 900mg (based on weight) for 24 months. This study completed in 2011 but results have yet to be published.

Safety: Idebenone has been well tolerated in trials.

BNF 11. Eye

Aflibercept intravitreal injection

Eylea

Bayer

Indication:

Macular oedema, secondary to central retinal vein occlusion (CRVO).

Current status:




2013

National guidance:

NICE: Aflibercept due Apr 2014,

ranibizumab, costing template, dexamethasone.


Target population: RVO affects 1–2% of

people aged over 40 years. In England and Wales about 17 per 100,000 people will require treatment for macular oedema following CRVO annually.


Implications: A new treatment option that will compete with ranibizumab

injection and dexamethasone implant.

Financial: Based on current prices, aflibercept cost is £816/month and dexamethasone implant cost is £870. PASs are in place for ranibizumab for wet age-related macular degeneration and diabetic macular oedema.


Pharmacology: Vascular endothelial growth factor inhibitor (VEGF) and placental growth factor inhibitor given monthly.

Efficacy: In the published PIII GALILEO study (n=177), at 6-months, 60.2% on aflibercept 2mg monthly and 22.1% on

control treatment, gained ≥15 letters of vision from baseline (p<0.01). The mean number of letters gained was 18 vs. 3.3, respectively (p<0.01). In the published PIII COPERNICUS (n=189), at 6 months, ≥15 letters were gained by 56.1% on aflibercept vs. 12.3% on placebo (p<0.01). Those on aflibercept gained a mean of 17.3 letters vs. a mean loss of 4 letters with placebo, p<0.01. From week 24 to week 52, all patients received aflibercept as needed. At 12 months, ≥15 letters were gained by 55.3% on aflibercept vs. 30.1% on placebo (p<0.01). Those on aflibercept gained a mean of 16.2 letters vs. a mean of 3.8 letters with placebo, p<0.01.



Eylea

Bayer

Indication:

Diabetic macular oedema (DMO).

Current status:

PIII.


2014.

National guidance:

NICE: Diabetes pathway, quality

standard, fluocinolone implant (rapid review due Nov 2013) ranibizumab, costing template.

Reviews: NIHR HSC Jun 2013, LNDG

Feb 2011.

Target population: About 322 patients with

diabetes have DMO per 100,000 people. 39% of these have clinically significant macular oedema, which can lead to blindness.


Implications: A new treatment option that will compete with ranibizumab.

Financial: As for aflibercept above.


Pharmacology: Vascular endothelial growth factor inhibitor (VEGF) and placental growth factor inhibitor given monthly.

Efficacy: The 12-month results of the PIII VIVID-DME and VISTA-DME trials of aflibercept 2mg monthly vs. aflibercept every

2 months vs. laser photocoagulation are available. In VIVID-DME mean change from baseline in best corrected visual acuity was 10.5 letters, 10.7 letters and 1.2 letters in the three groups, respectively. The results for VISTA-DME were 12.5, 10.7 and 0.2 letters, respectively (p<0.01 for both trials, both aflibercept groups vs. laser).





http://www.clinicaltrials.gov/ct2/show/study/NCT00758225?term=idebenone&rank=7




http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/125387s015s020lbl.pdf

http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/125387s015s020lbl.pdf


http://publications.nice.org.uk/ranibizumab-for-treating-visual-impairment-caused-by-macular-oedema-secondary-to-retinal-vein-ta283

http://guidance.nice.org.uk/TA283/CostingTemplate/xls/English


http://www.nhsc-healthhorizons.org.uk/files/downloads/1575/2032.bfc47534.VEGFTrapEyeEylea.pdf







http://pathways.nice.org.uk/pathways/diabetes/diabetes-overview

http://publications.nice.org.uk/diabetes-in-adults-quality-standard-qs6

http://publications.nice.org.uk/diabetes-in-adults-quality-standard-qs6

http://publications.nice.org.uk/fluocinolone-acetonide-intravitreal-implant-for-the-treatment-of-chronic-diabetic-macular-oedema-ta271


http://guidance.nice.org.uk/TA274/CostingTemplate/xls/English

http://www.hsc.nihr.ac.uk/topics/aflibercept-eylea-for-visual-impairment-due-to-dia/

http://www.medicinesresources.nhs.uk/upload/DMO_Feb_2011.pdf






Eylea

Bayer

Indication:

Macular oedema,

secondary to branch retinal vein occlusion (BRVO).

Pharmacology:

As for aflibercept above.

Current status:

PIII.


2015

Reviews: None.



BNF 13. Skin

Apremilast oral

Celgene

Indication:

Psoriasis, plaque, moderate to severe.

Current status:

PIII.


2014

National guidance:

NICE: Psoriasis pathway, assessment

and management, commissioning guide, costing report, quality standards; ustekinumab , adalimumab, infliximab, efalizumab and etanercept.

SIGN: Psoriasis.


Target population: Estimated prevalence of psoriasis in England is 1.63%; about 20% of people have moderate to severe disease (20 per 100,000). Plaque psoriasis is the most common form, affecting 80-90% of people. It is estimated 1.1% of people with psoriasis are eligible for biological treatment (7,100).


Implications: Likely to be licensed for use after conventional systemic therapies, but as an oral preparation may be considered for use before parenteral biological therapies. However, unlike established therapies, long -term efficacy and safety data are lacking.

Financial: Production costs, and therefore drug price, are likely to be lower than for biologicals (which cost £8,000-£11,000/year). Administration costs will also be lower.


Pharmacology: Inhibitor of type-4 cyclic nucleotide phosphodiesterase (PDE-4).

Efficacy: On-going studies of apremilast vs. placebo include PIII ESTEEM 1 and 2 (n=1,257 combined) and a PIIIb study

(n=240) vs. etanercept and placebo. The PIIIb study has enrolled only biological-naïve patients. In a published PIIb study (n=352) the primary outcome, 75% reduction in Psoriasis Area and Severity Index (PASI 75) at week 16, was achieved in 41% of patients on apremilast vs. 6% on placebo (p<0.0001). In ESTEEM 1, PASI 75 at 16 weeks was achieved by 33.1% of patients on apremilast vs. 5.3% on placebo (p<0.0001). Higher scores were seen in systemic- and biologic-naïve subjects vs. placebo (38.7% vs. 7.6%; p<0.0001 and 35.8% vs. 5.9%; p<0.0001, respectively).

Safety: No major safety issues have been reported.

Tofacitinib oral

Xeljanz

Pfizer

Indication:

Psoriasis, plaque,

moderate to severe.

Current status:

PIII.


2014

National guidance:

As for apremilast above.


Target population: As for apremilast above.


Implications: Tofacitinib will compete with other second line treatments in

adults who are candidates for systemic therapy. It has the advantage of oral administration but safety concerns may be an issue. This may limit its use to patients who have failed on an established biological.

Financial: In the US, it has been priced about 7% cheaper ($24,666 a year)

compared to etanercept and adalimumab.


Pharmacology: An immunosuppressant, janus kinase (JAK) 3 inhibitor (5 or 10mg twice daily).

Efficacy: Completed PIII studies include two 1-year placebo controlled trials (1 & 2 both n=825) with Physician´s Global Assessment (PGA) and PASI 75 response at week 16 as the co-primary outcomes, a 12-week trial (n=1,100) vs. etanercept with a primary outcome of PGA, and a withdrawal and re-treatment study (n=684). An open-label long-term safety study (n=3,200) is on-going. In a published PIIb dose-ranging study (2, 5 and 15mg twice daily), PASI 75 at week 12, was reported in 25%, 41% and 67% of patients, respectively, vs. 2% in patients on placebo.

Safety: Major concerns about its overall safety profile including serious infections, certain cancers, gastro-intestinal perforations, liver damage and hyperlipidaemia were among the reasons the CHMP recommended against approval in the EU for rheumatoid arthritis in April 13.



http://pathways.nice.org.uk/pathways/psoriasis

http://publications.nice.org.uk/psoriasis-cg153

http://publications.nice.org.uk/psoriasis-cg153

http://www.nice.org.uk/_gs/link/?id=69E8D8E6-9BE2-A01F-8419D1056597A69B

http://guidance.nice.org.uk/CG153/CostingReport/pdf/English



http://www.nice.org.uk/ta146



http://www.sign.ac.uk/guidelines/fulltext/121/

http://www.hsc.nihr.ac.uk/files/downloads/2000/2349.d85df2fe.Apremilastforpsoriasis_Jan13.pdf





http://www.ukmi.nhs.uk/applications/NDO/record_view.asp?newDrugID=5117

http://www.hsc.nihr.ac.uk/files/downloads/1977/2332.160e4102.Tofacitinib_Nov12.pdf







Novartis

Indication:

Psoriasis, plaque,

moderate to severe.

Current status:

PIII.


2014

National guidance:

As for apremilast above.


Target population: As for apremilast above.


Implications: Secukinumab targets a different immunological mediator to

currently available biological therapies and is likely to be used as an alternative to existing biologicals in patients who have failure, contraindication or intolerance to standard systemic treatments.

Financial: Likely to be around the same price as other biologicals (£8,000-

£11,000/year).


Pharmacology: First-in-class fully human monoclonal interleukin-17A (IL-17A) antibody given by s.c .injection as 5, weekly loading doses then monthly maintenance doses (150 or 300mg).

Efficacy: There are a number of on-going PIII studies, including four 1-year studies, FIXTURE (n=1,264), ERASURE (n=720), FEATURE (n=171) and JUNCTURE (n=171). The latter two use autoinjectors; only one study, FIXTURE, has an active control arm (etanercept). The primary outcomes are PASI scores and Investigators´ Global Assessment (IGA) at week 12. Two on-going PIII extension studies (n=1,220 and n=740) are collecting 2 additional years of data from either continuous or interrupted treatment regimens. Three PII dose-ranging studies have been published (one, two, three) showing effectiveness in induction and maintenance, but did not employ the regimen adopted in PIII studies.

Safety: Neutropenia has been reported.

Propranolol oral

Pierre Fabre

Indication:

Infantile haemangioma (IH), proliferating, requiring systemic therapy.

Current status:



2014

National guidance:

None relevant.

Reviews: None.

Target population: Around 3-5% of infants may be affected by IH and about 10% of these may require treatment during the proliferative stage, equating to about 6 cases per 100,000 people per year.


Implications: This will be the first drug licensed for this indication which may lead to more affected infants being considered for treatment.

Financial: Likely to cost considerably more than currently used unlicensed

alternatives such as corticosteroids and propranolol products.


Pharmacology: Beta-blocker.

Efficacy: A published PII trial compared propranolol or placebo for 6 months in 40 children aged between 9 weeks and 5 years with facial IH or IH at sites with potential for disfigurement. At week 24 the reduction in IH volume was 60% vs.14%, respectively (p=0.01). A PIII trial (n=460) has been completed but has yet to be published. A systematic review of uncontrolled trials reported a response rate over 90%.

Safety: See medicines.org.uk. Cardiac monitoring may be required.

Afamelanotide implant

Scenesse

Clinuvel

Indication:

Erythropoietic protoporphyria (EPP).

Current status:

Filed in EU Feb 2012 with orphan status. Launched in Italy (2010) and Switzerland (2012).


2013

National guidance:

None relevant.


Target population: EPP affects <2 per 100,000 people in the EU. Protoporphyrin accumulates in the skin and causes severe photosensitivity with sun exposure leading to burning, erythema and pain.


Implications: There are no other specific EPP treatments. Options include staying indoors, sun-blocking clothes and sunscreen.



Pharmacology: Synthetic analogue of alpha-melanocyte-stimulating hormone which induces the synthesis of melanin. Given as a controlled release dissolvable s.c implant.

Efficacy: In the PIII CUV029 study 74 patients received afamelanotide or placebo once every 60 days, over 9 months. Afamelanotide was associated with fewer phototoxic reactions measured by visual analogue scale (primary outcome; p=0.044) and a lower total median pain score (secondary outcome; 6.0 vs. 17.5, p=0.035). In the 12-month PIII CUV017 crossover trial 91 patients received afamelanotide or placebo implants every 2 months. Afamelanotide reduced the total number of days on which patients experienced pain (p<0.003) and all individual daily pain scores were lower vs. placebo (p<0.002). The US PIII CUV039 study (n=93) completed in April 2013 but results have not yet been made public. The EMA has delayed its decision on approval, possibly waiting for the results of this study.

Safety: No specific concerns have been identified.


http://www.nhsc-healthhorizons.org.uk/files/downloads/1805/2208.7d53ef75.Secukinumab.pdf
















http://clinicaltrials.gov/ct2/show/NCT00979745?intr=%22Afamelanotide%22&rank=2

http://apps.who.int/trialsearch/Trial.aspx?TrialID=EUCTR2007-000636-13-GB



BNF 14. Vaccines

Meningo-coccal group-B vaccine injection

Bexsero

Novartis

Indication:

Meningococcal B disease (MenB) immunisation, invasive disease caused by Neisseria meningitidis group B in subjects >2 months old.

Current status:

Licensed in the EU Jan 2013 - see prescribing information.


2013/2014

National guidance:

DH routine vaccination schedule 2013/14.

JCVI recommendation Jun 2013.

Reviews: None.

Target population: In the UK, the number of

cases of meningitis has halved over the last decade to around 25 per 100,000 in children <1 year of age and to <2 per 100,000 in all ages. Around 80% were caused by MenB. In 2011/12, there were 613 lab-confirmed cases of MenB and 33 deaths. Around 1 in 10 who survive will suffer major disabilities.


Implications: Surveys suggest the vaccine may cover around 73% of MenB

strains circulating in the UK. Although the vaccine has been shown to induce an immune response, effectiveness against invasive MenB disease has not been established.

Financial: The Joint Committee on Vaccination and Immunisation (JCVI) has recommended against including this in the routine immunisation programme as they do not consider it likely to be cost effective.

Likely commissioning route: CCG. PbR: Not applicable.

Pharmacology: Quadrivalent vaccine (4CMenB) given as a 2 or 3 dose course, possibly followed by a booster dose.

Efficacy: Results of a primary and booster PIII study have been published. In the primary study, 3,630 infants received routine vaccinations at 2, 4 and 6 months of age, either alone or with MenB vaccine. One month after the final dose, 84-100% of infants had a serological response to 4 reference MenB strains, without a clinically significant effect on the immunogenicity of routine vaccines. In the booster phase, 1,555 subjects aged 12 months received MenB vaccine either with or 1 month prior to MMR varicella-zoster virus vaccine. Over 95% showed a protective response to all four MenB vaccine components. A further PII/III study in infants which met all primary outcomes has been published. On-going studies are assessing persistence of antibody levels 5 years post-vaccination, and efficacy in children, adolescents and young adults.

Safety: See prescribing information.






https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/210828/8515_DoH_Complete_Imm_schedule_A4_2013_06_accessible.pdf

https://www.gov.uk/government/uploads/system/uploads/attachment_data/file/225002/12_Jun_2013_-_minutes_and_agenda.zip





Table 2. Drugs in Prescribing Outlook 2012 - development delayed

Generic and trade name

Company Indication and reason for delay.

Amrubicin

Calsed

Celgene Small cell lung cancer.

Development status uncertain following poor PIII results.

Apixaban

Eliquis

Pfizer Venous thromboembolism prevention in medically ill patients.

Development status uncertain in EU. Other new oral anticoagulant drugs have ceased development for this indication.

Axitinib

Inlyta

Pfizer Renal cell carcinoma.

Development discontinued following poor PIII results.

Farletuzumab Eisai Ovarian cancer.

The company is reviewing the development strategy in view of negative PIII results.

Imatinib

Ruvise

Novartis Pulmonary arterial hypertension.

EU filing withdrawn. The company stated it would not be able to address concerns about benefit-risk assessment within the timetable for the application procedure. See EMA Q&A.

Lorcaserin

Belviq

Arena Obesity.

EU filing withdrawn. The company stated it would not be able to address all of the concerns within the timetable for the application. See EMA Q&A.

Mipomersen

Kynamro

Genzyme

Hypercholesterolaemia (familial), homozygous and severe heterozygous.

Not recommended for approval in EU as licensing authority could not conclude that benefits outweigh risks. See EMA Q&A.

Peginesatide

Omontys

Takeda Anaemia due to chronic kidney disease in adults on dialysis.

EU filing withdrawn. The company stated that it would not be able to address concerns regarding the hypersensitivity reactions within the timetable for the application procedure. See EMA Q&A.

Phentermine/ topiramate

Qsiva

Vivus Obesity.

Not recommended for approval in EU as licensing authority could not conclude that benefits outweigh risks. See EMA Q&A.

Prasugrel

Efient

Eli Lilly Acute coronary syndrome (ACS), medical management.

Development status uncertain following poor PIII results.

Ridaforolimus oral

Jenzyl

Merck Bone and soft tissue sarcoma.

EU filing withdrawn based on a provisional view that data were not sufficient to permit licensing. See EMA Q&A.

Strontium ranelate sachet

Protelos

Servier Osteoarthritis.

A review of strontium ranelate is underway following evaluation of safety data showing an increased risk of serious heart problems, including heart attack.

Tertomotide

KAEL-GemVax

Pancreatic cancer.

Still in PIII trials but recent data from two studies failed to demonstrate any survival benefit.

Tivozanib Astellas Renal cell carcinoma.

Development discontinued.

Tofacitinib

Xeljanz

Pfizer Rheumatoid arthritis.

Not recommended for approval in EU due to overall safety concerns. See EMA Q&A.






http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002551/wapp/Initial_authorisation/human_wapp_000153.jsp&mid=WC0b01ac058001d128


http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002597/wapp/Initial_authorisation/human_wapp_000165.jsp&mid=WC0b01ac058001d128&source=homeMedSearch&category=human


http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002429/human_med_001622.jsp&mid=WC0b01ac058001d124





http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002350/human_med_001607.jsp&mid=WC0b01ac058001d124






http://www.emea.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/Protelos_and_Osseor/human_referral_prac_000025.jsp&mid=WC0b01ac05805c516f&source=homeMedSearch&category=human)






Table 3. Recent UK drug launches or licence extensions (Sep 2012 to Aug 2013)

Generic and brand name.

Company. Indication and relevant guidance. Full prescribing information can be found on the electronic medicines compendium at medicines.org.uk via brand name link.

BNF 1. Gastrointestinal system

Adalimumab

Humira - SmPC

AbbVie

Licence extension: Treatment of severe active Crohn's disease in patients aged 6 to 17 years – second-line.

Guidance: NICE: Crohn’s disease pathway. SMC: Restricted use. AWMSG: Recommended.


Linaclotide

Constella - SmPC

Almirall

Licensed indication: Treatment of moderate to severe irritable bowel syndrome (IBS) with constipation in adults.

Guidance: NICE: IBS pathway. SMC: restricted use. AWMSG: Not endorsed.

Reviews: MTRAC Jun 2013, NICE-MPC Apr 2013, RDTC Mar 2013.

Racecadotril

Hidrasec - SmPC

Abbott

Licensed indication: Treatment of acute diarrhoea in infants (older than 3 months), children

and adults when causal treatment is not possible.

Guidance: SMC: Not approved adults/children. AWMSG: Not endorsed adults/ not

recommended children.

Reviews: NICE-MPC adults/children Mar 2013, RDTC children Nov 2012.

BNF 2. Cardiovascular system

Apixaban

Eliquis - SmPC

Bristol Myers Squibb Pfizer

Licence extension: Prevention of stroke and systemic embolism in adults with non-valvular atrial fibrillation.

Guidance: NICE: Stroke pathway, apixaban, atrial fibrillation. SMC: Approved.

Reviews: RDTC Dec 2012, NPC Nov 2011.

Rivaroxaban

Xarelto - SmPC

Bayer

Licence extension: Pulmonary embolism (PE) – treatment, and prevention of recurrent PE and deep vein thrombosis.

Guidance: NICE: VTE pathway, rivaroxaban. SIGN: Venous thromboembolism. SMC: Approved.

Reviews: RDTC Mar 2013.

BNF 3. Respiratory system

Aclidinium

Eklira Genuair - SmPC

Almirall

Licensed indication: Symptom relief in chronic obstructive pulmonary disease (COPD).

Guidance: NICE: COPD pathway. SMC: Approved. AWMSG: Recommended.

Reviews: NICE-MPC Jan 2013, MTRAC Nov 2012, RDTC Oct 2012, NPC/UKMi Nov 2011.

Beclometasone/ formoterol

Fostair - SmPC

Chiesi

Licence extension: Regular maintenance treatment and ‘as needed’ for adults with asthma.

Guidance: NICE: Asthma. SIGN: Asthma.

Review: NICE-MPC Jun 2013.

C1-esterase inhibitor (human)

Berinert - SmPC

CSL Behring

Licence extension: Hereditary angioedema – pre-procedure prevention of acute attacks in adults and children.

Guidance: AWMSG: Recommended.

Reviews: None.

Colistimethate sodium

Colobreathe - SmPC

Forest Laboratories

Licensed indication: Cystic fibrosis – chronic lung infection with Pseudomonas aeruginosa in

patients aged six years and older.

Guidance: NICE: Colistimethate sodium.

Reviews: None.

Fluticasone propionate/ formoterol fumarate

Flutiform - SmPC

Napp

Licensed indication: Regular maintenance treatment for asthma.

Guidance: NICE: Asthma. SIGN: Asthma. SMC: Approved.

Reviews: NICE-MPC Oct 2012, MTRAC Sep 2012.

Glycopyrronium bromide

Seebri Breezhaler-SmPC

Novartis

Licensed indication: Symptom relief in adults with chronic obstructive pulmonary disease.

Guidance: NICE: COPD pathway. SMC: Approved. AWMSG: Recommended.

Reviews: NICE-MPC Jan 2013, RDTC Nov 2012, MTRAC Nov 2012.

http://www.medicines.org.uk/emc/default.aspx

http://www.medicines.org.uk/emc/medicine/21201/SPC/Humira+Pre-filled+Pen%2c+Pre-filled+Syringe+and+Vial/

http://pathways.nice.org.uk/pathways/crohns-disease

http://www.scottishmedicines.org.uk/SMC_Advice/Advice/880_13_adalimumab_Humira_Crohns_ABBREVIATED/adalimumb_Humira

http://www.awmsg.org/awmsgonline/app/appraisalinfo/749

http://www.medicines.org.uk/emc/medicine/27499/SPC/Constella+290+micrograms+hard+capsules/

http://pathways.nice.org.uk/pathways/irritable-bowel-syndrome-in-adults

http://www.scottishmedicines.org.uk/SMC_Advice/Advice/869_13_linaclotide_Constella/linaclotide_Constella


http://www.keele.ac.uk/media/keeleuniversity/fachealth/fachealthsop/mtrac/documents/summary/Linaclotide%20verdict%20and%20summary%203.pdf

http://publications.nice.org.uk/esnm16-irritable-bowel-syndrome-with-constipation-in-adults-linaclotide-esnm16/

http://rdtc.nhs.uk/nde-125-linaclotide

http://www.medicines.org.uk/emc/searchresults.aspx?term=Racecadotril&searchtype=QuickSearch

http://www.scottishmedicines.org.uk/SMC_Advice/Advice/832_12_racecadotril_Hidrasec/racecadotril_Hidrasec

http://www.scottishmedicines.org.uk/SMC_Advice/Advice/818_12_racecadotril_Hidrasec_Infants_Hidrasec_Children/racecadotril_Hidrasec_Infants_Hidrasec_Children




http://publications.nice.org.uk/esnm11-acute-diarrhoea-in-adults-racecadotril-esnm11

http://publications.nice.org.uk/esnm12-acute-diarrhoea-in-children-racecadotril-as-an-adjunct-to-oral-rehydration-esnm12

http://rdtc.nhs.uk/nde-120-racecadotril

http://www.medicines.org.uk/emc/medicine/24988/SPC/Eliquis+2.5+mg+film-coated+tablets/

http://pathways.nice.org.uk/pathways/stroke


http://publications.nice.org.uk/atrial-fibrillation-cg36

http://www.scottishmedicines.org.uk/SMC_Advice/Advice/836_13_apixiban_Eliquis/apixaban_Eliquis

http://rdtc.nhs.uk/nde-122-apixaban

http://www.npc.nhs.uk/rapidreview/?p=4674

http://www.medicines.org.uk/emc/searchresults.aspx?term=xarelto&searchtype=QuickSearch

http://pathways.nice.org.uk/pathways/venous-thromboembolism



http://www.scottishmedicines.org.uk/SMC_Advice/Advice/852_13_rivaroxaban_Xarelto/rivaroxaban_Xarelto

http://rdtc.nhs.uk/nde-124-rivaroxaban-pe

http://www.medicines.org.uk/emc/medicine/27001/SPC/Eklira+Genuair+322+micrograms+inhalation+powder/

http://pathways.nice.org.uk/pathways/chronic-obstructive-pulmonary-disease

http://www.scottishmedicines.org.uk/SMC_Advice/Advice/810_12_aclidinium_bromide_Eklira_Genuair/aclidinium_bromide_Eklira_Genuair


http://publications.nice.org.uk/esnm8-chronic-obstructive-pulmonary-disease-aclidinium-bromide-esnm8/

http://www.keele.ac.uk/media/keeleuniversity/fachealth/fachealthsop/mtrac/documents/summary/Aclidinium%20SUM%20final.pdf

http://rdtc.nhs.uk/nde-117-aclidinium-bromide

http://www.npc.nhs.uk/new_medicines/resp/copd/oth_aclidinium.php

http://www.medicines.org.uk/emc/medicine/21006/SPC/Fostair+100+6+inhalation+solution/



http://publications.nice.org.uk/esnm22-asthma-beclometasoneformoterol-fostair-for-maintenance-and-reliever-treatment-esnm22

http://www.medicines.org.uk/emc/medicine/21650/SPC/Berinert+500+IU/


http://www.medicines.org.uk/emc/medicine/27647/SPC/Colobreathe/


http://www.medicines.org.uk/emc/medicine/26954/SPC/flutiform+50+microgram+5+microgram%2c+125+microgram+5+microgram+and+250+microgram+10+microgram+per+actuation+pressurised+inhalation%2c+suspension/



http://www.scottishmedicines.org.uk/SMC_Advice/Advice/736_11_fluticasone_formoterol_mdi_inhaler_Flutiform/fluticasone_formoterol_Flutiform

http://publications.nice.org.uk/esnm3-asthma-fluticasoneformoterol-flutiform-combination-inhaler-esnm3

http://www.keele.ac.uk/media/keeleuniversity/fachealth/fachealthsop/mtrac/documents/summary/Flutiform%20VS%204.pdf

http://www.medicines.org.uk/emc/medicine/27138/SPC/Seebri+Breezhaler+Inhalation+Powder%2c+Hard+Capsules+44mcg/

http://pathways.nice.org.uk/pathways/chronic-obstructive-pulmonary-disease

http://www.scottishmedicines.org.uk/SMC_Advice/Advice/829_12_glycopyrronium_Seebri_Breezhaler/glycopyrronium_Seebri_Breezhaler


http://publications.nice.org.uk/esnm9-chronic-obstructive-pulmonary-disease-glycopyrronium-bromide-esnm9/

http://rdtc.nhs.uk/nde-119-glycopyrronium

http://www.keele.ac.uk/media/keeleuniversity/fachealth/fachealthsop/mtrac/documents/summary/Glycopyrronium%20SUM%20final%20(1).pdf





Ivacaftor

Kalydeco - SmPC

Vertex

Licensed indication: Cystic fibrosis in patients aged six years and older who have a G551D mutation in the CFTR gene.

Guidance: SMC: Not approved. AWMSG: Terminated, available for use in Wales.


Pirfenidone

Esbriet - SmPC

InterMune

Licensed indication: Idiopathic pulmonary fibrosis.

Guidance: NICE: IPF pathway, pirfenidone. SMC: Restricted use.

Reviews: LNDG Dec 2011.

BNF 4. Central nervous system

Aripiprazole

Abilify - SmPC

Otsuka

Licence extension: Moderate to severe manic episodes in bipolar I disorder in adolescents

aged 13 years and older.

Guidance: NICE: Aripiprazole. SMC: Due Sep 2013.

Reviews: None.

Atomoxetine

Strattera - SmPC

Eli Lilly

Licence extension: Attention deficit/hyperactivity disorder in adults, but only when pre-existing symptoms during childhood can be confirmed by a third-party.

Guidance: NICE: ADHD pathway. SIGN: Attention deficit and hyperkinetic disorders.

Reviews: None.

Etoricoxib

Arcoxia - SmPC

MSD

Licence extension: Pain associated with dental surgery.

Guidance: SMC: Not approved. AWMSG: Not endorsed.

Reviews: None.

Lisdexamfetamine dimesylate

Elvanse - SmPC

Shire

Licensed indication: Attention deficit/hyperactivity disorder in children aged six years and over – second-line.

Guidance: NICE: ADHD pathway. SIGN: Attention deficit and hyperkinetic disorders. SMC: Approved. AWMSG: In progress.

Reviews: NICE-MPC May 2013.

Nalmefene

Selincro - SmPC

Lundbeck

Licensed indication: Reduction of alcohol consumption in adults with alcohol dependence.

Guidance: NICE: Alcohol use: pathway. SIGN: Alcohol dependence. SMC: Due Oct 13. AWMSG: In progress.

Reviews: NIHR HSC Sep 2012, RDTC due TBC.

Naloxone

Prenoxad - SmPC

Martindale

Licensed indication: Reversal of opioid-induced respiratory depression, emergency use in the home or other non-medical setting.

Guidance: None.

Reviews: None.

Perampanel

Fycompa - SmPC

Eisai

Licensed indication: Epilepsy in patients aged 12 years and older – adjunctive therapy of partial seizures.

Guidance: NICE: Epilepsy pathway. SMC: Restricted use. AWMSG: Restricted use.

Reviews: NICE-MPC Dec 2012, NETAG Oct 2012, NIHR HSC Apr 2011.

Tafamidis

Vyndaqel - SmPC

Pfizer

Licensed indication: Transthyretin amyloidosis.



BNF 5. Infections

Ceftaroline

Zinforo - SmPC

AstraZeneca

Licensed indication: Complicated skin and soft tissue infections (cSSTI) or community acquired pneumonia (CAP).

Guidance: NICE: Pneumonia due TBC. SMC: Restricted use in cSSTI; not approved for CAP. AWMSG: Restricted use in cSSTI; not recommended for CAP.

Reviews: LNDG Sep 2012.

Elvitegravir/ cobicistat/ emtricitabine/ tenofovir

Stribild - SmPC

Gilead

Licensed indication: HIV-1 infection.

Guidance: SMC: Approved. AWMSG: In progress.

Reviews: LNDG Jan 2013.


http://www.medicines.org.uk/emc/medicine/27586/SPC/Kalydeco+150+mg+film-coated+tablets/

http://www.scottishmedicines.org.uk/SMC_Advice/Advice/827_12_ivacaftor_Kalydeco/ivacaftor_Kalydeco_Resubmission


http://wales.gov.uk/about/cabinet/cabinetstatements/2013/kalydeco/?lang=en

http://www.medicines.org.uk/emc/medicine/26942/SPC/Esbriet+267+mg+hard+capsules/

http://pathways.nice.org.uk/pathways/idiopathic-pulmonary-fibrosis


http://www.scottishmedicines.org.uk/SMC_Advice/Advice/835_13_pirfenidone_Esbriet/pirfenidone_Esbriet?iru=QATB4RGAEZ

http://www.medicinesresources.nhs.uk/upload/Pirfenidone_Dec%202011.pdf

http://www.medicines.org.uk/emc/medicine/18494/SPC/Abilify+Tablets%2c+Orodispersible+Tablets%2c+Oral+Solution+(Otsuka+%26+Bristol-Myers+Squibb)/


http://www.medicines.org.uk/emc/medicine/14482/SPC/Strattera+10mg%2c+18mg%2c+25mg%2c+40mg%2c+60mg%2c+80mg+or+100mg+hard+capsules./

http://pathways.nice.org.uk/pathways/attention-deficit-hyperactivity-disorder

http://sign.ac.uk/guidelines/fulltext/112/index.html

http://www.medicines.org.uk/emc/medicine/8734/SPC/Arcoxia+30mg%2c+60+mg%2c+90+mg+%26+120+mg+Film-coated+Tablets/

http://www.scottishmedicines.org.uk/SMC_Advice/Advice/847_12_etoricoxib_Arcoxia/etoricoxib_Arcoxia


http://www.medicines.org.uk/emc/medicine/27442/SPC/Elvanse+30mg%2c+50mg+%26+70mg+Capsules%2c+hard/

http://pathways.nice.org.uk/pathways/attention-deficit-hyperactivity-disorder


http://www.scottishmedicines.org.uk/SMC_Advice/Advice/863_13_lisdexamfetamine_dimesylate_Elvanse/lisdexamfetamine_dimesylate_Elvanse


http://publications.nice.org.uk/esnm19-attention-deficit-hyperactivity-disorder-in-children-and-young-people-lisdexamfetamine-esnm19/

http://www.medicines.org.uk/emc/medicine/27609/SPC/Selincro+18mg+film-coated+tablets/

http://pathways.nice.org.uk/pathways/alcohol-use-disorders



http://www.hsc.nihr.ac.uk/files/downloads/1933/2293.211215e1.Nalmefene_Sept12.pdf

http://www.medicines.org.uk/emc/medicine/27616/SPC/Prenoxad+1mg+ml+Injection/

http://www.medicines.org.uk/emc/medicine/26951/SPC/Fycompa+2mg%2c4mg%2c6mg%2c8mg%2c10mg%2c12mg+film-coated+tablets/

http://pathways.nice.org.uk/pathways/epilepsy

http://www.scottishmedicines.org.uk/SMC_Advice/Advice/819_12_perampanel_Fycompa/perampanel_Fycompa


http://publications.nice.org.uk/esnm7-partial-onset-seizures-in-epilepsy-perampanel-as-adjunctive-treatment-esnm7

http://www.netag.nhs.uk/files/appraisal-reports/Perampanel%20-%20NETAG%20appraisal%20report%20-%20Oct2012.pdf

http://www.nhsc-healthhorizons.org.uk/files/downloads/1559/2018.5807fd37.Perampanel.pdf

http://www.medicines.org.uk/emc/medicine/27125/SPC/Vyndaqel+20+mg+soft+capsules/

http://www.scottishmedicines.org.uk/SMC_Advice/Advice/877_13_tafamidis_meglumine_Vyndaqel_Non_Submission/tafamidis_meglumine_Vyndaqel_Non_Submission


http://www.medicines.org.uk/emc/medicine/26988/SPC/Zinforo+600+mg+powder+for+concentrate+for+solution+for+infusion/


http://www.scottishmedicines.org.uk/SMC_Advice/Advice/830_12_ceftaroline_fosamil_Zinforo/ceftaroline_fosamil_Zinforo

http://www.scottishmedicines.org.uk/SMC_Advice/Advice/830_12_ceftaroline_fosamil_Zinforo/ceftaroline_fosamil_Zinforo



http://www.medicinesresources.nhs.uk/upload/Ceftaroline_September12.pdf

http://www.medicines.org.uk/emc/medicine/27810/SPC/Stribild+150+mg+150+mg+200+mg+245+mg+film-coated+tablets/

http://www.scottishmedicines.org.uk/SMC_Advice/Advice/887_13_elvitegravir_cobicistat_emtricitabine_tenofovir_disoproxil_Stribild/elvitegravir_cobicistat_emtricitabine_tenofovir_disoproxil_Stribild?iru=QATB4RGAEZ


http://www.medicinesresources.nhs.uk/upload/QUAD_Jan13.pdf





Rifaximin

Targaxan - SmPC

Norgine

Licensed indication: Hepatic encephalopathy.

Guidance: SMC: Due Sep 2013.


BNF 6. Endocrine system

Dapagliflozin

Forxiga - SmPC

AstraZeneca

Licensed indication: Type 2 diabetes mellitus – monotherapy and add-on.

Guidance: NICE: Diabetes: pathway, dapagliflozin. SIGN: Diabetes. SMC: Restricted use.

Reviews: MTRAC Feb 2013, RDTC Dec 2012, LNDG Nov 2012, NPC/UKMI Mar 2011.

Hydrocortisone MR

Plenadren - SmPC

ViroPharma

Licensed indication: Adrenal insufficiency.


Reviews: UKMi Oct 2012.

Insulin degludec

Tresiba - SmPC

Novo Nordisk

Licensed indication: Diabetes mellitus.

Guidance: NICE: Diabetes: pathway. SMC: Not approved. AWMSG: Not endorsed. SIGN: Diabetes.

Reviews: MTRAC Feb 2013, NICE-MPC - T1DM and T2DM Nov 2012, RDTC Aug 2012, NPC/UKMi - T2DM Mar 2012, NIHR HSC - T1DM and T2DM Jan 2011.

Insulin glargine

Lantus - SmPC

Sanofi

Licence extension: Diabetes mellitus in children aged two to less than six years.

Guidance: NICE: Diabetes: pathway. SMC: Restricted use. AWMSG: Recommended. SIGN: Diabetes.

Reviews: None.

Linagliptin

Trajenta - SmPC


Licence extension: Type 2 diabetes mellitus– with insulin.

Guidance: NICE: Diabetes: pathway. SIGN: Diabetes. SMC: Restricted use. AWMSG: Recommended.

Reviews: RDTC Mar 2012.

Linagliptin/metformin

Jentadueto - SmPC


Licensed indication: Type 2 diabetes mellitus.

Guidance: NICE: Diabetes: pathway. SIGN: Diabetes. SMC: Restricted use. AWMSG: Recommended.

Reviews: None.

Lixisenatide

Lyxumia - SmPC

Sanofi


Guidance: NICE: Diabetes: pathway. SIGN: Diabetes. SMC: Due Sep 2013. AWMSG: In progress.

Reviews: NICE-MPC Jan 2013.

Pasireotide

Signifor - SmPC

Novartis

Licensed indication: Cushing's disease.


Reviews: NETAG Jul 2012, LNDG Feb 2012.

Saxagliptin/metformin

Komboglyze - SmPC

Bristol Myers Squibb-AstraZeneca EEIG


Guidance: NICE: Diabetes: pathway. SIGN: Diabetes. SMC: Restricted use.

Reviews: None.

BNF 7. Obstetrics, gynaecology, and urinary-tract disorders

Botulinum A toxin

Botox - SmPC

Allergan

Licensed extension: Urinary incontinence (UI) in adults with detrusor overactivity in a neurologic condition in patients unresponsive to/intolerant of antimuscarinic medication.

Guidance: NICE: UI in neurological disease pathway. SMC: Due Oct 2013. SIGN: UI. AWMSG: In progress.

Reviews: NICE-MPC Sep 2012.

Medroxyprogesterone acetate

Sayana - SmPC

Pfizer

Licensed indication: Contraception, three-monthly subcutaneous injection.

Guidance: None.

Reviews: None.


http://www.medicines.org.uk/emc/medicine/27427/SPC/TARGAXAN+550+mg+film-coated+tablets/

http://www.medicines.org.uk/emc/medicine/27188/SPC/Forxiga+5+mg++%26+10+mg+film+coated+tablets/




http://www.scottishmedicines.org.uk/SMC_Advice/Advice/799_12_dapagliflozin_Forxiga/dapagliflozin_Forxiga

http://www.keele.ac.uk/media/keeleuniversity/fachealth/fachealthsop/mtrac/documents/summary/Dapagliflozin%20sum%20final.pdf

http://rdtc.nhs.uk/nde-121-dapagliflozin

http://www.medicinesresources.nhs.uk/upload/Dapagliflozin_Nov12.pdf

http://nww.npc.nhs.uk/secure/new_medicines/cardio/diabetes2/resources/oth_dapagliflozin.pdf

http://www.medicines.org.uk/emc/medicine/27118/SPC/Plenadren+20mg+tablets/

http://www.scottishmedicines.org.uk/SMC_Advice/Advice/848_12_hydrocortisone_Plenadren/hydrocortisone_Plenadren


http://www.medicinesresources.nhs.uk/upload/documents/Evidence/Drug%20Specific%20Reviews/NMP%20Hydrocortisone%20MR.1.pdf

http://www.medicines.org.uk/emc/medicine/27359/SPC/Tresiba+100+units+mL+Pre-filled+Pen+(FlexTouch)/


http://www.scottishmedicines.org.uk/SMC_Advice/Advice/856_13_insulin_degludec_Tresiba/insulin_degludec_Tresiba



http://www.keele.ac.uk/media/keeleuniversity/fachealth/fachealthsop/mtrac/documents/summary/Degludec%20sum%20final.pdf

http://publications.nice.org.uk/esnm5-type-1-diabetes-insulin-degludec-esnm5/

http://publications.nice.org.uk/esnm4-type-2-diabetes-insulin-degludec-esnm4/

http://rdtc.nhs.uk/insulin-degludec-diabetes-mellitus

http://nww.npc.nhs.uk/secure/new_medicines/cardio/diabetes2/resources/oth_insulin_degludec.pdf

http://www.nhsc-healthhorizons.org.uk/topics/insulin-degludec-for-type-1-diabetes-mellitus

http://www.nhsc-healthhorizons.org.uk/topics/insulin-degludec-for-type-2-diabetes-mellitus

http://www.medicines.org.uk/emc/medicine/25506/SPC/Lantus+100+units+ml+solution+for+injection+in+a+vial/


http://www.scottishmedicines.org.uk/SMC_Advice/Advice/860_13_insulin_glargine_Lantus/insulin_glargine_Lantus



http://www.medicines.org.uk/emc/medicine/25000/SPC/Trajenta+5+mg+film-coated+tablets/



http://www.scottishmedicines.org.uk/SMC_Advice/Advice/850_13_linagliptin_Trajenta/linagliptin_Trajenta


http://rdtc.nhs.uk/nde-115-linagliptin

http://www.medicines.org.uk/emc/medicine/26999/SPC/Jentadueto+2.5+mg+850+mg+film-coated+tablets/



http://www.scottishmedicines.org.uk/SMC_Advice/Advice/840_13_linagliptin_metformin_Jentadueto/linagliptin_metformin_Jentadueto


http://www.medicines.org.uk/emc/medicine/27406/SPC/Lyxumia+20+micrograms+solution+for+injection/




http://publications.nice.org.uk/esnm10-type-2-diabetes-lixisenatide-esnm10/

http://www.medicines.org.uk/emc/medicine/26746/SPC/Signifor+Solution+for+Injection+0.3mg%2c+0.6mg%2c+0.9mg/

http://www.scottishmedicines.org.uk/SMC_Advice/Advice/815_12_pasireotide_Signifor/pasireotide_Signifor


http://www.netag.nhs.uk/files/recommendations/NETAG%20decision%20summary%20notice%20-%20Pasireotide%20for%20CD%20-July%202012.pdf

http://www.medicinesresources.nhs.uk/upload/Pasireotide_Feb2012.pdf

http://www.medicines.org.uk/emc/medicine/27311/SPC/Komboglyze+2.5mg-850mg+%26+2.5mg-1000mg+Tablets/



http://www.scottishmedicines.org.uk/SMC_Advice/Advice/870_13_saxagliptin_metformin_Komboglyze/saxagliptin_metformin_Komboglyze

http://www.medicines.org.uk/emc/medicine/20564/SPC/BOTOX+50+Units/

http://pathways.nice.org.uk/pathways/urinary-incontinence-in-neurological-disease



http://publications.nice.org.uk/idiopathic-overactive-bladder-syndrome-botulinum-toxin-a-esnm2

http://www.medicines.org.uk/emc/medicine/27798/SPC/SAYANA+PRESS+104+mg+0.65+ml+suspension+for+injection/





Mirabegron

Betmiga - SmPC

Astellas

Licensed indication: Overactive bladder – with symptoms of urge urinary incontinence (UI),

urgency and urinary frequency.

Guidance: NICE: Mirabegron. SIGN: UI. SMC: Approved.

Reviews: MTRAC Aug 2013, LNDG Mar 2013, RDTC Feb 2013.

Nomegestrol acetate/ estradiol

Zoely - SmPC

MSD

Licensed indication: Contraception, oral.


Reviews: NICE-MPC due Oct 2013.

Tadalafil

Cialis - SmPC

Eli Lilly

Licence extension: Benign prostatic hyperplasia.


Reviews: NICE-MPC May 2013, RDTC Apr 2013.

BNF 8. Malignant disease and immunosuppression

Abiraterone acetate

Zytiga - SmPC

Janssen-Cilag

Licence extension: Metastatic, castration-resistant, prostate cancer after failure of androgen deprivation therapy and when chemotherapy is not yet clinically indicated.

Guidance: NICE: PC pathway, Abiraterone. SMC: Not approved.

Reviews: LCNDG Jan 2013.

Aflibercept

Zaltrap - SmPC

Sanofi

Licensed indication: Colorectal cancer (CRC), metastatic – second-line.

Guidance: NICE: CRC pathway, aflibercept due Oct 2013. SIGN: CRC.SMC: Not approved.

Reviews: None.

Axitinib

Inlyta - SmPC

Pfizer

Licensed indication: Advanced renal cell carcinoma – second-line.

Guidance: NICE: Overdue. SMC: Not approved.


Bevacizumab

Avastin - SmPC

Roche

Licence extension: Platinum-sensitive epithelian ovarian (OC), fallopian tube or primary peritoneal cancer.

Guidance: NICE: OC pathway, bevacizumab. SIGN: OC. SMC: Not approved.


Bevacizumab

Avastin - SmPC

Roche

Licence extension: Metastatic colorectal cancer (CRC) in adults who have already been

treated with bevacizumab and chemotherapy.

Guidance: NICE: CRC pathway. SIGN: CRC.

Reviews: None.

Bortezomib

Velcade - SmPC

Janssen-Cilag

Licence extension: Multiple myeloma – subcutaneous administration.

Guidance: NICE: Bortezomib. SMC: Approved. AWMSG: Recommended.

Reviews: None.

Bortezomib

Velcade - SmPC

Janssen-Cilag

Licence extension: Multiple myeloma – re-treatment with bortezomib.

Guidance: NICE: Bortezomib.

Reviews: None.

Bortezomib

Velcade - SmPC

Janssen-Cilag

Licence extension: Multiple myeloma – first-line induction treatment of adults eligible for high-dose chemotherapy and stem cell transplantation.

Guidance: NICE: Bortezomib due Jan 2014.


Bosutinib

Bosulif - SmPC

Pfizer

Licensed indication: Chronic myeloid leukaemia, Philadelphia chromosome-positive – second-line.

Guidance: NICE: Haemato-oncology. SMC: Due Nov 2013.


Brentuximab

Adcetris - SmPC

Takeda

Licensed indication: Hodgkin’s lymphoma – relapsed/refractory post autologous stem cell transplant (ASCT) or when ASCT unsuitable.

Guidance: NICE: Haemato-oncology. SMC: Not approved. AWMSG: Not endorsed.



http://www.medicines.org.uk/emc/medicine/27429/SPC/Betmiga+25mg+%26+50mg+prolonged-release+tablets/



http://www.scottishmedicines.org.uk/SMC_Advice/Advice/862_13_mirabegron_Betmiga/mirabegron_Betmiga

http://centreformedicinesoptimisation.co.uk/download/4f697ec37a79b0afe7236cd154178ba9/Mirabegron-Verdict-Aug-13.pdf

http://www.medicinesresources.nhs.uk/upload/Mirabegron_finalMarch2013_2.pdf

http://rdtc.nhs.uk/nde-123-mirabegron

http://www.medicines.org.uk/emc/medicine/27581/SPC/Zoely+2.5+mg+1.5+mg+film-coated+tablets/

http://www.scottishmedicines.org.uk/SMC_Advice/Advice/898_13_nomegestrol_acetate_estradiol_Zoely_Non_Submission/nomegestrol_acetate_estradiol_Zoely


http://www.medicines.org.uk/emc/medicine/11363/SPC/Cialis+2.5mg%2c+5mg%2c+10mg+%26+20mg+film-coated+tablets/

http://www.scottishmedicines.org.uk/SMC_Advice/Advice/849_12_tadalafil_Cialis/tadalafil_Cialis


http://publications.nice.org.uk/esnm18-lower-urinary-tract-symptoms-secondary-to-benign-prostatic-hyperplasia-tadalafil-esnm18

http://rdtc.nhs.uk/nde-126-tadalafil-bph

http://www.medicines.org.uk/emc/medicine/24976/SPC/Zytiga+250+mg+tablets/



http://www.scottishmedicines.org.uk/SMC_Advice/Advice/873_13_abiraterone_Zytiga_Non_Submission/abiraterone_Zytiga

http://www.medicinesresources.nhs.uk/upload/documents/Evidence/Drug%20Specific%20Reviews/Abiraterone%20pre-docetaxel.pdf


http://www.medicines.org.uk/emc/medicine/27413/SPC/Zaltrap+25mg+ml+concentrate+for+solution+for+infusion/




http://www.scottishmedicines.org.uk/SMC_Advice/Advice/878_13_aflibercept_Zaltrap/aflibercept_Zaltrap

http://www.medicines.org.uk/emc/medicine/27051/SPC/Inlyta+1+mg+%26+5mg+film-coated+tablets/


http://www.scottishmedicines.org.uk/SMC_Advice/Advice/855_13_axitinib_Inlyta/axitinib_Inlyta

http://www.medicinesresources.nhs.uk/upload/documents/Evidence/Drug%20Specific%20Reviews/Axitinib%20as%20an%20option%20for%20second%20line%20advanced%20renal.pdf

http://www.medicines.org.uk/emc/medicine/15748/SPC/Avastin+25mg+ml+concentrate+for+solution+for+infusion/

http://pathways.nice.org.uk/pathways/ovarian-cancer



http://www.scottishmedicines.org.uk/SMC_Advice/Advice/853_13_bevacizumab_Avastin/bevacizumab_Avastin

http://www.medicines.org.uk/emc/medicine/15748/SPC/Avastin+25mg+ml+concentrate+for+solution+for+infusion/



http://www.medicines.org.uk/emc/medicine/17109/SPC/Velcade+3.5mg+powder+for+solution+for+injection/


http://www.scottishmedicines.org.uk/SMC_Advice/Advice/822_12_bortezomib_Velcade/bortezomib_Velcade






http://www.nhsc-healthhorizons.org.uk/files/downloads/1550/2009.7cec39a9.BortezomibVelcade.pdf

http://www.medicines.org.uk/emc/medicine/27795/SPC/Bosulif+100mg+and+500mg+Tablets/

http://guidance.nice.org.uk/CSGHO

http://www.medicines.org.uk/emc/medicine/27173/SPC/Adcetris+50+mg+powder+for+concentrate+for+solution+for+infusion/

http://guidance.nice.org.uk/CSGHO

http://www.scottishmedicines.org.uk/SMC_Advice/Advice/845_12_brentuximab_vedotin_Adcetris/brentuximab_vedotin_Adcetris


http://www.nhsc-healthhorizons.org.uk/files/downloads/1046/1552.2ee648ef4b17137107faf3fae20600ef.pdf





Brentuximab

Adcetris - SmPC

Takeda

Licensed indication: Relapsed/refractory systemic anaplastic large cell lymphoma.


Reviews: LCNDG Mar 2013, NIHR HSC Jan 2011.

Crizotinib

Xalkori - SmPC

Pfizer

Licensed indication: ALK-positive non-small cell lung cancer, advanced – second line.

Guidance: NICE: Lung cancer: pathway, crizotinib due Sep 2013. SIGN: Lung cancer. SMC: Not approved, resubmission due Oct 2013.

Reviews: LCNDG Nov 2012.

Decitabine

Dacogen- SmPC

Janssen-Cilag

Licensed indication: Acute myeloid leukaemia (AML) in patients aged at least 65 years who are unsuitable for standard chemotherapy.

Guidance: NICE: Decitabine. SMC: Not approved. AWMSG: Not endorsed.


Enzalutamide

Xtandi - SmPC

Astellas

Licensed indication: Prostate cancer, metastatic, castration-resistant – second-line.

Guidance: NICE: PC pathway. SMC: Due Nov 2013.


Lapatinib

Tyverb - SmPC

GlaxoSmithKline

Licence extension: HER2-positive, hormone receptor-negative metastatic breast cancer (BC) that has progressed on prior trastuzumab – in combination with trastuzumab and chemotherapy.

Guidance: NICE: Advanced BC pathway. AWMSG: Restricted use.


Lenalidomide

Revlimid - SmPC

Celgene

Licence extension: Myelodysplastic syndromes associated with a 5q chromosomal deletion in

patients with transfusion-dependent anaemia.

Guidance: NICE: Lenalidomide due Dec 2013.


Pertuzumab

Perjeta - SmPC

Roche

Licensed indication: Breast cancer (BC), metastatic HER2-positive disease – first-line with trastuzumab and docetaxel.

Guidance: NICE: Advanced BC pathway, pertuzumab due Nov 2013. SMC: Due Oct 2013.

Reviews: LCNDG Mar 2013.

Pomalidomide

Imnovid - SmPC Celgene

Licensed indication: Multiple myeloma, relapsed or refractory – in combination with dexamethasone, third-line.

Guidance: None.


Ponatinib

Iclusig - SmPC

Ariad

Licensed indication: Chronic myeloid leukaemia and acute lymphoblastic leukaemia.

Guidance: CML- bosutinib draft guidance, imatinib resistant/ intolerant patients


Rituximab

MabThera - SmPC

Roche

Licence extension: Vasculitis, anti-neutrophil cytoplasmic antibody (ANCA)-associated.

Guidance: NICE: Rituximab due Nov 2013.


Ruxolitinib

Jakavi - SmPC

Novartis

Licensed indication: Disease-related splenomegaly or symptoms in adults with chronic idiopathic myelofibrosis, post polycythaemia vera myelofibrosis or post essential thrombocythaemia myelofibrosis.

Guidance: NICE: Ruxolitinib. SMC: Not approved.

Reviews: RDTC Jan 2013, LCNDG Jun 2012.

Triptorelin SR

Decapeptyl SR - SmPC

Ipsen

New formulation: Prostate cancer, six-monthly preparation.

Guidance: NICE: PC pathway.

Reviews: NICE-MPC due Nov 2013.

Vismodegib

Erivedge - SmPC

Roche

Licensed indication: Basal cell carcinoma, metastatic or locally advanced.

Guidance: None.

Reviews: LCNDG Feb 2013.


http://www.medicines.org.uk/emc/medicine/27173/SPC/Adcetris+50+mg+powder+for+concentrate+for+solution+for+infusion/

http://www.scottishmedicines.org.uk/SMC_Advice/Advice/845_12_brentuximab_vedotin_Adcetris/brentuximab_vedotin_Adcetris


http://www.medicinesresources.nhs.uk/upload/documents/Communities/London_CNDG/Brentuximab%20SALCL.pdf

http://www.nhsc-healthhorizons.org.uk/files/downloads/1047/1553.ca1e99ac5432d726865958d3dc94db59.pdf

http://www.medicines.org.uk/emc/medicine/27168/SPC/Xalkori+200mg+and+250mg+hard+capsule/




http://www.scottishmedicines.org.uk/SMC_Advice/Advice/865_13_crizotinib_Xalkori/crizotinib_Xalkori

http://www.medicinesresources.nhs.uk/upload/documents/Evidence/Drug%20Specific%20Reviews/Crizotinib%20for%20second%20line%20ALK.pdf

http://www.medicines.org.uk/emc/medicine/27127/SPC/Dacogen++50+mg+powder+for+concentrate+for+solution+for+infusion./

http://publications.nice.org.uk/decitabine-for-the-treatment-of-acute-myeloid-leukaemia-terminated-appraisal-ta270

http://www.scottishmedicines.org.uk/SMC_Advice/Advice/846_12_decitabine_Dacogen/decitabine_Dacogen


http://www.medicines.org.uk/emc/medicine/27912/SPC/Xtandi+40mg+soft+capsules/


http://www.nhsc-healthhorizons.org.uk/files/downloads/1757/2171.27f0aa6f.MDV3100.pdf

http://www.medicines.org.uk/emc/medicine/20929/SPC/Tyverb/



http://www.nhsc-healthhorizons.org.uk/files/downloads/1755/2169.d038f2c8.LapatinibTyverb_withtrastuzumab.pdf

http://www.medicines.org.uk/emc/medicine/19841/SPC/Revlimid/


http://www.medicinesresources.nhs.uk/upload/documents/Communities/London_CNDG/Lenalidomide%20for%20the%20first%20line%20treatment.pdf

http://www.medicines.org.uk/emc/medicine/27473/SPC/Perjeta+420+mg+Concentrate+for+Solution+for+Infusion/


http://guidance.nice.org.uk/index.jsp?action=byId&o=13815

http://www.medicinesresources.nhs.uk/upload/documents/Communities/London_CNDG/pertuzumab%20in%20combination%20wth%20docetaxel.pdf


http://www.hsc.nihr.ac.uk/files/downloads/1967/2323.41a149ec.Pomalidomide_Nov12.pdf

http://www.medicines.org.uk/emc/medicine/28145/SPC/Iclusig+15mg+and+45mg+film-coated+tablets/

http://guidance.nice.org.uk/TAG/298/Consultation/DraftGuidance

http://publications.nice.org.uk/dasatinib-high-dose-imatinib-and-nilotinib-for-the-treatment-of-imatinib-resistant-chronic-myeloid-ta241

http://www.hsc.nihr.ac.uk/files/downloads/1928/2288.30ecdabc.Ponatinib_Sept12.pdf

http://www.medicines.org.uk/emc/medicine/2570/SPC/Mabthera+100mg+and+500mg+concentrate+for+solution+for+infusion/


http://www.nhsc-healthhorizons.org.uk/files/downloads/1708/2147.f85ae570.RituximabMabThera.pdf

http://www.medicines.org.uk/emc/medicine/26991/SPC/Jakavi+5mg%2c+15mg+and+20mg+Tablets/


http://www.scottishmedicines.org.uk/SMC_Advice/Advice/867_13_ruxolitinib_Jakavi/ruxolitinib_Jakavi

http://rdtc.nhs.uk/evaluation-report-ruxolitinib-myelofibrosis

http://www.medicinesresources.nhs.uk/upload/documents/Evidence/Drug%20Specific%20Reviews/Ruxolitinib.pdf

http://www.medicines.org.uk/emc/medicine/24154/SPC/Decapeptyl+SR+22.5mg/


http://www.medicines.org.uk/emc/medicine/28107/SPC/Erivedge+150+mg+hard+capsules/

http://www.medicinesresources.nhs.uk/upload/documents/Communities/London_CNDG/Vismodegib%20for%20locally%20advanced%20MBCC.pdf





BNF 9. Nutrition and blood

Deferasirox

Exjade - SmPC

Novartis

Licence extension: Treatment of chronic iron overload in patients aged at least 10 years with non-transfusion-dependent thalassemia syndrome.


Reviews: None.

Ferumoxytol

Rienso - SmPC

Takeda

Licensed indication: Iron deficiency anaemia in chronic kidney disease (CKD).

Guidance: NICE: Anaemia in CKD pathway. SIGN: CKD. SMC: Restricted use. AWMSG:

Restricted use.

Reviews: LNDG Oct 2012, NIHR HSC Jan 2011.

BNF 10. Musculoskeletal and joint diseases

Abatacept

Orencia - SmPC


New formulation: Rheumatoid arthritis (RA), moderate-to-severe active, subcutaneous formulation.

Guidance: NICE: RA pathway. SIGN: RA. SMC: Restricted use.

Reviews: None.

Canakinumab

Ilaris - SmPC

Novartis

Licence extension: Gouty arthritis – second-line.


Reviews: NICE-MPC Jul 2013.

Etanercept

Enbrel - SmPC

Pfizer

Licence extension: Paediatric use in juvenile idiopathic arthritis, oligoarticular, enthesitis-

related or psoriatic.

Guidance: NICE: Etanercept. SMC: Restricted use. AWMSG: In progress.

Reviews: None.

Tocilizumab

RoActemra - SmPC

Roche

Licence extension: Rheumatoid arthritis (RA) – monotherapy in inadequate responders to DMARDs or methotrexate.

Guidance: NICE: RA pathway. SIGN: RA. SMC: Restricted use.

Reviews: None.

Tocilizumab

RoActemra - SmPC

Roche

Licence extension: Juvenile idiopathic polyarthritis, polyarticular – second-line after methotrexate.

Guidance: None.


BNF 11. Eye

Aflibercept

Eylea - SmPC

Bayer

Licensed indication: Wet age related macular degeneration (AMD).

Guidance: NICE: Wet AMD. SMC: Approved.

Reviews: LNDG Mar 2013, NETAG Dec 2012.

Fluocinolone acetonide

Iluvien - SmPC

Alimera Sciences

Licensed indication: Diabetic macular oedema - second-line.

Guidance: NICE: Fluocinolone. SMC: Not approved.

Reviews: LNDG Feb 2011.

Ocriplasmin

Jetrea - SmPC

Alcon

Licensed indication: Symptomatic vitreomacular traction, including macular hole.

Guidance: NICE: Ocriplasmin due Oct 2013. SMC: Due Sep 2013.


Ranibizumab

Lucentis - SmPC

Novartis

Licence extension: Visual impairment due to choroidal neovascularisation secondary to pathologic myopia.

Guidance: SMC: Due Nov 2013.



http://www.medicines.org.uk/emc/medicine/18805/SPC/EXJADE+125+mg%2c+250mg%2c+500mg+dispersible+tablets/

http://www.scottishmedicines.org.uk/SMC_Advice/Advice/866_13_defasirox_Exjade/deferasirox_Exjade


http://www.medicines.org.uk/emc/medicine/26773/SPC/Rienso/

http://pathways.nice.org.uk/pathways/anaemia-management-in-people-with-chronic-kidney-disease


http://www.scottishmedicines.org.uk/SMC_Advice/Advice/833_13_ferumoxtol_Rienso/ferumoxytol_Rienso


http://www.medicinesresources.nhs.uk/upload/Ferumoxytol_Oct2012.pdf

http://www.nhsc-healthhorizons.org.uk/files/downloads/1413/1918.73e07fbd4ab9c6d277a81237bf94b17e.pdf

http://www.medicines.org.uk/emc/medicine/27216/SPC/ORENCIA+125+mg+solution+for+injection+(pre-filled+syringe)/

http://pathways.nice.org.uk/pathways/rheumatoid-arthritis


http://www.scottishmedicines.org.uk/SMC_Advice/Advice/888_13_abatacept_Orencia/abatacept_Orencia?iru=QATB4RGAEZ

http://www.medicines.org.uk/emc/medicine/22718/SPC/Ilaris+150mg+powder+for+solution+for+injection/

http://www.scottishmedicines.org.uk/SMC_Advice/Advice/883_13_canakinumab_Ilaris_Arthritis/canakinumab_Ilaris_Arthritis


http://publications.nice.org.uk/gouty-arthritis-canakinumab-esnm23

http://www.medicines.org.uk/emc/medicine/24761/SPC/Enbrel+10+mg+powder+and+solvent+for+solution+for+injection+for+paediatric+use./

http://publications.nice.org.uk/guidance-on-the-use-of-etanercept-for-the-treatment-of-juvenile-idiopathic-arthritis-ta35

http://www.scottishmedicines.org.uk/SMC_Advice/Advice/842_13_etanercept_Enbrel/etanercept_Enbrel


http://www.medicines.org.uk/emc/medicine/22311/SPC/RoActemra+20mg+ml+Concentrate+for+Solution+for+Infusion/

http://pathways.nice.org.uk/pathways/rheumatoid-arthritis


http://www.scottishmedicines.org.uk/SMC_Advice/Advice/774_12_tocilizumab_RoActemra/tocilizumab_RoActemra_Resubmission

http://www.medicines.org.uk/emc/medicine/22311/SPC/RoActemra+20mg+ml+Concentrate+for+Solution+for+Infusion/

http://www.nhsc-healthhorizons.org.uk/files/downloads/1894/2260.aaee465e.Tocilizumab_July2012.pdf

http://www.medicines.org.uk/emc/medicine/27224/SPC/Eylea+40mg+ml+solution+for+injection+in+a+vial/


http://www.scottishmedicines.org.uk/SMC_Advice/Advice/857_13_aflibercept_Eylea/aflibercept_Eylea

http://www.medicinesresources.nhs.uk/upload/Aflibercept_wetAMD_%20March13.pdf

http://www.netag.nhs.uk/files/appraisal-reports/Aflibercept%20for%20AMD%20-%20NETAG%20appraisal%20report%20-%20-Jan2013-%20-%20WEB%20VERSION.pdf

http://www.medicines.org.uk/emc/medicine/27636/SPC/ILUVIEN+190+micrograms+intravitreal+implant+in+applicator/

http://publications.nice.org.uk/fluocinolone-acetonide-intravitreal-implant-for-the-treatment-of-chronic-diabetic-macular-oedema-ta271

http://www.scottishmedicines.org.uk/SMC_Advice/Advice/864_13_fluocinolone_acetonide_Iluvien/fluocinolone_acetonide_Iluvien

http://www.medicinesresources.nhs.uk/upload/DMO_Feb_2011.pdf

http://www.medicines.org.uk/emc/medicine/27585/SPC/JETREA+0.5+mg+0.2+ml+concentrate+for+solution+for+injection/


http://www.hsc.nihr.ac.uk/files/downloads/1856/2088.e988d392.Ocriplasmin_amended_July2012.pdf

http://www.medicines.org.uk/emc/medicine/19409/SPC/Lucentis+10+mg+ml+solution+for+injection/

http://www.nhsc-healthhorizons.org.uk/files/downloads/1644/2089.62651bde.Ranibizumab.pdf





BNF 12. Ear, nose and oropharynx

Azelastine hydrochloride/ fluticasone propionate

Dymista - SmPC

Meda

Licensed indication: Moderate to severe seasonal and perennial allergic rhinitis.

Guidance: SMC: Due Dec 2013.

Reviews: None.

BNF 13. Skin

Aminolaevulinic acid

Ameluz - SmPC

Spirit Healthcare

Licensed indication: Actinic keratosis of mild to moderate intensity on the face and scalp.

Guidance: SMC: Approved. AWMSG: In progress.

Reviews: None.

Imiquimod 3.75%

Zyclara - SmPC

MEDA

Licensed indication: Actinic keratosis on the face and scalp in immunocompetent adults.

Guidance: None.

Reviews: MTRAC Jun 2013, RDTC Apr 2013.

Ingenol mebutate

Picato - SmPC

LEO Pharma

Licensed indication: Actinic keratosis in adults – first-line.

Guidance: SMC: Approved. AWMSG: Recommended.

Reviews: MTRAC Jun 2013, RDTC Apr 2013, NICE-MPC Mar 2013.


http://www.medicines.org.uk/emc/medicine/27579/SPC/Dymista+Nasal+Spray/

http://www.medicines.org.uk/emc/medicine/27817/SPC/Ameluz+78+mg+g+gel/

http://www.scottishmedicines.org.uk/SMC_Advice/Advice/811_12_5_aminolaevulinic_acid_Ameluz/5_aminolaevulinic_acid_Ameluz


http://www.medicines.org.uk/emc/medicine/27323/SPC/Zyclara+3.75++cream/

http://www.keele.ac.uk/media/keeleuniversity/fachealth/fachealthsop/mtrac/documents/summary/imiquimod%20verdict%20sum%20FINAL%20mark%202.pdf

http://rdtc.nhs.uk/evaluation-report-newer-topical-therapies-actinic-keratoses

http://www.medicines.org.uk/emc/medicine/27246/SPC/Picato+150+mcg+g+Gel/

http://www.scottishmedicines.org.uk/SMC_Advice/Advice/851_13_ingenol_mebutate_gel_Picato/ingenol_mebutate_gel_Picato


http://www.keele.ac.uk/media/keeleuniversity/fachealth/fachealthsop/mtrac/documents/summary/ingenol%20mebutate%20gel%20verdict%20FINAL.pdf

http://rdtc.nhs.uk/evaluation-report-newer-topical-therapies-actinic-keratoses

http://publications.nice.org.uk/esnm14-actinic-keratosis-ingenol-mebutate-gel-esnm14/


Patent expiries 2013 - 2015

Generic medicines have a significant impact on prescribing budgets and can offset, to some extent, costs

associated with the introduction of new medicines. Generic products can be marketed once the patent on the

original product has expired although manufacturers may apply for a Supplementary Protection Certificate (SPC) to

extend the effective patent life by up to 5 years (5½ years if it includes a Paediatric Investigation Plan). Expiry dates

below take account of SPCs. The table highlights those drugs where there is a greater potential for the availability

of a generic/biosimilar product. In addition, the table indicates where a licence for a generic/biosimilar product is in

the latter stages of the EU licensing process or is already available in the EU. However, it does not follow that the

generic/biosimilar product will be available in the UK as patent issues may differ between countries. Patent

legislation is complex and the information below should be used as a guide only.

* Drugs which have the greatest potential for generic/biosimilar preparations becoming available.

# Drugs where generic/biosimilar products are in later stages of EU licensing or are licensed in EU (see also over the page).

Patent extended by 6 months (paediatric extension).

Expiry date

Drug

2013

Feb Montelukast

Fosphenytoin sodium

Ganirelix

Mar Dorzolamide/ timolol #

Zidovudine/ lamivudine

Daclizumab

Apr Basiliximab

May Nelarabine

Tirofiban

Zoledronic acid #

Jun Capecitabine #

Nevirapine #

Sildenafil #

Jul Etonogestrel

Aug Raloxifene HCl #

Rizatriptan #

Clopidogrel hydrogen

sulphate

Oct Irbesartan/ hydrochlorothiazide

Nov Efavirenz

Rituximab *

Dec Telmisartan #

Expiry date

Drug

2014

Feb Alemtuzumab

Temoporfin

Zanamivir *

Mar Somatropin (synthetic hGH)

Apr Memantine HCl

May Anakinra

Escitalopram oxalate

Jun Abacavir

Hydroxyethyl starch

Moxifloxacin

Ulipristal acetate *

Jul Trastuzumab

Verteporfin

Aug Palivizumab

Sep Cetuximab *

Panitumumab

Oct Aripiprazole *

Nelfinavir mesylate

Paliperidone

Nov Insulin glargine

Icatibant acetate

Dec Almotriptan

Bevacizumab

Brinzolamide *

Omalizumab

Expiry date

Drug

2015

Feb Infliximab *

Mar Darifenacin

Tegafur/ uracil

Apr Aripiprazole *

May Clofarabine

Glatiramer

Insulin glargine

Jun Nepafenac

Tenecteplase

Jul Etanercept

Rasburicase

Aug Bivalirudin

Strontium ranelate

Sep Etoricoxib

Nateglinide

Sirolimus

Tiotropium *

Oct Alitretinoin

Nov Palonosetron

Pimecrolimus

Dec Eletriptan

Frovatriptan

Lopinavir/ ritonavir

Pemetrexed


Biosimilar developments

What are biosimilars?

Biosimilars are ‘generic’ biological medicines. Unlike conventional pharmaceuticals, which are generally low molecular weight organic compounds with a defined chemical structure, biologicals are large complex proteins that cannot be copied exactly. To gain a licence, the manufacturer must provide the EMA with adequate data to show that their biosimilar is physically, chemically, biologically and clinically similar to the approved originator product. This data will be derived from extensive laboratory analysis of molecular characteristics, in vitro and in vivo studies in multiple species of animals and phase I studies in humans to define pharmacokinetics, pharmacodynamics and toxicity. In addition, phase III studies are performed to show clinical efficacy and safety; post-marketing risk management plans and phase IV studies assess safety in routine practice. Consequently, development of a biosimilar is more costly and protracted (up to eight years) compared to that of a standard generic medicine.

What biosimilars are currently available or will soon be available?

Three drugs are currently available in the UK in biosimilar formulations: filgrastim, epoetin and somatropin. These are reasonably simple protein structures compared to monoclonal antibodies. The first monoclonal antibody biosimilar to be submitted for marketing approval in the EU, infliximab, is in the final stages of the licensing process; two brands of the same infliximab biosimilar (Inflectra and Remsima) were recommended for approval by the EMA in June 2013 with all the same indications as the originator product, Remicade, even though clinical studies have only been carried out in adults with ankylosing spondylitis (PI studies) and rheumatoid arthritis (PIII studies). Launch of infliximab biosimilar, if licensing is confirmed, will be delayed until the patent protecting the originator product expires.

What is the impact of biosimilars?

Marketed biosimilars are currently 5-20% cheaper than the originator products. Celltrion has stated that Remsima will cost at least 30% less than Remicade. Originators will no doubt seek to retain their market share; for example, by making their products more attractive by reformulating to simplify administration, or by offering competitive discounts.

What other biosimilars are in the pipeline?

The table below gives details of those medicines identified elsewhere in this document (Patent expiries) for which biosimilars are in clinical development. Further information on biosimilars that could be licensed in the UK in the near future is given in the table on the following page.

Drug name Patent expiry

Biosimilar Disease/Indication Highest development stage relevant to EU

Company

Bevacizumab 2014 BI 695502 Cancer PI Boehringer Ingelheim

Etanercept 2015 SB4 Rheumatoid arthritis PIII Samsung Bioepis

GP 2015 Plaque psoriasis PIII Sandoz

AFOLIA Pre-registration Finox

Infliximab 2015 CT P13 (Inflectra,

Remsima)

All inflammatory indications for which the originator is licensed

Recommended for approval Jun 2013

Celltrion, Hospira

Insulin glargine

2015 LY 2963016 Diabetes Pre-registration Eli Lilly/ Boehringer Ingelheim

Rituximab 2013 BI 695500 Rheumatoid arthritis PIII Boehringer Ingelheim

BI 695500 Non-Hodgkin's lymphoma PIII Boehringer Ingelheim

SAIT-101 Rheumatoid arthritis PIII Samsung

MK-8808 Follicular lymphoma PIII Merck

GP 2013 Follicular lymphoma PIII Sandoz

Trastuzumab 2014 ABP-980 Breast cancer PIII Amgen

CT P06 (CT-P6)

Breast cancer PIII Celltrion/ Hospira

Gastric cancer Celltrion/ Hospira


Infliximab

CT P13 injection

Inflectra/ Remsima

Hospira/ Celltrion

Indication:

Rheumatoid arthritis, adult and paediatric Crohn’s disease, adult and paediatric ulcerative colitis, ankylosing spondylitis, psoriatic arthritis and psoriasis.

Current status:

Recommended for approval in EU Jun 2013. First monoclonal antibody to have gone through the EU biosimilar regulatory process.


2014/2015

(Patent expiry 2015)

Pharmacology: Monoclonal tumour necrosis factor alpha (TNF-a) inhibitor. Originator product - Remicade.

Efficacy: Rheumatoid arthritis: CT P13 was compared to Remicade in a 54-week PIII study in 606 patients also receiving methotrexate. At all assessment points, there were no clinically significant differences between the two groups in efficacy or safety outcomes. In a PIII trial, safety was similar to that of the branded product, and in particular there was no statistically significant difference in the ratio of patients who developed anti-drug antibodies.

Follitropin alfa XM 17 injection

Ovaleap

Teva

Indication:

Fertility disorders: anovulation unresponsive to clomifene citrate; stimulation of multifollicular development in women undergoing assisted reproduction; with luteinising-hormone (LH) for stimulation of follicular development in severe LH and FSH deficiency; stimulation of spermatogenesis in men.

Current status:



2013

(Patent expired 2009)

Pharmacology: Human recombinant follicle stimulating hormone (FSH). Originator product – Gonal-f.

Efficacy: An international PIII study in 280 women undergoing assisted reproductive technologies compared XM17 to Gonal-f, administered for up to three cycles. The primary outcome was number of cumulus oocyte complexes retrieved.

Follitropin alfa AFOLIA injection

Bemfola

Finox

Indication:

Fertility disorders.

Current status:

Filed in the EU in Dec 2012.


2014

(Patent expired 2009)

Pharmacology: Human recombinant follicle stimulating hormone (FSH). Originator product – Gonal-f. Uses a different injector device to Gonal-f that reduces administration to three steps.

Efficacy: A single-blind European PIII study comparing Bemfola vs. Gonal-f in 410 women during the first or second cycle of assisted reproductive treatment has been completed. The primary outcome was the number of retrieved oocytes. A second PIII study vs. Gonal-f started in the US in May 2013. It is enrolling 1,106 women undergoing in vitro fertilisation and has a primary outcome clinical pregnancy rate.

Insulin glargine

LY 2963016 injection

Eli Lilly/ Boehringer Ingelheim

Indication:

Diabetes mellitus type 1 and 2 (T1DM, T2DM)

Current status:

Filed in the EU in Jul 2013.


2014/2015


Pharmacology: Recombinant human insulin analogue. Originator product - Lantus.

Efficacy: Two PIII studies vs. Lantus have been completed: ELEMENT 1 in 400 adults with T1DM in which it was used in combination with insulin lispro and ELEMENT 2 in 606 adults with T2DM used in combination with oral hypoglycaemics.

Trastuzumab

CT P06 injection

Hospira/ Celltrion

Indication:

Breast cancer, HER 2 positive, early and metastatic. Gastric cancer, HER2 positive.

Current status:

PIII.

Filed in Korea in Jun 2013 for the range of indication for which Herceptin is licensed.


2014/2015


Pharmacology: Anti-HER2 monoclonal antibody. Originator product - Herceptin.

Efficacy: A PIII study in 383 patients with HER2+ metastatic breast cancer showed CT-P6 and trastuzumab, both in

combination with paclitaxel, to have equivalent efficacy in terms in overall response rate and safety profile when given as first-line therapy every 3 weeks.









http://www.controlled-trials.com/ISRCTN74772901



http://clinicaltrials.gov/ct2/show/NCT01121666?term=NCT01121666










Index

AB Science ................... 19, 36, 53

Abatacept .................................. 66

Abbott ........................................ 61

AbbVie ...................................... 61

Abilify ........................................ 62

Abiraterone ............................... 64

ABT450/ ritonavir/ ABT267/

ABT333 ................................. 25

Aclidinium .................................. 61

Actoxumab/bezlotoxumab ......... 25

Adalimumab .............................. 61

Adasuve .................................... 20

Adcetris ............................... 64, 65

Adempas ................................... 16

Aegerion Pharmaceuticals ........ 16

Afamelanotide ........................... 58

Afatinib .......................... 30, 31, 32

Afinitor ....................................... 35

Aflibercept ............... 56, 57, 64, 66

Afrezza ...................................... 27

Alcon ......................................... 66

Alemtuzumab ...................... 10, 48

Alimera Sciences ...................... 66

Alipogene tiparvovec ................. 52

Alirocumab ................................ 16

Allergan ............................... 29, 63

Almirall ...................................... 61

Alogliptin ................................... 26

Alogliptin/metformin ................... 26

Alpharadin ................................. 40

Ameluz ...................................... 67

Amgen ..................... 16, 42, 44, 69

Aminolaevulinic acid .................. 67

Amrubicin .................................. 60

Anamorelin ................................ 33

Apaziquone ............................... 38

Apixaban ....................... 13, 60, 61

Apremilast ..................... 10, 54, 57

Arcoxia ...................................... 62

Arena ........................................ 60

Ariad .......................................... 65

Aripiprazole ............................... 62

Arzerra ...................................... 47

Astellas ......................... 60, 64, 65

AstraZeneca ...... 27, 42, 55, 62, 63

Asunaprevir/daclatasvir ............. 25

Ataluren ......................... 10, 20, 55

Atomoxetine .............................. 62

Aubagio ............................... 50, 51

Auxilium .................................... 30

Avastin .......................... 34, 41, 64

AWMSG ...................................... 4

Axitinib ................................ 60, 64

Azelastine hydrochloride/

fluticasone propionate ........... 67

Baxter ........................................ 48

Bayer .... 14, 16, 30, 35, 36, 37, 38,

40, 56, 57, 61, 66

Bazedoxifene/conjugated

estrogens............................... 28

Beclometasone/formoterol ........ 61

Bedaquiline ............................... 22

Belagenpumatucel-L ................. 32

Belviq ........................................ 60

Bemfola ..................................... 70

Bendamustine ........................... 45

Berinert ..................................... 61

Betmiga ..................................... 64

Bevacizumab ............ 9, 34, 41, 64

Bevacizumab biosimilar ............ 69

Bexsero ..................................... 59

Biogen ....................................... 50

Biogen Idec ......................... 49, 50

BioMarin .................................... 51

BiovaxID ................................... 45

Biovest International ................. 45

Boehringer Ingelheim ... 13, 30, 31,

32, 63, 69, 70

Bortezomib .......................... 46, 64

Bosulif ....................................... 64

Bosutinib ................................... 64

Botox ................................... 29, 63

Botulinum A toxin ................ 29, 63

Brain cancer vaccine ................. 30

Brentuximab ........................ 64, 65

Bristol Myers Squibb .... 25, 27, 39,

42, 43, 61, 63, 66

Budesonide/ formoterol ............. 19

Bufomix Easyhaler .................... 19

C1-esterase inhibitor ................. 61

Cabozantinib ....................... 31, 40

Calsed ....................................... 60

Canagliflozin ............................. 26

Canagliflozin/metformin ............ 26

Canakinumab ...................... 53, 66

Cangrelor .................................. 15

Carfilzomib ................................ 46

Ceftaroline ................................ 62

Celgene .................. 54, 57, 60, 65

Celltrion ............................... 69, 70

Celsion ...................................... 37

Ceptaris Therapeutics ............... 48

Chiesi .................................. 52, 61

Chlormethine ............................ 48

Cialis ......................................... 64

Clevidipine ................................ 17

Cleviprex ................................... 17

Clinuvel ..................................... 58

Cobicistat .................................. 23

Cobimetinib ............................... 44

Colistimethate sodium ............... 61

Collagenase clostridium

histolyticum ........................... 30

Colobreathe .............................. 61

Cometriq ............................. 31, 40

Constella ................................... 61

Crizotinib ................................... 65

CSL Behring ............................. 61

Custirsen ................................... 39

Dabigatran ................................ 13

Dabrafenib ............................ 9, 43

Daclizumab ............................... 50

Dacogen ................................... 65

Dacomitinib ............................... 32

Dapagliflozin ............................. 63

Dapagliflozin/metformin ............ 27

Daratumumab ........................... 46

Dasiprotimut-T .......................... 45

DCVax-L ................................... 30

Decapeptyl ................................ 65

Decitabine ................................. 65

Deferasirox ............................... 66

Defibrotide ............................ 8, 17

Defitelio ..................................... 17

Dendreon .................................. 39

Desmoteplase ........................... 15

Dextromethorphan/ quinidine 8, 21

Dimethyl fumarate .............. 10, 50

Dolutegravir .............................. 23

Doxorubicin heat-sensitive ........ 37

Duavive ..................................... 28

Dymista ..................................... 67

Efient ........................................ 60

Eisai ...................31, 32, 42, 60, 62

Eklira Genuair ........................... 61

Eli Lilly ......... 37, 60, 62, 64, 69, 70

Eliquis ........................... 13, 60, 61

Elosulfase alfa .................... 10, 51

Eltrombopag ....................... 10, 51

Elvanse ..................................... 62

Elvitegravir/ cobicistat/

emtricitabine/ tenofovir .......... 62

Enbrel ....................................... 66

Enobosarm ............................... 33

Enzalutamide ............................ 65

Eribulin ................................ 32, 42

Erismodegib .............................. 44

Erivedge ................................... 65

Esbriet ...................................... 62

Espanda ................................... 18

Estybon ..................................... 48

Etanercept ................................ 66

Etanercept biosimilar ................ 69

Etoricoxib .................................. 62

Everolimus ............................ 8, 35

Evolcumab ................................ 16

Exelixis ............................... 31, 40

Exenatide .................................. 27

Exjade ....................................... 66

Eylea............................. 56, 57, 66

Farletuzumab ............................ 60

Ferumoxytol .............................. 66

Fingolimod ................................ 50

Finox ................................... 69, 70

Fluocinolone acetonide ............. 66

Fluticasone propionate/

formoterol fumarate ............... 61

Flutiform .................................... 61

Follitropin alfa biosimilar ........... 70

Forest Laboratories................... 61

Forxiga ...................................... 63

Fostair ....................................... 61

Fresenius Medical Care ............ 19

Fycompa ................................... 62

Ganetespib ............................... 32

Gazyva ..................................... 47


Gentium .................................... 17

Genzyme ....................... 20, 48, 60

Gilead ...................... 23, 24, 25, 62

Gilead Sciences ........................ 47

Gilenya ...................................... 50

Giotrif ............................ 30, 31, 32

GlaxoSmithKline ..... 18, 40, 43, 44,

47, 51, 65

Glybera ..................................... 52

Glycopyrronium bromide ........... 61

Golimumab .......................... 11, 53

Grupo Ferrer ............................. 20

GTXi .......................................... 33

Halaven ............................... 32, 42

Helsinn ...................................... 33

Herceptin ................................... 34

Hidrasec .................................... 61

Hospira ................................ 69, 70

Humira ...................................... 61

Hydrocortisone .......................... 63

Ibrutinib ..................................... 47

Iclusig ........................................ 65

Idebenone ................................. 56

Idelalisib .................................... 47

Ilaris .................................... 53, 66

Iluvien ........................................ 66

Imatinib ..................................... 60

Imiquimod ................................. 67

Imnovid ..................................... 65

Indacaterol/ glycopyrronium ...... 18

Inflectra ..................................... 70

Infliximab biosimilar ............. 69, 70

Ingenol mebutate ...................... 67

Inlyta ................................... 60, 64

Insulin inhaled ........................... 27

Insulin degludec ........................ 63

Insulin degludec/ insulin aspart .. 8,

27

Insulin glargine .......................... 63

Insulin glargine biosimilar .... 69, 70

Intarcia therapeutics .................. 27

Intercept .................................... 12

InterMune .................................. 62

Invokana ................................... 26

Ipilimumab ....................... 9, 39, 42

Ipsen ......................................... 65

Ivacaftor .................................... 62

Jakavi ........................................ 65

Janssen-Cilag .. 22, 24, 26, 46, 47,

48, 54, 64, 65

Jenson ...................................... 21

Jentadueto ................................ 63

Jenzyl ........................................ 60

Jetrea ........................................ 66

Kadcyla ............................... 33, 34

KAEL-GemVax .......................... 60

Kalydeco ................................... 62

Kinaction ................................... 36

Komboglyze .............................. 63

Krystexxa .................................. 55

Kynamro .................................... 60

Kyprolis ..................................... 46

L(C)NDG ..................................... 4

Lantus ....................................... 63

Lapatinib ................................... 65

Laquinimod ......................... 10, 49

Latuda ....................................... 20

LDK378 ..................................... 32

Lemtrada ................................... 48

Lenalidomide ............................ 65

Lenvatinib ................................. 31

LEO Pharma ............................. 67

Lesinurad .................................. 55

Levact ....................................... 45

Linaclotide ................................. 61

Linagliptin .................................. 63

Linagliptin/ metformin ................ 63

Liraglutide ................................. 21

Lisdexamfetamine dimesylate ... 62

Lixisenatide ............................... 63

LNDG .......................................... 4

Lojuxta ...................................... 16

Lomitapide ................................ 16

Lorcaserin ................................. 60

Loxapine ................................... 20

Lucane Pharma ........................ 52

Lucanix ..................................... 32

Lucentis .................................... 66

Lumacaftor ................................ 20

Lundbeck ............................ 15, 62

Lurasidone ................................ 20

Lyxumia .................................... 63

MabThera ................................. 45

MannKind Corporation .............. 27

Martindale ................................. 62

Masitinib .................... 9, 19, 36, 53

Meda ......................................... 67

Medroxyprogesterone acetate .. 63

Mekinist ..................................... 44

Meningococcal group-B vaccine 59

Merck .................................. 60, 69

Mipomersen .............................. 60

Mirabegron ................................ 64

MSD 11, 15, 25, 41, 53, 55, 62, 64

MTRAC ....................................... 4

Nalfurafine ................................ 19

Nalmefene ................................ 62

Naloxone ................................... 62

Napp ................................... 45, 61

Neoquin .................................... 38

NETAG ....................................... 4

Nexavar .................. 30, 35, 37, 38

NHSC .......................................... 4

NICE ........................................... 4

NICE-MPC .................................. 4

Nomegestrol acetate/ estradiol . 64

Norgine ..................................... 63

Northwest Biotherapeutics ........ 30

Novartis 17, 18, 19, 28, 32, 35, 44,

50, 53, 54, 58, 59, 60, 61, 63,

65, 66

NovaRx Corporation ................. 32

Novo Nordisk ................ 21, 27, 63

NPC ............................................ 4

NPS Pharmaceuticals ............... 12

Nuedexta .................................. 21

Oasmia ..................................... 41

Obeticholic acid......................... 12

Obinutuzumab .................... 10, 47

Ocriplasmin ............................... 66

Odanacatib ............................... 55

Ofatumumab ....................... 10, 47

Olaparib .................................... 42

Omacetaxine meppesuccinate . 46

Omalizumab ............................. 19

Omontys ................................... 60

OncoGenex .............................. 39

Onyx ......................................... 46

Orencia ..................................... 66

Orion Pharma ........................... 19

Ostarine .................................... 33

Otsuka ...................................... 62

Otsuka Pharmaceuticals ........... 29

Ovaleap .................................... 70

Paclical ..................................... 41

Paclitaxel .................................. 41

Palbociclib ................................ 35

Pari Pharma .............................. 22

Pasireotide .......................... 28, 63

Pazopanib ............................. 9, 40

Peginesatide ............................. 60

Peginterferon beta-1a ............... 49

Pegloticase ............................... 55

Perampanel .............................. 62

Perjeta ...................................... 65

Pertuzumab .............................. 65

Pfizer .... 13, 28, 32, 35, 57, 60, 61,

62, 63, 64, 65, 66

Pheburane ................................ 52

Phentermine/ topiramate .......... 60

Picato ........................................ 67

Pierre Fabre .............................. 58

Pirfenidone ............................... 62

Plegridy ..................................... 49

Plenadren ................................. 63

Pomalidomide ........................... 65

Ponatinib ................................... 65

Pradaxa .................................... 13

Prasugrel .................................. 60

Prenoxad .................................. 62

Propranolol ............................... 58

Protelos .................................... 60

Provenge .................................. 39

PTC Therapeutics ..................... 55

Qsiva ........................................ 60

Racecadotril .............................. 61

Radium-223 .............................. 40

Ramucirumab ........................... 37

Ranibizumab ............................. 66

RDTC .......................................... 4

Regorafenib .................... 9, 36, 37

Remsima .................................. 70

Revestive .................................. 12

Revlimid .................................... 65

Revolade .................................. 51

Ridaforolimus ............................ 60

Rienso ...................................... 66

Rifaximin ................................... 63

Rigosertib ................................. 48

Riociguat ................................... 16

Rituximab ........................ 9, 45, 65

Rituximab biosimilar.................. 69

Rivaroxaban ............. 8, 14, 15, 61

RoActemra ................................ 66

Roche ... 33, 34, 41, 44, 45, 47, 64,

65, 66

Ruvise ....................................... 60

Ruxolitinib ................................. 65


Ryzodeg .................................... 27

Samsca ..................................... 29

Samsung ................................... 69

Samsung Bioepis ...................... 69

Sandoz ...................................... 69

Sanofi ................ 16, 50, 51, 63, 64

Savient ...................................... 55

Saxagliptin/metformin ................ 63

Sayana ...................................... 63

Scenesse .................................. 58

Sebelipase alfa.......................... 52

Secukinumab ................ 53, 54, 58

Seebri Breezhaler ..................... 61

Selincro ..................................... 62

Serelaxin ................................... 17

Servier ....................................... 60

Shire .......................................... 62

SIGN ........................................... 4

Signifor ................................ 28, 63

Simeprevir ................................. 24

Simponi ............................... 11, 53

Sipuleucel-T .............................. 39

Situro ......................................... 22

SMC ............................................ 4

Sodium phenylbutyrate ............. 52

Sofosbuvir ................................. 24

Sofosbuvir/ledipasvir ................. 25

Sorafenib ................. 30, 35, 37, 38

Sovrima ..................................... 56

Spectrum ................................... 38

Spirit Healthcare ........................ 67

Stelara ....................................... 54

Stivarga ............................... 36, 37

Strattera .................................... 62

Stribild ....................................... 62

Strontium ranelate ..................... 60

Sunesis ..................................... 47

Synageva BioPharma ............... 52

Synribo ...................................... 46

Synta ......................................... 32

Tadalafil .................................... 64

Tafamidis .................................. 62

Tafinlar ...................................... 43

Takeda . 11, 12, 20, 26, 56, 60, 64,

65, 66

Talimogene laherparepvec ....... 44

Targaxan ................................... 63

Tecfidera ................................... 50

Teduglutide ............................... 12

Teriflunomide ................ 10, 50, 51

Tertomotide ............................... 60

Teva .............................. 46, 49, 70

The Medicines Company .... 15, 17

ThermoDox ............................... 37

Tivozanib .................................. 60

Tobramycin ............................... 22

Tocilizumab ............................... 66

Tofacitinib ........................... 57, 60

Tolvaptan .............................. 8, 29

Trajenta ..................................... 63

Trametinib ............................. 9, 44

Translarna ................................. 55

Trastuzumab biosimilar ....... 69, 70

Trastuzumab emtansine . 8, 33, 34

Trastuzumab/ hyaluronidase . 9, 34

Trebananib ................................ 42

Tresiba ...................................... 63

Triptorelin .................................. 65

Tybost ....................................... 23

Tyverb ....................................... 65

UKMi ........................................... 4

Ultibro Breezhaler ..................... 18

Umeclidinium ............................ 18

Umeclidinium/ vilanterol ............ 18

Ustekinumab ............................. 54

Valchlor ..................................... 48

Vantobra ................................... 22

Vedolizumab ....................... 11, 12

Velcade ............................... 46, 64

Vertex ................................. 20, 62

Victoza ...................................... 21

ViiV healthcare UK ................... 23

Vimizim ..................................... 51

Vintafolide ............................. 9, 41

Vipdomet .................................. 26

Vipidia ....................................... 26

ViroPharma ............................... 63

Vismodegib ............................... 65

Vivus ......................................... 60

Vosaroxin .................................. 47

Votrient ..................................... 40

Vyndaqel ................................... 62

Vynfinit ...................................... 41

Winfuran ................................... 19

Xalkori ....................................... 65

Xarelto ................................ 14, 61

Xeljanz ...................................... 57

Xiapex ....................................... 30

Xolair ........................................ 19

Xtandi ....................................... 65

Yervoy ................................ 39, 43

Zaltrap ...................................... 64

Zenapax .................................... 50

Zinforo ...................................... 62

Zoely ......................................... 64

Zyclara ...................................... 67

Zytiga ........................................ 64

Acknowledgements

Key contributors:

Helen Davis, North West MI Centre.

Alexandra Denby, London MI Service - Northwick Park.

Stephen Erhorn, Regional Drug & Therapeutics Centre, Newcastle.

Jim Glare, West Midlands MI Service.

Peter Golightly, Trent MI Centre.

Sue Gough, Wessex Drug & MI Centre.

Justine Howard, North West MI Centre.

Joanne McEntee, North West MI Centre.

Christine Proudlove, North West MI Centre.

Jill Rutter, North West MI Centre.

The following are acknowledged for commenting on draft versions, providing professional advice or technical and quality assurance support:

Alison Alvey, South West MI and Training Centre.

Liz Arkell, University Hospital of South Manchester NHS Foundation Trust.

Lindsay Banks, North West MI Centre.

David Erskine, London and South East MI Centre.

Simone Henderson, North West MI Centre.

Ashley Marsden, North West MI Centre.

Helen Potter, Cheshire, Warrington & Wirral Area Team NHS England.

Christine Randall, North West MI Centre.

Gail Woodland, Welsh MI centre and All Wales Medicines Strategy Group.

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