The staggered 2-step approach for treatments with profound

effect on immunity

Gavin Giovannoni Barts and The London

Disclosures

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.

The Multiple Sclerosis 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

Dise

ase

Seve

rity

NR-SPMS RRMS CIS RIS R-SPMS

PPMS

Control Multiple sclerosis

Brain atrophy occurs across all stages of the disease

De Stefano, et al. Neurology 2010

n= 963 MSers

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

Cognition in early multiple sclerosis

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

Post-inflammatory neurodegeneration

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

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%

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

Prop

ortio

n of

pat

ient

s w

ho a

re s

till a

live

Time (Years)

Occupational functioning

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

At what level of physical disability does unemployment occur?

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

Quality of life of patients with MS in Europe

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

The Effect of MS on Quality of 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.

Util

ity

EDSS and Utility* Show a Significant Inverse Relationship1†

Util

ity

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 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9

Theoretical model: treat early and effectively

Natural course of disease

Later intervention

Later treatment

Treatment at diagnosis Intervention

at diagnosis

Time Disease Onset

Disa

bilit

y

Escalation to Natalizumab Is More Effective Than Switching Between IFN/GA

0

25

50

75

100

% P

atie

nts

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

×

Should multiple sclerosis be redefined as a dementia?

Definition of 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

www.multiple-sclerosis-research.org

What is the pathological substrate of MS dementia?

11,000 to 1

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

Defining the window of opportunity to treat MS?

“The window of 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

Dise

ase

Seve

rity

NR-SPMS RRMS CIS RIS R-SPMS

PPMS

“The window of 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

Dise

ase

Seve

rity

NR-SPMS RRMS CIS RIS R-SPMS

PPMS

Choosing a treatment strategy?

survival analysis

“hit hard and early ”

MS is an autoimmune disease hypothesis

15-20 year experiment

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

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

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

FeederStudy

Baseline

FeederStudyEnd

SafetyStudyEnd

STRATABaseline

STRATA48 Weeks

STRATA96 Weeks

STRATA144 Weeks

STRATA192 Weeks

STRATA240 Weeks

1 Year 2 Years 3 Years 4 Years 5 Years

Cessation/ Treatment Gap*

Original Placebo Original Natalizumab Original Placebo – Now on Natalizumab

Mea

n ED

SS S

core

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

31

WWW.MS-RES.ORG

WWW.MS-RES.ORG

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

0

5

10

15

20

25

30

35

40

6-month 9-month 12-month

Prop

ortio

n of

Pat

ient

s (%

)

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)

Definition of 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 preventable dementia.”