Treating MS in 2014

Professor Gavin Giovannoni

Blizard Institute, Barts and The London School of Medicine and Dentistry

Disclosures Professor Giovannoni has received personal compensation for participating on Advisory Boards in relation to clinical trial design, trial steering committees and data and safety monitoring committees from: Abbvie, Bayer-Schering Healthcare, Biogen-Idec, Canbex, Eisai, Elan, Fiveprime, Genzyme, Genentech, GSK, GW Pharma, Ironwood, Merck-Serono, Novartis, Pfizer, Roche, Sanofi-Aventis, Synthon BV, Teva, UCB Pharma and Vertex Pharmaceuticals.

Regarding www.ms-res.org survey results in this presentation: please note that no personal identifiers were collected as part of these surveys and that by completing the surveys participants consented for their anonymous data to be analysed and presented by Professor Giovannoni.

Professor Giovannoni would like to acknowledge and thank Biogen-Idec, Genzyme and Novartis for making available data slides on natalizumab, alemtuzumab and fingolimod for this presentation.

www.ms-res.org

Questions: the MSers perspective

To make an informed decision you need to ask and understand the following questions:

1. Are you sure that you have MS?

2. What types of MS do you have?

3. What prognostic group do you fall into?

4. What is the risk of not having any treatment?

5. Do you have active MS?

6. Am I eligible for treatment with a DMT?

7. Do you understand the difference between the treatment strategies of maintenance and escalation and induction therapy?

8. What is the therapeutic target?

9. Can we cure MS?

Question: Are you sure that you have MS?

MS misdiagnosis rate of ~5%

Engell T. A clinico-pathoanatomical study of multiple sclerosis diagnosis. Acta Neurol Scand. 1988 Jul;78(1):39-44.

CDMS 485/518 (94%) - SENSITIVITY = True+ve /(True+ve + False-ve)

MS mimics

NMO

Shimizu et al. IFNβ-1b may severely exacerbate Japanese optic-spinal MS in neuromyelitis optica spectrum. Neurology. 2010 Oct 19;75(16):1423-7.

Migraine

Kleinschmidt-DeMasters et al. PML complicating treatment with natalizumab and interferon beta-1a for multiple sclerosis. N Engl J Med. 2005 Jul 28;353(4):369-74

Module Identifier

Question: What types of MS do you have?

Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology. 1996 Apr;46(4):907-11.

RRMS R-SPMS/NR-SPMS PPMS RPMS

relapsing forms of MS vs. non-relapsing MS

Question: What prognostic group do you fall into?

Good prognosis Poor prognosis

Young

Female sex

Optic neuritis

Isolated sensory symptom

Full recovery from attack

Long interval to second

relapse

No disability after 5 years

Normal MRI / low lesion load

CSF negative for OCBs

Older age of onset

Male sex

“Multifocal“ onset

Efferent system affected (motor,

cerebellar, bladder)

High relapse rate in the first 2-5 years

Substantial disability after 5 years

Abnormal MRI with large lesion load

Genomic factors (e.g. ApoE4, KIF1B)

CSF positive for OCBs

Adapted from Miller et al., Lancet Neurology 2005: 4; 281-288

Question: What prognostic group do you fall into?

Favourable

Indeterminate

Poor

time Aim of

treatment

Relapsing-MS

Active Inactive Highly-active Rapidly-evolving severe

Active Inactive HA RES

A population of newly diagnosed CISers/MSers

Long-term outcomes under the current Rx paradigm

Long-term outcomes under the T2T-NEDA paradigm

Question: What is the risk of not having any treatment?

MS is one of the most common causes of neurological disability in young adults2

Natural history studies indicate that it takes a median time of 8, 20 and 30 years to reach the irreversible disability

levels of EDSS 4, 6 and 7, respectively3

Up to 75% increased annualized divorce rate4

Life expectancy is reduced by 5-10 years5

7.5x greater than suicide rate than the general population6

2 out of 3 patients with RRMS were unemployed due to the disease7

Utilit

y

EDSS Status

EDSS and utilitya show a significant inverse relationship1,b

aUtility measures are derived from EQ-5D using the EuroQoL instrument. bAdapted from Orme et al 2007. Error bars depict 95% confidence intervals. Half points on EDSS are not shown on graph axis, except at EDSS 6.5.

1.Orme M et al. Value In Health. 2007;10:54-60. 2.WHO. 2008.[TK] 3. Confavreaux, Compston. 2005.[TK] 4. Coles et al. 2001.[TK] 5. Confavreaux, Vukusic. 2006.[TK] 6. Sadovnick et al. Neurology 1991;41:1193-6.

7. Morales-Gonzales. Mult Scler. 2004;10:47-54.

Consequences of increasing EDSS scores: loss of employment1

0

10

20

30

40

50

60

70

80

90

Work Capacity by Disability Level

0.0/1.0 2.0 3.0 4.0 5.0 6.0 6.5 7.0 8.0/9.0

EDSS Score

Pro

po

rtio

n o

f P

ati

en

ts ≤

65

Ye

ars

Old

Wo

rkin

g (

%)

The proportion of patients employed or on long-term sick leave is calculated as a percentage of patients aged 65 or younger.

1. Kobelt G et al. J Neurol Neurosurg Psychiatry. 2006;77:918-926;

2. Pfleger CC et al. Mult Scler. 2010;16:121-126.

Spain

Sweden

Switzerland

United Kingdom

Netherlands

Italy

Germany

Belgium

Austria

~10 yrs2

www.ms-res.org

www.ms-res.org

Question: Do you have active MS?

vs.

1

2

3

Clinical

MRI

Biomarkers

Question: Am I eligible for treatment with a DMT?

MSer

Neurologist

Payers

Regulator

Question: Am I eligible for treatment with a DMT?

MS is an autoimmune disease hypothesis

15-20 year experiment

“hit hard and early ”

Question: Do you understand the difference between the treatment strategies of maintenance and escalation and induction therapy?

What is your treatment philosophy? maintenance-escalation vs. induction

survival analysis

Treatment Selection & treating-2-target

Choosing therapy

X Y Z

Define the Individual’s MS

No

Treatment failure? Yes

• Patient’s preferences?

• Your choice?

Individual measures:

• Evidence of disease activity?

• Tolerability/safety?

• Adherence?

• Drug or inhibitory markers?

Monitoring

• MS prognosis

• Life style and goals

• Shared goals for therapy

Rebaseline

Rebaseline:

• IFNβ, natalizumab, fingolimod,

teriflunomide, DMF=3-6 months

• Glatiramer acetate=9 months

• Alemtuzumab=24 months

DMF=dimethyl fumarate.

Treatment Ladder

1st-line A

1st-line B

1st-line C

1st-line D

1st-line E

2nd-line N

2nd-line M

3rd-line y

3rd-line X

Case studies

38-year-old teacher with relapsing–remitting MS under the care of a hospital in central London Glatiramer acetate treatment for 3 years (good adherence and tolerance) Relapse with a mild left sensory loss Referred to me for a second opinion Switched to interferon β (intramuscular interferon β-1a; www.msdecisions.org.uk) Mild persistent flu-like side effects and lymphopenia 12/12’s neutralizing antibodies screen negative Volunteers for new research programme, which included a gadolinium-enhanced MRI protocol

Teacher

38-year-old teacher with relapsing–remitting MS As a result of fatigue and cognitive problems she is forced to take

early retirement Although fully functional she develops depression and anxiety In her spare time she spends a lot of time on the web and becomes

an expert patient Widely read

Net savvy; regular follower of www.ms-res.org

Teacher X

The relapsing MS DMT doughnut

CIS, clinically isolated syndrome; DMT, disease-modifying therapy; GA, glatiramer acetate; IFN, interferon; RIS, radiologically isolated syndrome; RRMS, relapsing–remitting MS.

Inactive RRMS

CIS

RIS or asymptomatic MS

Suboptimal responders?

Active

RRMS IFN β

or

GA

IFN β

Highly active RRMS Fingolimod Natalizumab

Teacher X

Teacher X

Ian Rogers. ACNR 2007: 7(3);14.

Case 2

Case 3

What is the therapeutic target?

No evident disease activity: NEDA

Gd, gadolinium. 1. Havrdova E, et al. Lancet Neurol 2009; 8:254–260; 2. Giovannoni G, et al. Lancet Neurol 2011; 10:329–337.

Treat-2-target

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

Relapses

Unreported relapses

Clinical disease progression

Subclinical relapses: focal MRI activity

Focal gray and white matter lesions not detected by MRI

Brain atrophy

Spinal fluid neurofilament levels

MS Iceberg

Clinical activity

Focal MRI activity

Hidden focal and diffuse MRI activity

Microscopic or biochemical pathology

Biomarkers

Control Multiple sclerosis

Brain atrophy occurs across all stages of the disease

De Stefano, et al. Neurology 2010

n= 963 MSers

Treatment effect on disability predicted by effect on T2-lesion load and brain atrophy

Meta-analysis of treatment effect on EDSS worsening (y) vs effects on MRI lesions

and brain atrophy, individually or combined, in 13 placebo-controlled RRMS trials

(13,500 patients)

Sormani MP et al. Ann Neurol. 2014;75:43-49.

Which drugs slow the rate of brain atrophy in MSers?

1. Interferon beta a. Betaferon x b. Avonex ? c. Rebif x

2. Glatiramer acetate (Copaxone) x 3. Mitoxantrone (Novantrone) x 4. Natalizumab (Tysabri) 5. Fingolimod (Gilenya) 6. Teriflunomide (Aubagio) x 7. Alemtuzumab (Lemtrada) 8. Dimethyl-fumarate (Tecfidera) ?

Rheumatoid arthritis End-stage joint disease

Can you cure MS?

To cure MS do we need to know the cause?

EBV Vitamin D

Smoking Genes

We work on the hypothesis that MS is an autoimmune disease.

Multiple

Sclerosis

Environ-ment

Genes

The autoimmune hypothesis

Multiple

Sclerosis

Environ-ment

Genes

Survival Curves

85%

50%

30%

0%

15yrs 25yrs 40yrs 50yrs

100% Benign MS

Proportioned of treated MSers are cured

Natural history

Unrealistic expectation

Delayed onset of SPMS

Defining a cure: a working definition

85%

50%

30%

0%

15yrs 25yrs 40yrs 50yrs

100%

Proportioned of treated MSers are cured

Natural history

NEDA = no evident disease activity

survival analysis

“highly effective treatments”

MS is an autoimmune disease hypothesis

15-20 year experiment

Can we repeat the animal experiment in MS?

Multiple

Sclerosis

Environ-ment

Genes

Neuro-restoration

Remyelination

Neuroprotection

Anti-inflammatory

Therapeutic pyramid

Anti-ageing

Brain

Health

Initiative

MRI Events

1st clinical attack

Time (Years)

Subclinical disease

Inflammation

Brain volume loss

Neuroaxonal loss

Dis

eas

e S

eve

rity

SPMS RRMS

1st MRI lesion

Relapses

CIS RIS R-SPMS

RIS = radiologically isolated syndrome; CIS = clinically isolated syndrome, RRMS = relapsing-remitting MS; R-SPMS = relapsing secondary progressive MS; SPMS = secondary progressive MS; PPMS = primary progressive MS

SPMS: Natalizumab, Siponimod, DMF

Late SPMS: SMART STUDY fluoxetine, amiloride, riluzole

Early SPMS: PROXIMUS oxcarbazepine

CIS: PHENYTOIN RRMS: ? DE-FLAMES STUDY

PPMS

PPMS: Fingolimod, Ocrelizumab, Laquinimod

SP&PPMS: Ibudilast

Giovannoni & Cutter; Lancet Neurol 2006; 5: 887–94.

T2T-NEDA diffusion curve

• MSer

• Neurologist

• Payers

• Regulator

Have we got it wrong?

EBV Vitamin D

Smoking Genes

Multiple

Sclerosis

Environ-ment

Genes

Is MS due to a virus?

Charcot Project

INSPIRE Trial (Raltegravir)

Etc. etc. etc.

Nogo, MAG, OMgP

Lingo-1-NgR-p75NTR

GAP-43

NCAM

Neuregulin

Agents in trial: • Benztropine: anticholinergic

• BIIB033: anti-LINGO-1

• Clemastine: anti-histamine

• GSK239512: histamine H(3)

receptor antagonist

• IRX4204 & Bexarotene:

RXR-agonist

• rHIgM22: oligodendrocyte

target

• VX15: anti-SEMA4D Courtesy of Sharmilee Gnanapavan, MBBS, BmedSci, PhD.

Remyelination

Markers of Remyelination

Image courtesy of Klaus Schmierer.

3 6 9 12 24

EDSS

0

TIME

Active (confirmed improvement)

Placebo (confirmed progression)

Exit EDSS showing improved function

Shadow plaque MRI - MTR

Schmierer et al. Ann Neurol 2004;56:407–415.

Conclusions

MS is a bad disease – Mortality, disability, unemployment, divorce, suicide cognitive impairment,

etc.

Era of individualised profiling – Prognosis, risk, treatment and monitoring

New treatment paradigm – Maintenance vs. induction therapy

– Therapeutic ladder vs. early highly-effective treatments as a 1st-line option

– Improved risk mitigation tools

– New treatment paradigm of treat-2-target of NEDA or no evidence of disease activity

– Future target to prevent organ damage

Is it fair to make MSers wait 20 years for the outcome of an ongoing experiment?

Watch out for a black swan?