Download - Sequencing workshop treatment algorithm
This meeting has been initiated, organised and funded by Merck
Professor Gavin GiovannoniBarts and The London School of Medicine & Dentistry
Expert opinions on switching:Treatment algorithms
Disclosures
Over the last 15 years, I have received personal compensation for participating in advisory boards in relation to clinical trial design, trial steering committees, and data and safety monitoring committees from:
Abbvie, Almirall, Atara Bio, Bayer-Schering Healthcare, Biogen, Canbex, Eisai, Elan, Fiveprime, Genzyme, Genentech, GSK, GW Pharma, Ironwood, MSD, Merck Serono, Novartis, Pfizer, Roche, Sanofi, Synthon BV, Teva, UCB Pharma and Vertex Pharmaceuticals
Learning objectives
ObjectiveTo provide sufficient information on specific DMT sequences and help attendees develop a strategy for managing the associatedrisks with particular sequences
Questions to considerDrawing upon the available evidence and guidance on MS DMT sequencing, explore what the existing data suggest are the logical sequences of MS DMTs
Establish which specific sequences are useful/successful
Outline the differences between continuous immunosuppression and discontinuous immunosuppression. Establish how this informs treatment sequencing
Explore other factors that may influence treatment sequencing. How might these affect the treatment algorithm?
OutcomesExplore sequences for the following populations:
● Sequencing due to lack of efficacy (of another DMT)
● Sequencing due to risk (AE)
● Sequencing due to lifestyle decision (e.g. family planning)
● Stopping DMT’s due to SPMS
AE, adverse event; DMT, disease-modifying therapy; SPMS, secondary progressive multiple sclerosis.
Mitoxantrone*2000 (RMS/SPMS)
Evolving therapeutic landscape
*Licensed in the US, Germany, Austria and France#Unlicensed
BMT/HSCT, bone marrow transplant/haematopoietic stem cell transplantation; IFN, interferon; IM, intramuscular; RMS, relapsing multiple sclerosis;RRMS, relapsing-remitting multiple sclerosis; R-SPMS, relapsing-secondary progressive multiple sclerosis; PPMS, primary progressive multiple sclerosis; SC, subcutaneous
1994 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014 2016 2018
SC IFN beta-1b1995 (RMS)
IM IFN beta-1a1997 (RMS)
BMT/HSCT#
1997 (RMS)
SC IFN beta-1a1998 (RMS)
Glatiramer acetate20 mg/mL2003 (RMS)
Natalizumab2006 (RRMS)
Fingolimod2011 (RRMS)
Alemtuzumab2013 (RRMS)
Teriflunomide2013 (RRMS)
Dimethyl fumarate2014 (RRMS)
Peginterferon beta-1a2014 (RRMS)
Glatiramer acetate40 mg/mL2015 (RMS)
Daclizumab2016 (RMS)
Oral cladribine2017 (RMS)
Ocrelizumab2018 (RMS/PPMS)
Draft treatment algorithm for multiple sclerosis disease-modifying therapies
ABN NHS England, DraftPlease note the ordering of drugs within each category is alphabetical and not intended to indicate a heirarchy of treatment
Switch due to disease activity Switch due to intolerance
Rescue therapyfor continuedinflammatory activitywhilst on second-linetherapy
Second-line therapyfor disease activitywhilst on first-linetherapy
First-line therapy
Presentation
Alternative first-linetherapy due tointolerance
No treatment
Beta-interferon
No treatment
Beta-interferon
Alemtuzumab, rarely
See note 9Beta-interferon
Glatiramer acetateTeriflunomide
Dimethyl fumarate
Alemtuzumab
No changeAlemtuzumab
CladribineDaclizumab
NatalizumabAutologous haematopoietic stem cell transplant
Beta-interferon
Dimethyl fumarate
Alemtuzumab, but see note 7
Glatiramer acetate
Teriflunomide
Alemtuzumab
Cladribine
Natalizumab
AlemtuzumabCladribineFingolimod
Natalizumab(Daclizumab)
Alemtuzumab
Cladribine
Natalizumab
(Daclizumab)
Clinically isolatedsyndrome with
multiple MRI lesions
Clinically isolatedsyndrome & MRI activity,
i.e. McDonald MS
RRMS:1 relapse in 2 years AND
radiological activity
RRMS:2 significant relapses
in last 2 years
Rapidly evolvingsevere MS
Alemtuzumab
Cladribine
Fingolimod
(Daclizumab)
Highlyactive MS
CSF, cerebrospinal fluid; Gd, gadolinium.
No evidence of disease activity: NEDA-4
No evidence of disease activity defined as:1,2
No relapses
No sustained disability progression
No MRI activity
No new or enlarging T2 lesions
No Gd-enhancing lesions
Treat-2-target
1. Havrdova E, et al. Lancet Neurol 2009; 8:254–260; 2. Giovannoni G, et al. Lancet Neurol 2011; 10:329–337.
Normalisation of brain atrophy rates
Normalisation of CSF neurofilament levels
Alem, alemtuzumab; Clad, cladribine tablets; Dac, daclizumab; DMF, dimethyl fumarate; Fingo, fingolimob; GA, glatiramer acetate; *HSCT, Hematopoietic stem cell transplantation (not licensed in the UK for MS);IFN beta, interferon-beta; NABs, neutralising antibodies; NEDA, no evident disease activity; Nz, natalizumab; Rx, treatment; Teri, teriflunomide; T2T, treating-to-target
Barts-MS T2T NEDA algorithm
Choose therapy
Define the individual’s MS
Choose a therapeutic strategy
Maintenance-escalation Immune reconstruction therapy (IRT)
Choose therapy
Nz/DacFingo/DMF/TeriIFN beta/GA HSCT*CladAlem
Initiate switch or Escalate Rx Complete course/Re-treat
Re-baseline Re-baseline
Monitoring Monitoring
Treatment failure? Breakthrough disease
Yes No No Yes
What is an immune reconstitution therapy or IRT?
An immune reconstitution therapy (IRT) is, by definition,given as a short course, i.e. intermittently and not continuously,
and has the ability to induce long-term remission and insome cases the possibility of a cure
*In multiple sclerosis, inflammatory activity typically refers to clinical relapses and/or focal MRI activity (new T2 lesions and or Gd-enhancing lesions)Gd, gadolinium; IRT, immune reconstitution therapy; MRI, magnetic resonance imaging
Please note that an IRT is not given continuously and additional courses of the therapyare only given if there is a recurrence of inflammatory activity*
What is a maintenance therapy?
*In multiple sclerosis, inflammatory activity typically refers to clinical relapses and/or focal MRI activity (new T2 lesions and or Gd-enhancing lesions)Gd, gadolinium; MRI, magnetic resonance imaging
A maintenance therapy is, by definition, given continuously,without an interruption in dosing, and although it has the
ability to induce long-term remission it cannot result in a cure
Please note that maintenance therapy is given continuously and if while on therapythere is a recurrence of, or ongoing, inflammatory activity*, it is an indication that there is a suboptimal response
Mitoxantrone*2000 (RMS/SPMS)
Maintenance vs IRT
*Licensed in the US, Germany, Austria and France#Unlicensed
BMT/HSCT, bone marrow transplant/haematopoietic stem cell transplantation; IFN, interferon; IM, intramuscular; IRT, immune reconstitution therapy; RMS, relapsing multiple sclerosis;RRMS, relapsing-remitting multiple sclerosis; R-SPMS, relapsing-secondary progressive multiple sclerosis; PPMS, primary progressive multiple sclerosis; SC, subcutaneous
1994 1996 1998 2000 2002 2004 2006 2008 2010 2012 2014 2016 2018
SC IFN beta-1b1995 (RMS)
IM IFN beta-1a1997 (RMS)
BMT/HSCT#
1997 (RMS)
SC IFN beta-1a1998 (RMS)
Glatiramer acetate20 mg/mL2003 (RMS)
Natalizumab2006 (RRMS)
Fingolimod2011 (RRMS)
Alemtuzumab2013 (RRMS)
Teriflunomide2013 (RRMS)
Dimethyl fumarate2014 (RRMS)
Peginterferon beta-1a2014 (RRMS)
Glatiramer acetate40 mg/mL2015 (RMS)
Daclizumab2016 (RMS)
Oral cladribine2017 (RMS)
Ocrelizumab2018 (RMS/PPMS)
IRTsMaintenance treatments
The following are not licensed for MS in the UK: laquinimod, daclizumab, mitoxantrone, anti-CD20 therapies, and BMT. BMT/HSCT, bone marrow transplant/haematopoietic stem cell transplantation;GA, glatiramer acetate; IFN, interferon; IRTs, immune reconstitution therapies; NEDA, no evidence of disease activity; SPMS, secondary progressive multiple sclerosis
Maintenance therapies vs immune reconstitution therapies (IRTs)
Continuous treatmentAdherence potential problem
Low to very high efficacy
Reversible
Perceived to be lower riskCumulative, or increased, risk with time
ExamplesGA, IFN beta, teriflunomide, BG12, fingolimod,natalizumab, daclizumab, anti-CD20
Breakthrough diseaseSuboptimal or failure to respondNEDA reliable metric for efficacy
Rebound activityHighly likelyCan be life-threatening
Pregnancy
No potential for a cureReboundSPMS and progressive brain atrophy
Maintenance therapies IRTs
Short-courses or pulsed therapyAdherence seldom a problem
High to very high efficacy
Irreversible
Perceived to be higher riskFrontloading of risk or reduced risk with time
ExamplesNon-selective: mitoxantrone, alemtuzumab, BMT/HSCTSemi-selective: cladribine (minimal impact on innate immunity)
Breakthrough diseaseMarker for retreatmentNEDA unreliable to assess efficacy
Rebound activityLess likelyUnlikely to be life-threatening
Pregnancy
Potentially ‘curative’?15–20 year experiment
What is active MS?
2001Clinical
2009Clinical and MRI
2014Clinical or MRI
Inactive MS: no relapses orMRI activity in the last 24 months
Active MS: relapses in the last 12 or 24 monthsand/or MRI activity in the last 12 months
Highly active MS: relapses in thelast 12 months and MRI
activity in the last 12 months
Rapidly-evolving severe MS (RES):two disabling attacks in a
12-month period andMRI evidence of activity during
this period
MRI, magnetic resonance imaging
What is active MS?
2001Clinical
2009Clinical and MRI
2014Clinical or MRI
Inactive MS: no relapses or MRI activity in the last 24 months (NEDA)
MRI, magnetic resonance imaging; NEDA, no evidence of disease activity
Active MS: relapses in the last 12 or 24 monthsand/or MRI activity in the last 12 months
Highly active MS: relapses in thelast 12 months and MRI
activity in the last 12 months
Rapidly-evolving severe MS (RES):two disabling attacks in a
12-month period andMRI evidence of activity during
this period
100 MSers
Who are the responders?
20:80
?
40:60
?
80:20
?
2.36
2.692.54
2.38 2.36 2.39
3.13 3.073.22 3.24 3.21 3.15
2.9
2.69 2.722.84 2.85 2.79
0
0.5
1
1.5
2
2.5
3
3.5
4
Me
an E
DSS
sco
re
Original placebo
Original natalizumab
Original placebo, now on natalizumab
Natalizumab STRATA: stable EDSS scores for up to 5 years
Kappos L, et al. Presented at ECTRIMS; October 10–13, 2012; Lyon, France: P520.
1 Year 2 Years 3 Years 4 Years 5 Years
Cessation/
treatment gap*
*p<0.0001; EDSS, Expanded Disability Status Scale
n=380 707 381 707 280 552 385 709 274 569 230 479 205 462 194 427 174 393
Feederstudy
baseline
Feederstudyend
Safetystudyend
STRATAbaseline
STRATA48 weeks
STRATA96 weeks
STRATA144 weeks
STRATA192 weeks
STRATA240 weeks
Alem, alemtuzumab; Clad, cladribine tablets; Dac, daclizumab; DMF, dimethyl fumarate; Fingo, fingolimob; HDA, high disease activity; GA, glatiramer acetate;*HSCT, hematopoietic stem cell transplantation (not licensed in the UK for MS); IFN beta, interferon-beta; Nz, natalizumab; RES, rapidly-evolving severe; Teri, teriflunomide
Treatment ladder
HDA/RES
IFN beta
Teri
GA
DMF
Alem
Nz Clad
Fingo
Alem
Clad
Nz
Dac HSCT*
RES
Fingo Clad
Alem
Nz
Level 1
Level 2
Level 3
EDSS
IFN beta NatalizumabJun 2000 May 2014
6.0
3.5 3.5
EDSS, Expanded Disability Status Scale; IFN, interferon
17 year-old girl, myelitis
Jun 2000
Natalizumab
Jan 2008
Clumsy left hand
Jan 2002
Pins and needles in legs
Oct 2003
Right optic neuritis
Mar 2004
Brainstem syndrome;diplopia and ataxia
Dec 2007
Cervical cord relapse;weak left arm with pain
Jan 2008
NEDA (no evidence of disease activity)
Feb 2008 to May 2014
Bladder dysfunction
Mild urinary frequency
Depression, anxietyand fatigue
No depression, anxiety or fatigue
Reduced mobility Fully mobile
Residual deficits:
• Walking distance >500 m
• Unable to run
• Exercise induces intermittent sensory symptoms in left arm
• Mild urinary frequency
1st year university. Left optic neuritis
Feb 2001
IFN beta
Feb 2001
MRI – progressive brain atrophy
Is this patient in long-term remission?
Dec 2007 Jul 2010 Jul 2013
Pregnancy in multiple sclerosis
Vukusic S, et al. Brain. 2004;127:1353–1360
Delivery
0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1 2 3 4 1 2 3 1 2 3 4 5 6 7 8
Trimestersbefore pregnancy
Trimestersduring pregnancy
Trimestersafter pregnancy
Pregnancy
An
nu
al r
esp
on
se r
ate
a. Total number of administrations over the first 12 months of treatment; b. 10 tablets refers to a patient weighing 50 – <60 kgIFN, interferon; sc, subcutaneous; SmPC, Summary of Product Characteristics
Treatment burden
1. Rebif® EU SmPC; 2. Copaxone® SmPC; 3. Aubagio® EU SmPC; 4. Tecfidera® EU SmPC; 5. Tysabri® EU SmPC; 6. Gilenya® EU SmPC; 7. Lemtrada® EU SmPC; 8. Zinbryta® EU SmPC; 9. Mavenclad EU SmPC;10. Ocrevus EU SmPC
Natalizumab5
Teriflunomide3
Dimethyl fumarate4
Fingolimod6
Alemtuzumab7
Daclizumab8
Cladribine9
Glatiramer acetate2
sc IFN beta-1a1
Ocrelizumab10
12 Totala10 118 96 74 52 3Pre-dose 1
Month
156
365
365
730
12
365
5
12
10b
3
Adherence
In MS, patients with long gaps in treatment are at greater risk of relapse thanmore adherent patients1
Lower adherence to MS therapy is associated with a higher risk of relapse2
1. Al-Sabbagh A, et al. J Neurol 2008;255(Suppl. 2):S79; 2. Steinberg SC, et al. Clin Drug Invest 2010;30:89–100
MPR, Medication Possession Ratio
Good adherenceis important for
optimising outcomes
0.90
≥80
An
nu
al r
esp
on
se r
ate
0.95
1.00
1.05
1.10
1.15
<80 <75 <70 <65 <60
MPR (%)
Comparison of relapse risk ratios bylevel of adherence in patients with MS2
Patients could have reported more than one reason for non-adherence. When counting injection-related reasons for non-adherence, each patient was counted only once.GAP, Global Adherence Project
Forgetfulness is a primary cause of non-adherence
Devonshire V, et al. Eur J Neurol 2011;18:69–77
0
Re
aso
ns
for
mis
sin
g o
ne
or
mo
re in
ject
ion
s
Patients (%)
Pregnancy/planned pregnancyNot confident in treatment benefits
Financial reasonsNobody available to administer
Did not feel need for injectionDid not pick up medicine
DepressionWeakness
Skin reactionInjection anxiety
Dosing schedule difficult/inconvenientHeadache
Pain at injection siteFlu-like symptoms
FatigueOther
Tired of taking injectionsForgot to administer
10 20 30 40 50 60
1%2%2%
3%4%
5%6%
8%9%
10%10%10%
12%13%
15%17%
20%50%
Psychological factors– forgetfulness and complacency –
impact adherence
Observational GAP study
NB. Screening for latent infections, in particular TB and hepatitis B/C, must be performed prior to initiation of cladribine in Year 1 and 2. Numbers indicate the number of blood tests. CV, cardiovascular; DMT, disease-modifying therapy; hypersens., hypersensitivity; MRI, magnetic resonance imaging; SmPC, Summary of Product Characteristics; TB, tuberculosis.
DMT monitoring burden
1. Rebif® EU SmPC; 2. Copaxone® UK PI; 3. Aubagio® EU SmPC; 4. Tecfidera EU SmPC; 5. Tysabri® EU SmPC; 6. Gilenya® EU SmPC; 7. Lemtrada® EU SmPC; 8. Zinbryta® EU SmPC; 9. Mavenclad EU SmPC.
Blood Test Ophthalmology CV monitoring MRI Urinalysis
Renal function and cardiac function to be monitored in cases of renal impairment and pre-existing cardiac disorder, respectively
IFN beta-1a
Glatirameracetate2
Teriflunomide3
Dimethylfumarate4
Natalizumab5
Fingolimod6
Alemtuzumab7
Daclizumab8
Cladribine9
Pre-doseFirstdose
Month1
Month2
Month3
Month4
Month5
Month6
Month7
Month8
Month9
Month10
Month11
Month12
Immuno-suppression
TB screening
Infusionreaction
Vigilancefor skin
reactions
×2 ×2
×2
×3
×2
×2 ×2 ×3
×2
×2 ×2 ×3
×2
×2 ×2 ×3
×2
×3×3
×2×2×2×2
×2
×2×2×2
Hypersens.
×2
×3
TB screening×3
TB screening
Immunosuppression
Definition:Immunosuppression is a reduction of the activation or efficacy of the immune system
This definition refers to short-term/intermittent (induction) and long-term persistent immunosuppression (maintenance)
Immunomodulatory (not immunosuppressive)Interferon-betaGlatiramer acetate
Immunomodulatory (possibly immunosuppressive)TeriflunomideDaclizumab
ImmunosuppressiveMitoxantroneNatalizumab (selective compartment)Fingolimod and other S1P modulatorsDimethyl fumarateAlemtuzumabOcrelizumab (anti-CD20)1
Cladribine (purine analogue)
For a drug to be considered an immunosuppressantit should:
1. Cause significant lymphopenia
2. Be associated with opportunistic infections
3. Reduce the antibody response to vaccines
4. Be associated with secondary malignancies
1. Ocrevus EU SmPC.
Continuous(e.g. fingolimod, natalizumab)
Short-term(e.g. alemtuzumab, cladribine)
Immunosuppression
PML, progressive multifocal leukoencephalopathy
1. Persistent immunosuppression
2. Risk increases with time (cumulative)a. Increased risk of PML (complex pathogenesis)b. Increased risk of other opportunistic infectionsc. Increased risk of secondary malignancy
3. Live vaccines contraindicated
4. High risk of exotic infectionsa. Dengueb. Zikac. Etc
5. Pregnancy not recommended
6. Long-term burden of pharmacovigilance
1. Short-term immunosuppression
2. Short-term risk (front-loaded)a. Low risk of PMLb. Low risk of other opportunistic infectionsc. Low risk of secondary malignancy
3. Live vaccines not necessarily contraindicated
4. Low risk of exotic infections if travel occursafter immune reconstitution
5. Pregnancy opportunity post immune reconstitution
6. Less of a pharmacovigilance burden
Immunosuppression
PML, Progressive multifocal leukoencephalopathy; PCP, Pneumocystis carinii pneumonia; TB, tuberculosis
Continuous(e.g. fingolimod, natalizumab)
Short-term(e.g. alemtuzumab, cladribine)
Listeria TB PCP
ZosterNocardia
Frontloadingrisk
Cumulativerisk
Global natalizumab PML riskestimate by treatment epoch
(as of Feb. 28, 2017)TYSABRI PML risk estimates by treatment epoch
Basal cell carcinoma
1. Biogen, on file. https://medinfo.biogen.com/secure/download?doc=workspace%3A%2F%2FSpacesStore%2Fded9df8f-d785-444a-ae89-888bef72aa7e&type=pmldoc&path=null&dpath=null&mimeType=null
Derisking immunosuppression
CSF, cerebrospinal fluid; FBC, full blood count; LFTs, liver function tests; U&E, urea and electrolytes;HIV, human immunodeficiency virus; VZV, varicella zoster virus; TB, tuberculosis; LP, lumbar puncture; DMTs, disease-modifying therapies;IRTs, immune reconstitution therapies; PCP, Pneumocystis carinii pneumonia; TFTs, thyroid function tests; PML, progressive multifocal leukoencephalopathy; MRI, magnetic resonance imaging
Baseline Infusion DMTs and IRTs Monitoring
1. FBC: leukocytes/platelets
2. LFTs, U&E, urine
3. Pregnancy tests
4. Immunoglobin levels
5. Serum protein electrophoresis
6. Serologya. HIV 1/2b. Hepatitis B/Cc. VZVd. Syphilise. TB Elispot/Quantiferon assay
7. Cervical smear
8. Vaccinations
9. MRI
10. LP (CSF analysis)
11. Listeria prophylaxis
1. Infusion reactionsa. Corticosteroidsb. Anti-histaminesc. Anti-pyretics
2. Antibioticsa. Anti-herpesb. Listeria/PCP prophylaxis
1. Bloodsa. FBC: leukopeniab. TFTs, LFTs, U&E, …
2. Urinea. Autoimmuneb. Renal dysfunction
3. MRIa. Disease activityb. PML
4. Infectiona. Serologyb. CSF
5. Disease activity
6. Pregnancy
7. Malignancya. Skin, cervical, breastb. Etc.
The following are not licensed for MS in the UK: laquinimod, daclizumab, mitoxantrone, anti-CD20 therapies, and BMT. BMT/HSCT, bone marrow transplant/haematopoietic stem cell transplantation;GA, glatiramer acetate; IFN, interferon; IRTs, immune reconstitution therapies; NEDA, no evidence of disease activity; SPMS, secondary progressive multiple sclerosis
Maintenance therapies vs immune reconstitution therapies (IRTs)
Continuous treatmentAdherence potential problem
Low to very high efficacy
Reversible
Perceived to be lower riskCumulative, or increased, risk with time
ExamplesGA, IFN beta, teriflunomide, BG12, fingolimod,natalizumab, daclizumab, anti-CD20
Breakthrough diseaseSuboptimal or failure to respondNEDA reliable metric for efficacy
Rebound activityHighly likelyCan be life-threatening
Pregnancy
No potential for a cureReboundSPMS and progressive brain atrophy
Maintenance therapies IRTs
Short-courses or pulsed therapyAdherence seldom a problem
High to very high efficacy
Irreversible
Perceived to be higher riskFrontloading of risk or reduced risk with time
ExamplesNon-selective: mitoxantrone, alemtuzumab, BMT/HSCTSemi-selective: cladribine
Breakthrough diseaseMarker for retreatmentNEDA unreliable to assess efficacy
Rebound activityLess likelyUnlikely to be life-threatening
Pregnancy
Potentially ‘curative’?15–20 year experiment
Case study 1
42 year-old journalist, married with 2 children,
War correspondent – frequent travel to Afghanistan, Ukraine, Iraq and Syria
Diagnosed RRMS late 2014:
Initial symptoms of sensory symptoms in feet and Lhermitte’s phenomenon
Treated with dimethyl fumarate (Tecfidera)
Two disabling attacks in 2015 – ataxia and spinal cord lesion with weak legs
Diagnosis:
Rapidly-evolving severe (RES) MS
Treatment:
Eligible for fingolimod, natalizumab and alemtuzumab
Natalizumab contraindicated as found to be JCV-seropositive (index 1.86)Offered fingolimod – was not keen about long-term immunosuppression Interested in HSCT (not eligible under local guidelines) or alemtuzumab
Major concerns about monitoring and accessing urgent treatment when abroadas war correspondent
Joint decision to treat him with parenteral cladribine* (two cycles given Jan/Feb 2016 and 2017)
*Only cladribine tablets are licensed for the treatment of MSHSCT, haematopoietic stem cell transplantation; JCV, JC virus; RRMS, relapsing-remitting multiple sclerosis
Vaccinations
Gilenya EU SmPC
Vaccination
During and for up to two months after treatment with GILENYA,vaccination may be less effective. The use of live attenuatedvaccines may carry a risk of infections and should therefore beavoided (see sections 4.4 and 4.8).
Immunisations
In a randomised, open label study of 60 patients with relapsingMS there was no significant difference in the humoral immuneresponse to a recall antigen (tetanus toxoid) and only slightlyslower and reduced humoral immune response to a neoantigen(keyhole limpet haemocyanin) was observed in patients whowere treated with TYSABRI for 6 months compared to anuntreated control group. Live vaccines have not been studied.
Tysabri EU SmPC
Vaccines
It is recommended that patients have completed local immunisationrequirements at least 6 weeks prior to treatment with LEMTRADA.The ability to generate an immune response to any vaccine followingLEMTRADA treatment has not been studied.
The safety of immunisation with a live viral vaccine following a courseof LEMTRADA treatment has not been formally studied in controlledclinical trials in MS and should not be administered to MS patientswho have recently received a course of LEMTRADA.
Varicella zoster virus antibody testing/vaccinationAs for any immune modulating medicinal product, before initiatinga course of LEMTRADA treatment, patients without a history ofchickenpox or without vaccination against varicella zoster virus (VZV)should be tested for antibodies to VZV. VZV vaccination of antibody-negative patients should be considered prior to treatment initiationwith LEMTRADA. To allow for the full effect of the VZV vaccinationto occur, treatment with LEMTRADA should be postponed to 6 weeksfollowing vaccination.
Lemtrada EU SmPC
Live or live attenuated vaccines
Treatment with MAVENCLAD should not be initiated within 4 to 6 weeks after vaccination with live or attenuated live vaccinesbecause of a risk of active vaccine infection. Vaccination with live or attenuated live vaccines should be avoided during andafter cladribine treatment as long as the patient’s white blood cell counts are not within normal limits. Mavenclad EU SmPC
Case study 2
48 year-old woman (born 1969),married, two children, employed as a counsellor
1996: Probable first symptoms with mild transient sensory symptoms in legs
2001: Diagnosed with MS after an episode of weakness in right hand
2003: Right optic neuritis
2004: Weakness in legs with bladder involvement
2005–2007: CLARITY study (active treatment)
2008–2010: CLARITY EXTENSION (placebo)
2005–2015: NEDA, EDSS 3.0 (stable), walking unrestricted
April 2015: Numbness and pain right side of face, MRI new T2 lesion in brainstem
Refused platform DMTs(interferon-beta, glatiramer acetate, dimethyl fumarate, teriflunomide, alemtuzumab)
Treated with parenteral cladribine, June 2015*
*Only cladribine tablets are licensed for the treatment of MS DMTs, disease-modifying therapies; EDSS, Expanded Disability Status Scale; MRI, magnetic resonance imaging; MS, multiple sclerosis; NEDA, no evidence of disease activity
*p<0.05, **p<0.001, ***p<0.0001 study drug vs comparator. NEDA values are calculated from individual studies; conclusions drawn from comparing NEDA values should be done so with caution.NEDA defined as no relapses, no 3-month confirmed CDP, and no new T1 Gd+ lesions and no new enlarging or enlarged T2 lesions on cranial MRI (except CLARITY, CARE-MS I and CARE-MS II: based on no 6-month CDP).CDP, confirmed disability progression; Gd+, gadolinium-enhancing; IFN, interferon; IM, intramuscular; MRI, magnetic resonance imaging; NEDA, no evidence of disease activity; SC, subcutaneous.
48 48 47
3937
33 32
2528
23
2925
17
7
13 14 14 15 14
0
10
20
30
40
50
60
NEDA rates in Phase 3 trials
1. Traboulsee A, et al. Neurology 2016;86 [PL02.004]; 2. Giovannoni G, et al. Lancet Neurol 2011;10:329‒337; 3. Cohen AJ, et al. Lancet 2012;380:1819–1828; 4. Havrdova E, et al. Lancet Neurol 2009;8:254‒260;5. Bevan CJ, Cree BA. JAMA Neurol 2014;71:269‒270; 6. Coles AJ, et al. Lancet 2012;380:1829–1839; 7. Kappos L, et al. AAN 2016:115; 8. Giovannoni G, et al. Neurology 2012;78: PD5.005; 9. Freedman M, et al. Neurology 2012;78:PD5.007
37
OPERA I1
Ocrelizumaba
vsSC IFN
beta-1a
OPERA II1
Ocrelizumaba
vsSC IFN
beta-1a
CLARITY2
Cladribine tablets
vsplacebo
CARE-MS I3
Alemtuzumab vs
SC IFNbeta-1a
AFFIRM4
Natalizumabvs
placebo
FREEDOMS5
Fingolimod vs
placebo
CARE-MS II6
Alemtuzumab vs
SC IFNbeta-1a
DECIDE7
Daclizumab vs
IM IFNbeta-1a
DEFINE8
Dimethylfumarate
vsplacebo
TEMSO9
Teriflunomidevs
placebo
Pat
ien
ts a
chie
vin
g N
EDA
(%
)
*** *** *** * *** ** *** *** * **
27
NEDA, no evident disease activity; NEDA-2, clinical only (relapse-free and progression-free); NEDA-3, clinical and focal MRI activity;NEDA-4/5, clinical and focal MRI activity free and normalising brain atrophy loss and normalisation of CSF neurofilament levels.Alem, alemtuzumab; Clad, cladribine tablets; Dac, daclizumab; DMF, dimethyl fumarate; Fingo, fingolimod; GA, glatiramer acetate; IFN, interferon; Nz, natalizumab; Teri, teriflunomide
“Flipping the pyramid in MS”
Inactive
MS diseaseactivity
Active
Highly-active
Rapidly-evolvingsevere
NEDA-1/2Clinical activity
NEDA-3Focal MRI activity
NEDA-4/5Brain atrophy and
CSF neurofilament levels
Conventionalstep-care
Rapidescalation
Earlytop-down
IFN beta/GA/Teri/DMF
IFN beta/GA/Teri/DMF
Nz/Alem/Fingo/Dac/Clad
Fingo/Dac/Clad Fingo/Dac/Clad
Nz/Alem Nz/Alem
A new classification of disease-modifying therapies for RMS
Maintenance/escalation therapy (MET) Immune reconstitution therapy (IRT)
Chronic therapy that is maintained and/orescalated over time resulting in
immune function only during active treatment
Short course therapy resulting in long-termqualitative changes in immune function
Immunomodulation … Immunosuppression Semi-selective IRT (SIRT)
IRT that semi-selectivelyaffects the adaptive
immune systeme.g. cladribine
Non-selective IRT (NIRT)
IRT that affects boththe innate & adaptive
immune systemse.g. alemtuzumab
MET that results incontinuous
immunomodulatione.g. interferon-beta,glatiramer acetate
MET that results incontinuous
immunosuppressione.g. fingolimod, ocrelizumab
Derisked METe.g. natalizumab, dimethyl fumarate,
teriflunomide, daclizumabRMS, relapsing multiple sclerosis
It is not only benefits and risks
LymphopaeniaCardiac issuesHepatic issues
PregnancyWorkTravelOthers
PML, progressive multifocal leukoencephalopathy
Drug–drug interactionsCarry-over/rebound/sequencing
InactiveActiveHighly-active/rapidly-evolving severe
Personal factors
Drug effects
ImmunosuppressionPML riskOther
Monitoring frequency
ComorbiditiesAdherence
Safety profileTolerability
Patient profile
Potentialdrug issues
Disease activity/prognosis
Conclusions
Changing therapeutic landscape; more complex – more choice
DMTs are either maintenance or IRTs● IRTs (semi-selective or non-selective)
DMTs immunomodulatory and/or immunosuppressive● Long-term/maintenance vs short-term/induction
Risks of MS vs benefits of treatment vs risks of treatment
De-risking treatments● Baseline screening● Monitoring● Timely switching● Switch from maintenance (cumulative) to induction (front-loaded) risk
DMT specific knowledge
Databasing (pharmacovigilance monitoring, pregnancy, registries)
Can we really implement an algorithm?
What about stopping criteria?
DMTs, disease-modifying therapies; IRTs, immune reconstitution therapies; MS, multiple sclerosis