The s The stagger ered 2-step a p app pproach h for t trea - PowerPoint PPT Presentation

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 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 M Multiple Sc Sclerosi osis s Spectrum PPMS RIS CIS RRMS R-SPMS NR-SPMS First RRMS SPMS Subclinical clinical disease event Inflammation Axonal loss Disease Severity Brain volume Time (Years) MRI Events Subclinical inflammation, demyelination, and neurodegeneration may be present for months, or even years, before a patient experiences clinical symptoms 1 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.

Control Multiple sclerosis

Brain atrophy occurs across all stages of the disease n= 963 MSers De Stefano, et al. Neurology 2010

Cog ognition on in early m multiple scl cleros osis 60% 57% 40% MSers failing ≥ 2 cognitive 20% p < 0.0001 tests 7% 0% CISers Healthy Controls -20% n = 40 n = 30 Deficits were found mainly in memory, speed of information processing, attention and executive functioning. Feuillet et al. Mult Scler. 2007.

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

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 100% Proportion of patients who are still alive 95% IFNB-1b 250 µg 90% Placebo 85% 80% 75% HR=0.532 (95% CI: 0.314–0.902) 70% 46.8% reduction in hazard ratio Log rank, P =0.0173 65% 0 2 4 6 8 10 12 14 16 18 20 22 Time (Years) At risk: IFNB-1b 250 µg 124 124 121 118 104 Placebo 123 120 117 109 88 Goodin et al Neurology. 2012 Apr 24;78(17):1315-22.

Occu ccupational f funct ction oning Pfleger et al. Multiple Sclerosis 2010; 16(1) 121–126.

At what level of of p physical d disability doe oes unemployment occu occur? Kobelt et al. Neurol Neurosurg Psychiatry 2006;77:918–926.

Quality o of 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.

Th The Effect ct of of M MS on on Quality of of L Life 1† EDSS and Utility* Show a Significant Inverse Relationship MS is one of the most common • 0.9 causes of neurological disability 0.8 in young adults 2 0.7 0.6 • Natural history studies indicate 0.5 Utility 0.4 Utility that it takes a median time of 8, 0.3 20, and 0.2 0.1 30 years to reach the irreversible 0 –0.1 disability levels of EDSS scores –0.2 4.0, 6.0, and 7.0, respectively 3 –0.3 –0.4 0.0 1.0 2.0 3.0 4.0 5.0 6.0 6.5 7.0 8.0 9.0 EDSS Status *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. 16

Theoretical model: treat early and effectively Natural course of disease Later Disability treatment Later intervention Treatment at diagnosis Intervention at diagnosis Time Disease Onset

Escalati tion t to o Natalizumab ab Is M Mor ore e Effectiv ective e Than S Switch ching B Betw tween een I IFN/GA Escalate to Natalizumab, n=106 Switch Between IFN/GA, n=161 Over 24 months* 100 P <0.0001 P <0.0045 P =0.0003 P <0.0001 75 % Patients 83 77 67 50 59 51 51 × 36 25 21 0 No No EDSS No MRI Disease Relapses Progression Activity Activity Free  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. 18

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

Definition on of of 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

www.multiple-sclerosis-research.org

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

11,000 000 t to 1 Trapp, et al. NEJM 1998;338:278-85

Defining t the w window of of opp oppor ortunity t to o treat M MS?

“The w e window o of opportunity” PPMS RIS CIS RRMS R-SPMS NR-SPMS First RRMS SPMS Subclinical clinical disease event Inflammation Axonal loss Disease Severity Brain volume Time (Years) MRI Events 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.

“The w e window o of opportunity” PPMS RIS CIS RRMS R-SPMS NR-SPMS First RRMS SPMS Subclinical clinical disease event Inflammation Axonal loss Disease Severity Brain volume Time (Years) MRI Events 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.

Cho Choosing a a trea eatmen ent s strategy egy?

Wha hat i is y you our t treatment phi philosophy? y? mainten enan ance-esc scalati tion v vs. induction survival analysis “hit hard and early ” MS is an autoimmune disease hypothesis 15-20 year experiment

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

STRATA: Patients Had Stable EDSS Scores for Up to 5 Years Cessation/ Original Placebo Treatment Gap* Original Natalizumab 4.0 Original Placebo – Now on Natalizumab 3.5 3.24 Mean EDSS Score 3.22 3.21 3.15 3.13 3.07 3.0 2.90 2.84 2.85 2.79 2.69 2.72 2.69 2.54 2.5 2.39 2.36 2.38 2.36 2.0 1.5 1.0 0.5 0.0 n = 380 707 381 707 280 552 385 709 274 569 230 479 205 462 194 427 174 393 Feeder Feeder Safety STRATA STRATA STRATA STRATA STRATA STRATA Study Study Study Baseline 48 Weeks 96 Weeks 144 Weeks 192 Weeks 240 Weeks 1 Year 2 Years 3 Years 4 Years 5 Years Baseline End End * P <0.0001 Kappos L et al. Presented at ECTRIMS; October 10–13, 2012; Lyon, France P520. 31

WWW.MS-RES.ORG

WWW.MS-RES.ORG

CARE-MS II CARE-MS II: Risk of Sustained Disability over Intervals of up to 1 Year 40 43% reduction 39% reduction 42% 35 p=0.0127 p=0.0446 reduction Proportion of Patients (%) SC IFNB-1a 44 µg p=0.0084 Alemtuzumab 12 mg 30 25 20 21.1 18.8 15 15.2 12.7 10 11.1 9.5 5 0 6-month 9-month 12-month (Primary Endpoint) (Post Hoc Analyses) SAD Timeframe Alemtuzumab reduced the risk of disability accumulation sustained for intervals of up to 1 year vs. SC IFNB-1a Includes events with onset during 2-year core study, and confirmation in the extension. Data on file, Genzyme Corporation.