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The s The stagger ered 2-step a p app pproach h for t trea eatm tmen ents w ts with pr profound effec ect o on i n immun unity Gavin Giovannoni Barts and The London Discl clos osures I has received personal compensation for

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The s The stagger ered 2-step a p app pproach h for t trea eatm tmen ents w ts with pr profound effec ect o

  • n i

n immun unity

Gavin Giovannoni Barts and The London

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SLIDE 2

Discl clos

  • sures

I 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, Almirall, 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.

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SLIDE 3
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The M Multiple Sc Sclerosi

  • sis

s Spectrum

Subclinical inflammation, demyelination, and neurodegeneration may be present for months, or even years, before a patient experiences clinical symptoms1

MRI=magnetic resonance imaging; RIS =radiologicallty-isolated syndrome; CIS=clinically-isolated syndrome; RRMS=relapsing-remitting MS; SPMS=secondary progressive MS R-SPMS=relapsing SPMS; NR-SPMS=non-relapsing SPMS; PPMS=primary progressive MS

  • 1. Stüve O et al. Drugs 2008;68:73-83; Image adapted from Compston A, Coles AJ. Lancet 2008;372:1502-17.

MRI Events

SPMS First clinical event

Time (Years)

RRMS Subclinical disease Inflammation Brain volume Axonal loss

Disease Severity

NR-SPMS RRMS CIS RIS R-SPMS PPMS

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Control Multiple sclerosis

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Brain atrophy occurs across all stages of the disease

De Stefano, et al. Neurology 2010 n= 963 MSers

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57% 7%

  • 20%

0% 20% 40% 60%

CISers n = 40

Feuillet et al. Mult Scler. 2007.

Healthy Controls n = 30

p < 0.0001

Deficits were found mainly in memory, speed of information processing, attention and executive functioning.

MSers failing ≥ 2 cognitive tests

Cog

  • gnition
  • n in early m

multiple scl cleros

  • sis
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Coles et al. J Neurol. 2006 Jan;253(1):98-108.

Post-inflammatory neurodegeneration

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21 21-yea ear l long-ter erm f follow-up o p of IFNb Nb-1b s b study udy

time from study r randomizati tion t to d death th 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

Goodin et al Neurology. 2012 Apr 24;78(17):1315-22. 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% 2 4 6 8 10 12 14 16 18 20 22 Proportion of patients who are still alive Time (Years)

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Occu ccupational f funct ction

  • ning

Pfleger et al. Multiple Sclerosis 2010; 16(1) 121–126.

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At what level of

  • f p

physical d disability doe

  • es

unemployment occu

  • ccur?

Kobelt et al. Neurol Neurosurg Psychiatry 2006;77:918–926.

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SLIDE 15

Quality o

  • f life

e of pa patien ents w ts with M h MS S in n Europe

Kobelt et al. J Neurol Neurosurg Psychiatry 2006;77:918–926.

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SLIDE 16

Th The Effect ct of

  • f M

MS on

  • n Quality of
  • f L

Life

  • 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 scores 4.0, 6.0, and 7.0, respectively3

16 *Utility measures are derived from EQ-5D using the EuroQoL instrument; †error bars depict 95% CIs. Half points on EDSS are not shown on graph axis, except at EDSS score 6.5. EDSS=Expanded Disability Status Scale; EQ-5D=European Quality of Life-5 Dimensions; QoL=quality of life.

  • 1. Adapted from Orme M et al. Value In Health. 2007;10:54-60; 2. WHO and MS International Foundation (MSIF).

http://apps.who.int/bookorders/anglais/detart1.jsp?sesslan=1&codlan=1 &codcol=15&codcch=747. Accessed March 6, 2012;

  • 3. Confavreaux C et al. Brain 2003; 176:770-782. 4. Compston A, Coles A. Lancet. 2008;372:1502-1517.

Utility EDSS and Utility* Show a Significant Inverse Relationship

1†

Utility EDSS Status 0.0 1.0 2.0 3.0 4.0 5.0 6.0 6.5 7.0 8.0 9.0 –0.4 –0.3 –0.2 –0.1 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9

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SLIDE 17

Theoretical model: treat early and effectively

Natural course

  • f disease

Later intervention Later treatment Treatment at diagnosis Intervention at diagnosis

Time

Disease Onset

Disability

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SLIDE 18

Escalati tion t to

  • Natalizumab

ab Is M Mor

  • re

e Effectiv ective e Than S Switch ching B Betw tween een I IFN/GA

25 50 75 100 % Patients

Escalate to Natalizumab, n=106 Switch Between IFN/GA, n=161

Data from a postmarketing, prospective, observational study in 285 RRMS patients for whom treatment with IFNβ or GA therapy failed. After failure of IFNβ or GA therapy, patients were switched to either natalizumab (n=106) or IFNβ/GA (n=161). *There were no differences at 12 month between the two groups in proportions of patients free from relapse, disability progression, MRI activity, and combined activity. Prosperini L et al. Mult Scler. 2012;18:64-71.

No EDSS Progression No MRI Activity Disease Activity Free

P<0.0001 P=0.0003 P<0.0001

51 36 51 21 83 67 77 59 No Relapses

P<0.0045

Over 24 months*

18

×

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Sh Should multiple s sclerosis b be e rede defined ed a as a a de demen entia?

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Definition

  • n of
  • f d

dementia

Dementia is a loss of mental ability severe enough to interfere with normal activities of daily living, lasting more than six months, not present since birth, and not associated with a loss or alteration of consciousness.

  • Normal activities of daily living
  • Physical
  • Mental
  • Social
  • Occupational
  • Lasting more than six months
  • Not present since birth
  • Not associated with a loss or alteration of consciousness

      

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www.multiple-sclerosis-research.org

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What i is the p e pathologi gical sub ubstrate of e of MS de demen entia?

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11,000 000 t to 1

Trapp, et al. NEJM 1998;338:278-85

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Defining t the w window of

  • f
  • pp
  • ppor
  • rtunity t

to

  • treat M

MS?

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SLIDE 25

“The w e window o

  • f opportunity”

MRI=magnetic resonance imaging; RIS =radiologicallty-isolated syndrome; CIS=clinically-isolated syndrome; RRMS=relapsing-remitting MS; SPMS=secondary progressive MS R-SPMS=relapsing SPMS; NR-SPMS=non-relapsing SPMS; PPMS=primary progressive MS

  • 1. Stüve O et al. Drugs 2008;68:73-83; Image adapted from Compston A, Coles AJ. Lancet 2008;372:1502-17.

MRI Events

SPMS First clinical event

Time (Years)

RRMS Subclinical disease Inflammation Brain volume Axonal loss

Disease Severity

NR-SPMS RRMS CIS RIS R-SPMS PPMS

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SLIDE 26

“The w e window o

  • f opportunity”

MRI=magnetic resonance imaging; RIS =radiologicallty-isolated syndrome; CIS=clinically-isolated syndrome; RRMS=relapsing-remitting MS; SPMS=secondary progressive MS R-SPMS=relapsing SPMS; NR-SPMS=non-relapsing SPMS; PPMS=primary progressive MS

  • 1. Stüve O et al. Drugs 2008;68:73-83; Image adapted from Compston A, Coles AJ. Lancet 2008;372:1502-17.

MRI Events

SPMS First clinical event

Time (Years)

RRMS Subclinical disease Inflammation Brain volume Axonal loss

Disease Severity

NR-SPMS RRMS CIS RIS R-SPMS PPMS

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SLIDE 27

Cho Choosing a a trea eatmen ent s strategy egy?

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survival analysis “hit hard and early ” MS is an autoimmune disease hypothesis 15-20 year experiment

Wha hat i is y you

  • ur t

treatment phi philosophy? y?

mainten enan ance-esc scalati tion v

  • vs. induction
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SLIDE 29

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

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SLIDE 30
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SLIDE 31

STRATA: Patients Had Stable EDSS Scores for Up to 5 Years

*P<0.0001 Kappos L et al. Presented at ECTRIMS; October 10–13, 2012; Lyon, France P520. 2.36 2.69 2.54 3.13 3.07 3.22 3.24 3.21 3.15

2.38 2.36 2.39 2.90 2.69 2.72 2.84 2.85 2.79

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0

Feeder Study Baseline Feeder Study End Safety Study End STRATA Baseline STRATA 48 Weeks STRATA 96 Weeks STRATA 144 Weeks STRATA 192 Weeks STRATA 240 Weeks

1 Year 2 Years 3 Years 4 Years 5 Years

Cessation/ Treatment Gap* Original Placebo Original Natalizumab Original Placebo – Now on Natalizumab

Mean EDSS Score

n = 380 707 381 707 280 552 385 709 274 569 230 479 205 462 194 427 174 393 31

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WWW.MS-RES.ORG

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WWW.MS-RES.ORG

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CARE-MS II: Risk of Sustained Disability over Intervals of up to 1 Year

Alemtuzumab reduced the risk of disability accumulation sustained for intervals of up to 1 year vs. SC IFNB-1a 21.1 18.8 15.2 12.7 11.1 9.5

5 10 15 20 25 30 35 40

6-month 9-month 12-month

Proportion of Patients (%) 42% reduction p=0.0084 39% reduction p=0.0446 43% reduction p=0.0127 SAD Timeframe SC IFNB-1a 44 µg Alemtuzumab 12 mg

Includes events with onset during 2-year core study, and confirmation in the extension. Data on file, Genzyme Corporation.

CARE-MS II (Primary Endpoint) (Post Hoc Analyses)

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SLIDE 36

Definition

  • n of
  • f d

dementia

Dementia is a loss of mental ability severe enough to interfere with normal activities of daily living, lasting more than six months, not present since birth, and not associated with a loss or alteration of consciousness.

  • Normal activities of daily living
  • Physical
  • Mental
  • Social
  • Occupational
  • Lasting more than six months
  • Not present since birth
  • Not associated with a loss or alteration of consciousness

      

“Multiple sclerosis is possibly a preventa table dementia.”