MS UpdateMS Update

Gavin GiovannoniGavin GiovannoniBarts and The London School of Medicine and DentistryBarts and The London School of Medicine and Dentistry

CLINICAL SERVICE

Dr Janet Williamson National Director, NHS Improvement

www.ms-res.org

Gastrostomy

Primary Care Referral Diagnosis Minimal impairment

Moderateimpairment

Severeimpairment

End oflife care

Prevention

Cognition

Depression

Fatigue

Bladder

Bowel

Sexual dysfunction Tremor

Pain

Swallowing

Spasticity

Falls

Balance problems

Insomnia

Restless legs

Studying

Employment

RelapsesDMTs

Fertility

Rehab

Suprapubiccatheter

Intrathecal baclofern

Palliative Care

Physiotherapy

Speech therapy

OccupationalTherapy

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

Socialservices Legal aid

1st line

2nd line

maintenanceescalation

induction

risks

adverse events

monitoring

disease-free

family counselling

vD

A ‘holistic’ approach to MS

Life expectancyLife expectancy

Survival in MSers is shortened by 8 to 12 yearsSurvival in MSers is shortened by 8 to 12 years

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

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

500 5 10 15 20 25 30 35 40 450

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 80Approximate Patient Age

General PopulationRRMS95% CI

21-year long-term follow-up of IFNb-1b studytime 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 µgPlacebo

124123

124120

121117

118109

10488

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

Disease modificationDisease modification

13

The pipelineThe pipeline

Interferons

Phase I

Phase II

Phase III

Marketed

Anti-proliferationagents

Avonex

Atacicept

CampathRituximab

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-093BG12

AJM-300

Nerispirdine

Interferon Tau

Interferon omega

Peg IFN (BIIB017)

Fc- IF

ATX-MS-1467

Firategrast

Ofatumumab

Sativex

Lymphocyte trafficking

TBC4746

MLN-0002

Targeted Immune regulation

PI2301

R1295

Copaxone

Laquinimod

Fampridine SR

683699 (T-0047)

OcrelizumabLY-2127399

Disability

Time

6 months 12 months 24 months

Active

Placebo

6 months

Relapsing MS

1. Delay attacks / onset of MS2. Reduce number of attacks3. Reduce severity of attacks4. Reduce disability5. Delay onset of SPMS

Treat early

Treatmentat diagnosis Intervention

at diagnosis

Time

Disease Onset

Disability

Any Negative EDSS=6 SPMS Wheelchair

% R

isk

Rel

ativ

e to

Lo

w E

xpo

sure

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

Source: Poster Goodin et al AAN 2011

Emerging DMTs

18

Emerging DMTs for relapsing MSphase 3 & 4

Oral1. 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

Parenteral1. Alemtuzumab (anti-CD52) – 55% reduction in ARR relative to IFNβ-1a

2. Ocrelizumab (anti-CD20) – 80% reduction in ARR relative to placebo3. Daclizumab (anti-CD25) – 54% reduction in ARR relative to placebo

?

Recruiting

Oral therapiesOral 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

0.1720.189

53%reduction

vs. placeboP<0.0001

48%reduction

vs. placeboP<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.

FingolimodFingolimod

24

LAQUINIMOD

0.1

0.2

0.3

0.4

Annu

aliz

ed R

elap

se R

ate*

Placebo Laquinimod 0.6 mg

0.290.37

IM IFN-β-1a 30 mcg(Avonex®)

0.27

21% ReductionP=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% ReductionP=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

Ter

iflu

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 therapiesInjection 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, SwitzerlandDavid Li, University of British Columbia, Vancouver, Canada

Peter A Calabresi, Johns Hopkins University, Baltimore, MD, USAPaul O’Connor, University of Toronto, Toronto, ON, Canada

Amit Bar-Or, McGill University, Montreal, CanadaFrederik Barkhof, VU Medical Center, Amsterdam, The Netherlands

Ming Yin, Genentech Inc, South San Francisco, CA, USADavid Leppert, F Hoffmann-La Roche Ltd, Basel, SwitzerlandRobert Glanzman, F Hoffmann-La Roche Ltd, Nutley, NJ, USA

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

0.1690.125

0.636

0.364

0.0

0.2

0.4

0.6

0.8

1.0p=0.0014

p=0.0005

0-24 weeks

80%80% 73%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

aliz

ed r

elap

se r

ate

Placebo (n=196)

DAC HYP150 mg (n=201)

DAC HYP300 mg (n=203)

54% reduction, P<0.0001

50% reduction, P=0.0002

Confidential

35 © Copyright 2011 Biogen Idec & Select - Company Confidential

SafetySafety

NatalizumabNatalizumab

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: NATALIZUMABTreatment – disease modifying: NATALIZUMAB

Immunological VelcroImmunological 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 HighestRelative PML Risk

< 1 in 10,000< 1 in 10,000 1 in 941 in 941 in 2561 in 256 1 in 6681 in 6681 in 18871 in 1887

Mitoxantrone Mitoxantrone AzathioprineAzathioprineMethotrexateMethotrexate

CyclophosphamideCyclophosphamideMycophenolate Mycophenolate

CladribineCladribineRituximabRituximab

Etc.Etc.

Progressive MSProgressive MS

www.ms-res.orgwww.ms-res.org

Disability

Time

12 months 24 months 36 months

Active

PlaceboProgressive 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 MS2. Reduce number of attacks3. Reduce severity of attacks4. Reduce disability5. Delay onset of SPMS

Delayed Progression1 Stabilised Progression2

Improved Function3 Recovered Function4

WHAT ARE YOUR EXPECTATIONS OF A THERAPY FOR PROGRESSIVE MS?WHAT ARE YOUR EXPECTATIONS OF A THERAPY FOR PROGRESSIVE MS?

48

1

2

3

www.ms-res.orgwww.ms-res.org

Active tablet

Placebo tablet

Year 1 Year 2 Year 3560 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

ActivePlacebo

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

Spinalfluid

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 SprotteTwo 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 puncturesUltrasound-guide lumbar punctures

Brain Brain atrophyatrophy

or or shrinkageshrinkage

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

Progressive MSProgressive MS• Two PPMS clinical trialsTwo PPMS clinical trials

• FingolimodFingolimod• OcrelizumabOcrelizumab

• One SPMS clinical trialOne SPMS clinical trial• NatalizumabNatalizumab• ? Oxcarbazepine? Oxcarbazepine

• Symptomatic treatmentsSymptomatic treatments• SativexSativex• Fampridine (Fampyra)Fampridine (Fampyra)

Walking and spasticityWalking and spasticity

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

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

ConclusionsConclusions• Current first-line therapies are only moderately effectiveCurrent first-line therapies are only moderately effective

• Safe, but are associated with troublesome side effects and poor adherenceSafe, but are associated with troublesome side effects and poor adherence• Escalation therapies (Escalation therapies (NatalizumabNatalizumab))

• More effective but serious adverse effectsMore effective but serious adverse effects• JCV testing optimises risk:benefitJCV testing optimises risk:benefit

• A healthy drug pipeline A healthy drug pipeline • 3 oral agents look to emerge from the pipeline3 oral agents look to emerge from the pipeline• AlemtuzumabAlemtuzumab, , daclizumabdaclizumab and and anti-CD20anti-CD20 most exciting of the parenteral most exciting of the parenteral

therapies in phase 2/3therapies in phase 2/3• Symptomatic treatmentsSymptomatic treatments

• SativexSativex• FampridineFampridine

• Patient factors – risk assessment tools, education and a focus on wellnessPatient factors – risk assessment tools, education and a focus on wellness• Neuroprotection – several phase 2 trials currently been undertaken with oral Neuroprotection – several phase 2 trials currently been undertaken with oral

agentsagents

Questions?Questions?

www.ms-res.orgwww.ms-res.org

g.giovannoni@qmul.ac.ukg.giovannoni@qmul.ac.uk

Prof. Gavin GiovannoniProf. Gavin GiovannoniDepartment of NeurologyDepartment of NeurologyRoyal London HospitalRoyal London HospitalWhitechapel, London E1 1BBWhitechapel, London E1 1BB