MS Update

Gavin Giovannoni Barts and The London School of Medicine and Dentistry

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CLINICAL SERVICE

Dr Janet Williamson National Director, NHS Improvement

www.ms-res.org

Gastrostomy

Primary Care Referral Diagnosis Minimal impairment

Moderate impairment

Severe impairment

End of life care

Prevention

Cognition

Depression

Fatigue

Bladder

Bowel

Sexual dysfunction Tremor

Pain

Swallowing

Spasticity

Falls

Balance problems

Insomnia

Restless legs

Studying

Employment

Relapses DMTs

Fertility

Rehab

Suprapubic catheter

Intrathecal baclofern

Palliative Care

Physiotherapy

Speech therapy

Occupational Therapy

Nurse specialists

Counselling

Neuroradiology

Neurophysiology

Clinical trials

Gait

Neuroimmunology

Pressure sores

Driving

Anxiety

DMTs

Functional neurosurgery

Oscillopsia

Sexual dysfunction

Pseudobulbar affect

Seizures

Advanced directive

Assisted suicide

Colostomy

Tendonotomy

Relationships

Travel vaccination

Social services Legal aid

1st line

2nd line

maintenance escalation

induction

risks

adverse events

monitoring

disease-free

family counselling

vD

A ‘holistic’ approach to MS

Life expectancy

Survival in MSers is shortened by 8 to 12 years

Survival Probability of Norwegian Patients with RRMS (Hordaland County, Western Norway, 1953–2003)

RRMS=relapsing-remitting MS. Adapted from Torkildsen NG et al. Mult Scler. 2008;14:1191-1198.

50 0 5 10 15 20 25 30 35 40 45 0

10

20

30

40

50

60

70

80

90

100

Surv

ival

(%

)

Years After Onset

30 35 40 45 50 55 60 65 70 75 80 Approximate Patient Age

General Population

RRMS

95% CI

21-year long-term follow-up of IFNb-1b study time from study randomization to death

Early treatment (3 years) with IFNb-1b was associated with a 47% reduction in the risk of dying over 21 years compared with initial placebo treatment

Source: Poster Goodin et al AAN 2011

At risk:

IFNB-1b 250 µg

Placebo

124

123

124

120

121

117

118

109

104

88

HR=0.532 (95% CI: 0.314–0.902)

46.8% reduction in hazard ratio

Log rank, P=0.0173

IFNB-1b 250 µg

Placebo

65%

70%

75%

80%

85%

90%

95%

100%

0 2 4 6 8 10 12 14 16 18 20 22

Pro

po

rtio

n o

f p

ati

en

ts w

ho

are

sti

ll a

live

Time (Years)

Disease modification

13

The pipeline

Interferons

Phase I

Phase II

Phase III

Marketed

Anti-proliferation agents

Avonex

Atacicept

Campath Rituximab

Novantrone

Rebif

Betaferon/ Extavia

Teriflunomide

Tysabri

Zenapax

Pixantrone

Targeted mAbs/Fc-Ab

Cladribine

Fingolimod

Azathioprine

= oral administration

= injectable

Riluzole

Symptomatic Tx

Vaccine, tolerisation

Tovaxin

ATL-1102

MM-093 BG12

AJM-300

Nerispirdine

Interferon Tau

Interferon omega

Peg IFNb (BIIB017)

Fc- IFb

ATX-MS-1467

Firategrast

Ofatumumab

Sativex

Lymphocyte trafficking

TBC4746

MLN-0002

Targeted Immune regulation

PI2301

R1295

Copaxone

Laquinimod

Fampridine SR

683699 (T-0047)

Ocrelizumab

LY-2127399

Disability

Time

6 months 12 months 24 months

Active

Placebo

6 months

Relapsing MS

1. Delay attacks / onset of MS 2. Reduce number of attacks 3. Reduce severity of attacks 4. Reduce disability 5. Delay onset of SPMS

Treat early

Natural course of disease

Later intervention

Later treatment

Treatment at diagnosis Intervention

at diagnosis

Time Disease Onset

Disability

Any Negative EDSS=6 SPMS Wheelchair

% R

isk R

ela

tive t

o L

ow

Exp

osu

re

Long-term follow-up 16 years IFN-beta exposure 80% vs. 20%

Source: Poster Goodin et al AAN 2011

Emerging DMTs

18

Emerging DMTs for relapsing MS phase 3 & 4

Oral

1. Fingolimod – 53% reduction in ARR relative to placebo

2. Cladribine – 55% reduction in ARR relative to placebo

3. BG12 – 53% reduction in ARR relative to placebo

4. Teriflunomide – 31% reduction in ARR relative to placebo

5. Laquinimod – 21% reduction in ARR relative to placebo

Parenteral

1. Alemtuzumab (anti-CD52) – 55% reduction in ARR relative to IFNβ-1a

2. Ocrelizumab (anti-CD20) – 80% reduction in ARR relative to placebo

3. Daclizumab (anti-CD25) – 54% reduction in ARR relative to placebo

?

Recruiting

Oral therapies

BG12

22

Annualized Relapse Rate at 2 Years (Secondary Endpoint)

0

0.1

0.2

0.3

0.4

0.5

0.6

Placebo(n=408)

BG-12 BID(n=410)

BG-12 TID(n=416)

AR

R (

95%

CI)

*

0.364

0.172 0.189

53% reduction

vs. placebo

P<0.0001

48% reduction

vs. placebo

P<0.0001

*ARR calculated with negative binomial regression, adjusted for baseline EDSS score (≤2.0 vs >2.0), baseline age (<40 vs ≥40), region, and number of relapses in the 1 year prior to study entry.

Fingolimod

24

LAQUINIMOD

0.1

0.2

0.3

0.4

An

nu

aliz

ed R

elap

se R

ate*

Placebo Laquinimod 0.6 mg

0.29

0.37

IM IFN-β-1a 30 mcg (Avonex®)

0.27

21% Reduction P=0.03

*Adjusted for baseline EDSS, number of relapses in 2-year pre-study, country, baseline T2 lesion volume and GdE-T1 status at baseline scan.

0

29% Reduction P=0.002

PRIMARY ENDPOINT: ANNUALIZED RELAPSE RATE*

27

Vollmer T, et al. Presented at: 5th Joint Triennial Congress of the European and Americas Committee for Treatment and Research in Multiple

Sclerosis. October 19-22, 2011. Amsterdam, NL. Abstract 148. Multiple Sclerosis. 2011;17:S507.

Teriflunomide

Teriflunomide significantly reduced relapse rate

by 31% in both dose groups vs placebo

0.369

0.370

0.539

0 0.1 0.2 0.3 0.4 0.5 0.6

14 mg

7 mg

Placebo

Teri

flu

no

mid

e

Adjusteda annualised relapse rate

RRR: 31.2% p=0.0002

RRR: 31.5% p=0.0005

aAdjusted for EDSS score strata at baseline and takes duration of treatment into account

ARR, annualised relapse rate; RRR, relative risk reduction;

EDSS, Expanded Disability Status Scale

Injection therapies

Efficacy and safety of ocrelizumab in patients with relapsing-remitting multiple sclerosis

Results of a Phase II, randomised, placebo-controlled, multicentre trial

Ludwig Kappos, University Hospital, Basel, Switzerland

David Li, University of British Columbia, Vancouver, Canada

Peter A Calabresi, Johns Hopkins University, Baltimore, MD, USA

Paul O’Connor, University of Toronto, Toronto, ON, Canada

Amit Bar-Or, McGill University, Montreal, Canada

Frederik Barkhof, VU Medical Center, Amsterdam, The Netherlands

Ming Yin, Genentech Inc, South San Francisco, CA, USA

David Leppert, F Hoffmann-La Roche Ltd, Basel, Switzerland

Robert Glanzman, F Hoffmann-La Roche Ltd, Nutley, NJ, USA

Jeroen Tinbergen, F Hoffmann-La Roche Ltd, Basel, Switzerland

Stephen L Hauser, UCSF, San Francisco, CA, USA

ECTRIMS, 13–16 OCTOBER 2010, GÖTEBURG, SWEDEN

ARR at Week 24

OCR 2000 mg

0-24

(n=55)

OCR 600 mg

0-24

(n=55)

Placebo

0-24

(n=54)

IFN beta-1a

0-24

(n=54)

ARR

0.169 0.125

0.636

0.364

0.0

0.2

0.4

0.6

0.8

1.0 p=0.0014

p=0.0005

0-24 weeks

80% 73%

A Randomized, Double-Blind, Placebo-controlled

Study to Evaluate the Safety and Efficacy of

Daclizumab HYP Monotherapy in Relapsing Remitting

Multiple Sclerosis: Primary Results of the

SELECT Trial

Gavin Giovannoni1, Ralf Gold,2 Krzysztof Selmaj,3 Eva Havrdova,4

Xavier Montalban,5 Ernst-Wilhelm Radue,6 Dusan Stefoski,7 Randy

Robinson,8 Katherine Riester,9 Jacob Elkins,9 Gilmore O’Neill9

1Queen Mary University of London, Barts and The London School of Medicine and

Dentistry, UK2St. Josef-Hospital/Ruhr-University Bochum, Bochum, Germany; 3Medical University of Lodz, Lodz, Poland;4Charles University in Prague, Prague,

Czech Republic; 5Hospital Vall d'Hebron University, Barcelona, Spain; 6University

Hospital Basel, Basel, Switzerland. 7Rush University Medical Center, Chicago, IL.

USA; 8Abbott Biotherapeutics, Redwood City, CA, USA; 9Biogen Idec, Cambridge,

MA, USA

Confidential

0.46

0.210.23

0.00

0.05

0.10

0.15

0.20

0.25

0.30

0.35

0.40

0.45

0.50

Annualized Relapse Rate

Estimated from a negative binomial regression model adjusted for number of relapses in

1-year period prior to study entry, baseline EDSS (≤2.5 vs. >2.5), and age (≤35 vs. >35)

34

An

nu

alize

d r

ela

pse r

ate

Placebo

(n=196)

DAC HYP

150 mg

(n=201)

DAC HYP

300 mg

(n=203)

54%

reduction,

P<0.0001

50%

reduction,

P=0.0002

Confidential

35 © Copyright 2011 Biogen Idec & Select - Company Confidential

Safety

Natalizumab

AFFIRM Highly Active* 1 (n= 148 for TYSABRI, 61 for PBO)

81%

64%

reduction in annualised relapse rate vs. placebo over 2 years (p < 0.001)

reduction in the risk of disability progression, sustained for 24 weeks, as assessed over 2 years (p =0.008)

*Patients with ³ 2 relapses and ³ 1 Gd+ lesion in year prior to entry

1. Natalizumab SmPC

Natalizumab

Treatment – disease modifying: NATALIZUMAB

Immunological Velcro

NATALIZUMAB

Progressive multifocal leukoencephalopathy

Kleinschmidt-DeMasters,et al. N Engl J Med. 2005 Jul 28;353(4):369-74.

Natalizumab PML risk stratification tool

Anti-JC virus antibody status

Negative Positive

Prior immunosuppressant use

Natalizumab treatment

>2 Years

Natalizumab treatment

>2 Years

No Yes

No Yes No Yes

Lowest Highest Relative PML Risk

< 1 in 10,000 1 in 94 1 in 256 1 in 668 1 in 1887

Mitoxantrone

Azathioprine

Methotrexate

Cyclophosphamide

Mycophenolate

Cladribine

Rituximab

Etc.

Progressive MS

www.ms-res.org

Disability

Time

12 months 24 months 36 months

Active

Placebo Progressive MS

1. Reduce rate of disability progression

Disability

Time

6 months 12 months 24 months

Active

Placebo

6 months

Compared to relapsing MS

1. Delay attacks / onset of MS 2. Reduce number of attacks 3. Reduce severity of attacks 4. Reduce disability 5. Delay onset of SPMS

Delayed Progression 1 Stabilised Progression 2

Improved Function 3 Recovered Function 4

WHAT ARE YOUR EXPECTATIONS OF A THERAPY FOR PROGRESSIVE MS?

48

1

2

3

www.ms-res.org

Active tablet

Placebo tablet

Year 1 Year 2 Year 3

560 MS’ers

280 MS’ers

280 MS’ers

Disability

Time

Year 1 Year 2 Year 3

Active

Placebo

Disability

Time

Year 1 Year 2 Year 3

Active Placebo

Year 3 Year 4 Year 5

~600 MS’ers

~300 MS’ers

300 MS’ers

Year 1 Year 2 Year 6 Year 7

Recruitment Trial Data analysis ? Registration

7 years

Petzold et al. J Neurol Neurosurg Psychiatry. 2005 Feb;76(2):206-11.

Spinal fluid neurofilament levels

Spinal fluid

neurofilament levels

Disability (EDSS) and 3 years

Axonal damage in relapsing MS is markedly reduced by natalizumab

Gunnarsson et al. Ann Neurol 2010; Epub.

=

Recruitment Trial Data analysis

6 months

6 months 60 MS’ers

6 months

LP1 LP2 LP3

30 MS’ers active tablet

30 MS’ers placebo tablet

2 years

6 months

600 MS’ers for 7 years 60 MS’ers for 2 years

3 LPs = 10x as many trials in a ⅓ of the time

New paradigm

Can we make LPs safer?

Two types of spinal needle tips: the Quincke and Sprotte

Evans R W et al. Neurology 2000;55:909-914

Traumatic

or

cutting needle

Atraumatic

or

non-cutting needle

Ultrasound-guide lumbar punctures

Brain atrophy

or shrinkage

Kappos et al. N Engl J Med. 2010 Feb 4;362(5):387-401.

Progressive MS

• Two PPMS clinical trials

• Fingolimod

• Ocrelizumab

• One SPMS clinical trial

• Natalizumab

• ? Oxcarbazepine

• Symptomatic treatments

• Sativex

• Fampridine (Fampyra)

Walking and spasticity

Sustained-release oral fampridine in multiple sclerosis: a randomised, double-blind, controlled trial

Goodman et al. Lancet 2009; 373: 732–38.

http://www.youtube.com/watch?v=xZwPlTdEKFE

Fampridine responder 1

Fampridine responder 2

http://www.youtube.com/watch?v=PTdgJ2m37L0

Conclusions • Current first-line therapies are only moderately effective

• Safe, but are associated with troublesome side effects and poor adherence

• Escalation therapies (Natalizumab)

• More effective but serious adverse effects

• JCV testing optimises risk:benefit

• A healthy drug pipeline

• 3 oral agents look to emerge from the pipeline

• Alemtuzumab, daclizumab and anti-CD20 most exciting of the parenteral

therapies in phase 2/3

• Symptomatic treatments

• Sativex

• Fampridine

• Patient factors – risk assessment tools, education and a focus on wellness

• Neuroprotection – several phase 2 trials currently been undertaken with oral

agents

Questions?

www.ms-res.org

g.giovannoni@qmul.ac.uk

Prof. Gavin Giovannoni

Department of Neurology

Royal London Hospital

Whitechapel, London E1 1BB