Changing Paradigms in MS Therapies National Association of Managed Care Physicians November 15, 2013

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1 Changing Paradigms in MS Therapies National Association of Managed Care Physicians November 15, 2013 John R. Corboy, MD, FAAN Professor of Neurology University of Colorado School of Medicine Co-Director, Rocky Mountain MS Center at Anschutz Medical Campus Disclosures Research support from, or consulting for NIH NMSS JDRF NIAID, Immune Tolerance Network Teva Neurosciences Novartis Lilly Peptimmune Genentech Celgene Therapeutics 1

2 Objectives Discuss modern drug therapy for MS Discuss new medications for MS Discuss risk issues in MS therapy Discuss alternative paradigms for MS therapy True agenda: convince you that early intervention with higher efficacy medications is the best choice in MS 3 What is Multiple Sclerosis (MS)? A presumptively autoimmune disorder affecting the CNS exclusively A complex disorder with genetic and environmental causes Can affect anyone, but greatest risk in young women Most common cause of disability in young women, second most common cause in young men, after trauma 4 2

3 Nomenclature- Phenotype, not Pathology Relapsing-Remitting (RRMS) about 85% Primary Progressive (PPMS) about 15% Secondary Progressive (SPMS) Majority of RRMS converts to progressive disease Progressive-Relapsing (PRMS), about 1% Clinically Isolated Syndrome (CIS), ie first attack,?what amount of risk of 2 nd attack? Inflammation 3

4 Demyelination Axonal Transection in MS Trapp et al. N Engl J Med. 1998;338:278. 4

5 MS: Prognostic Factors UNFAVORABLE Older age at onset, African American, male, high relapse rate, short interval to second relapse, early cerebellar or motor involvement, early disability, cognitive impairment, high T2 lesion load on first brain MRI, atrophy and T1 holes on MRI, PPMS, smoker FAVORABLE Young at onset, Caucasian, female, low relapse rate, longer time to second relapse, mostly sensory symptoms, no early disability, normal brain MRI at presentation, non-smoker PEDIATRIC MS under age 18 onset, about 5% of new Acts like RRMS, with much earlier onset and disability PPMS = primary progressive MS. Prognosis without Therapy 10-20% have benign MS Rare attacks, little disability Post-hoc determination About 5% have malignant MS Rapidly progressive Wheelchair-bound in 5 Years, bed-bound in 10 Years Most between these extremes Newer data suggests overall better prognosis? More people diagnosed by MRI with benign MS 5

6 Key Parameters in MS Management: Disability Expanded Disability Status Scale Death Normal neurologic exam Minimal disability Increased limitation in walking ability Patient Disability Classification Need for walking assistance 6.5 Restriction to wheelchair Helpless bed patient Expanded Disability Status Scale (EDSS) = Rating system used by neurologists and clinical trial investigators to follow the progression of disability in MS 1 Kurtzke. Neurology. 1983;33: Kurtzke. Neurology. 1983;33:1444. Early lesions are often hypointense on T1 (left), and some show leakage of contrast (right enhancement) due to BBB damage 6

7 PROTON DENSITY FLAIR 23 YO WOMAN WITH VERY ACTIVE RRMS Periventricular lesions Note thinning of corpus callosum and holes at base 7

8 T1 without contrast FLAIR 45 YO WOMAN WITH MODERATELY ADVANCED MS Holes, atrophy (note enlarged ventricles), confluent lesions MS Treatment Patient behavioral changes Exercise, Vitamin D, no smoking;? salt Treat acute attacks High dose steroids, IV or oral Use of ACTH difficult to justify, $$$$$ Symptomatic therapies Dalfampridine - Ampyra Disease modifying therapies (DMTs) Alter the natural history of the disease 8

9 Higher Vitamin D Levels Associated with Less New MS Activity Table 1. Rate Ratios (95% Confidence Intervals) for Clinical Relapse and New Active Lesions for Each 50-nmol/L Difference in Serum 25(OH)D Endpoint 0 to 60 Months 12 to 60 Months 24 to 60 Months Clinical relapse 0.73 ( ) 0.43 ( ) 0.41 ( ) New active lesions 0.61 ( ) 0.54 ( ) 0.37 ( ) Ascherio, et al ECTRIMS Poster 2013, Copenhagen. Based on Long term follow-up of the BENEFIT trial of early vs delayed treatment with interferon β-1b. Vitamin D taken as average at baseline, 6 and 12 months 17 Effect of Increasing Levels of Vitamin D on MS Activity Table 2. Results by Quintile of Vitamin D Levels Risk Ratio for Relative Annual Annualized Quintile Vitamin D New Active Change in T2 Change in EDSS Range (nmol/l) Lesions Up to 5 Lesion Volume, Score (6 Months Years Years 1 to 5 (%) to 5 Years) Ascherio, et al ECTRIMS Poster 2013, Copenhagen. Based on Long term follow-up of the BENEFIT trial of early vs delayed treatment with interferon β-1b. Vitamin D taken as average at baseline, 6 and 12 months 18 9

10 MS and Salt: Farez et al ECTRIMS, Copenhagen, October, patients, RRMS Followed for 2 years Na+ intake measured in urine samples Clinical/MRI outcomes every 3 months vs a low salt intake Medium salt intake had 2.75 x relapse rate High salt intake (>4.8 g/day) had 3.95 x relapse rate; 3.4 x risk of developing a new MRI lesion; on average had 8 more lesions WHO recommends salt intake not exceed 2 g/day, but average is g/day Modern Era of MS Therapy 1993 Interferon β-1b (Betaseron ) 1996 Interferon β-1a (Avonex ) 1996 Glatiramer Acetate (Copaxone ) 1999 Mitoxantrone (Novantrone ) 2002 Interferon β-1a (Rebif ) 2004 Natalizumab (Tysabri ) 2010 Fingolimod (Gilenya ) 2012 Teriflunomide (Aubagio approved 9/12/12) Dimethyl Fumarate (Tecfidera, FDA approved 3/27/13), Alemtuzumab (approved by EMA 9/17/13); Ocrelizumab, Laquinimod, Daclizumab, and others pending further research results 10

11 Teriflunomide (Aubagio ) Taken daily, 7 mg or 14 mg (most use 14mg) Generally well-tolerated Monitor LFTS monthly x 4-6 months Cannot use in pregnancy age women OR men Pregnancy category X Transient hair loss in about 15% Modest effects on relapse rate, disability Compared to either DMF or fingolimod, has had a modest impact on the field overall Dimethyl Fumarate (Tecfidera ) Oral, 240 mg BID GI upset, flushing in 40% Especially first few weeks; 15-20% may DC Taking with food may help; first 2 weeks at 120 BID Small % have significant lymphocytopenia Similar to Fumaderm; used to Rx psoriasis Four cases of PML with this or a compounded version About 50% relapse reduction; 70-80% less Gad+ lesions; less impressive effects on slowing disability or slowing brain atrophy 11

12 Immunotherapy Implementation Modern Therapy in 2013 First-Line Therapy aka Platform Therapy ABC-R (Avonex, Betaseron, Copaxone, Rebif) Medications Older Low risk Modest reward Poor tolerance and compliance, all injectable (SQ or IM) Some data in combination with others Lower cost Second-Line Therapy Escalation/Rescue Approach Natalizumab, Fingolimod, DMF,Teriflunomide, and Off-Label (Rituximab, Cyclophosphamide, Mycophenolate, others) Newer Higher risk perceived Greater reward, probably Better tolerance and compliance oral and intravenous Higher cost Determinants of Therapy Choice Patient issues Ease of use, mode of administration, side effects Risk issues, with highly variable interpretations Efficacy Cost issues May see major differences between meds, but all expensive Doctor issues Familiarity with medications, tried and trusted Risk issues, with highly variable interpretations Efficacy Insurance issues Typically requires failure of first-line therapies prior to payment for second-line therapies, ie 1+ step edits 12

13 Risk Assessment in MS Patients R. Fox et al, AAN, 2013 Patients accept more risk than their MDs Risk tolerance is highly variable Men tolerate more risk than women Those with greater disability tolerate more risk Those with a recent relapse tolerate more risk Thus, risk tolerance should be a patient determination, or It is the MD s job to inform the patients what is the risk, it is the patient s job to conclude how they respond to the risk 25 Logic for a New Paradigm MS is a bad disease Most untreated patients develop disability Mortality is higher than age-matched controls Disability is predicted by early relapses and MRI changes, ie the first five years matter Early treatment matters, even with lower mortality Old therapies are partial at best Old therapies are all about the same efficacy Most newer medications are better FOCUS ON EFFICACY as primary determinant of medication choice 13

14 Most Untreated MS Patients Develop Disability MS is a Bad Disease Mean time to DSS 6 (needing a cane) 15 years Perhaps less in those seen from onset of symptoms Weinshenker et al. Brain. 1989;112(Pt 1): London, Ontario database. Figure 1 Standardized mortality ratios for all causes of mortality. For each study, number of observed deaths/number of expected deaths in the matched general population is indicated in brackets. Scalfari A et al. Neurology 2013;81: American Academy of Neurology 14

15 Relapse Rate for Men and Women from Onset and by Current Age (A) from Onset (n = 2477), (B) by Patient s Current Age (n = 2477) From the population perspective, the impact of any therapeutic agent targeting the inflammatory processes in MS, and hence ability to modify recurrence of relapses, has the greatest potential during periods of high relapse activity. Tremlett et al. J Neurol Neurosurg Psych. 2008;79: by BMJ Publishing Group Ltd Figure 1 annualized relapse rate in the first 5 years and time to Expanded Disability Status Scale (EDSS) 6 (A); annualized relapse rate in the first 5 years and time to SPMS (B) Tremlett H et al. Neurology 2009;73: by Lippincott Williams & Wilkins 15

16 From: Early Relapses, Onset of Progression, and Late Outcome in Multiple Sclerosis JAMA Neurol. 2013;70(2): doi: /jamaneurol Scalfari, et al. Copyright 2012 American Medical Association. All rights reserved. Patients with More Relapses Reach DSS6 More Rapidly Based on the London Ontario dataset, relapses in the first 2 years correlate with increased disability progression in RRMS 1 years* years years * P <0.001 vs 3 or more relapses P = vs 3 or more relapses Data from London Ontario study 2 1. Lublin FD. J Neurol Sci. 2007;256(suppl 1):S14-S Scalfari A, et al. Brain. 2010;133(Pt 7):

17 Figure 2. The net change in Expanded Disability Status Scale (EDSS) score from before an exacerbation to after. Lublin F D et al. Neurology 2003;61: by Lippincott Williams & Wilkins The costs and consequences of multiple sclerosis relapses: A managed care perspective Thomas J. Morrow National Association of Managed Care Physicians, Glenn Allen, Virginia, USA Journal of the Neurological Sciences 256 (2007) S39 S44 Table 2 Direct and indirect costs associated with increasing EDSS score EDSS Score Costs Medical costs $1,255 $2,825 $8,691 Patient work time losses $6,341 $15,995 $24,513 Patient leisure time losses $1,301 $4,705 $14,789 Unpaid caregiver time $1,701 $4,554 $3,704 Totals $10,064 $28,079 $51,697 Adapted from Grima et al. [13]

18 Because both direct and indirect costs of MS increase markedly as disability progresses (Table 2) [13], the next logical cost-saving focus would appear to be an effort to delay progression of disability and the associated neurologic disturbances leading to comorbidities. Indeed, it is imperative for both patient and pocketbook that disability be prevented or at least delayed as much as possible using the most effective therapies available. The costs and consequences of multiple sclerosis relapses: A managed care perspective Thomas J. Morrow National Association of Managed Care Physicians, Glenn Allen, Virginia, USA Journal of the Neurological Sciences 256 (2007) S39 S44 35 MRI Predicts Disease Activity Early MRI in disease course predicts relapse disease activity early Spine lesions even/especially in RIS Posterior fossa lesions Enhancing lesions Early MRI predicts long term disability Brain atrophy over 2 years predicts EDSS at 8 y T1 holes T2 lesion burden on first scan and in first 5 years predicts EDSS change and progression to SPMS T2 lesion change at 1 y predicts EDSS change 18

19 Figure 1. Patients (n = 138) were categorized into quartiles based on the amount of atrophy during the phase III trial, i.e., change in brain parenchymal fraction (BPF) from baseline to year 2. (57 (44 reach EDSS 6.0) by year 8 Fisher E et al. Neurology 2002;59: by Lippincott Williams & Wilkins Eight-year follow-up study of brain atrophy in patients with MS Fisher E et al. Neurology 2002;59:

20 Baseline T2 Lesion Number Correlates with Disease Progression 1-4 Giovannoni. Early and aggressive treatment in MS. May Number of T2 Lesions at Baseline 1 0 (n=34) 1-3 (n=22) 4-9 (n=20) 10+ (n=31) Patients with EDSS >3 26% (9) 36% (8) 50% (10) 65% (20) Patients with EDSS 6 6% (2) 18% (4) 35% (7) 45% (14) 1. Fisniku LK, Brex PA, Altmann DR, et al. Brain. 2008; 131(3): Morrissey SP, Miller DH, Kendall BE, et al. Brain. 1993; 116: O Riordan JI, Thompson AJ, Kingsley PE, et al. Brain. 1998; 121: Brex PA, Ciccarelli O, O Riordan JI, et al. NEJM. 2002; 346: The data presented for years 5, 10, 14, and 20 were obtained from different publications based on the same longitudinal study. Median T2 lesion volume (T2LV) (cm3) over time for patients groups. Fisniku L K et al. Brain 2008;131: Disability and T 2 MRI lesions: a 20 year follow up of patients with relapse onset of multiple sclerosis 20

21 Eur J Neurol Nov;16(11): Epub 2009 Jun 15. Oneyear MRI scan predicts clinical response to interferon beta in multiple sclerosis. Prosperini et al Poor clinical response was defined as the occurrence of a sustained disability progression of 1 point in the Expanded Disability Status Scale (EDSS) during the follow up period of 4.8 years on average. Responders in white, poor responders in grey. Early Treatment Matters Kaplan-Meier survival curves for time from pivotal trial randomization to death over 21 years (A,B), and from onset of clinical symptoms to death (C,D), in patients treated with interferon beta-1b vs Placebo Goodin D et al. Neurology 2012;78:

22 % Reduction in relapse rates Effect on Annual Relapse Rates: Summary of Phase III Trials %* P=0.002 P= % P=0.04 IM IFNβ-1a (Avonex) 30 µg (30 µg QW) 31% P= IFNβ-1b (Betaseron) µg (250 µg QOD) 29% P<0.001 SC IFNβ-1a (Rebif) 66 µg (22 µg TIW) Weekly dose 32% P< SC IFNβ-1a (Rebif) 132 µg (44 µg TIW) 29% NS P=0.055 GA (Copaxone) 140 mg (20 mg QD) Note: Results shown are from separate clinical studies. *For patients who had been in the study for 2 years. GA = glatiramer acetate; IFN = interferon; IM = intramuscular; SC = subcutaneous. Jacobs et al. Ann Neurol. 1996;39:285; Betaseron package insert; Johnson et al. Neurology. 1995;45:1268; PRISMS Study Group. Lancet. 1998;352:1498; Rebif package insert; Copaxone package insert. Comparison Trials First-Line Therapies IFNβ-1b 500 µg vs 250 µg vs GA BEYOND trial IFNβ-1b 250 µg vs GA BECOME trial IFNβ-1a 44 µg SC TIW vs GA REGARD trial IFNβ-1a 30 µg IM QW vs GA Combi-Rx trial 22

23 REGARD Trial In IFNβ-1a vs GA, no difference in primary outcome of time to relapse, secondary clinical outcomes, and most MRI measures. There were less new enhancing lesions in the IFN group. MRI = magnetic resonance imaging. Mikol et al. Lancet Neurol. 2008;7: Disease Activity Free over 36 Months by Treatment Group: No Relapse Activity, EDSS Progression or CUA %DAF Status at Three Years 23

24 Long Term Effects of DMTs In Glatiramer acetate 15 year LTFU study, even in those who stayed on drug for the entire 15 years, 35% developed SPMS (mean disease duration 22 years) *** 20 year data at ECTRIMS, October 2013 = 47% develop SPMS In Avonex 15 year LTFU study, almost 1/3 of those still on drug reached EDSS 6.0, and almost twice as many no longer on drug reached EDSS 6.0 (Bermel RA, et al Intramuscular interferon β-1a therapy in patients with relapsing-remitting multiple sclerosis: a 15-year follow-up study. Mult Scler 2010; 16: ). LTFU Glatiramer Acetate Ongoing Treatment Group 100/231 = 43% Mean duration of use 13.6 years Mean change EDSS at last observation 0.96 Mean EDSS change per year 0.2 Reach EDSS % Withdrawn group 131/231 = 57% Mean duration of use 4.8 years Mean change EDSS at last observation 1.0 Mean EDSS change per year 0.5 Reach EDSS % 48 24

25 20 Years of Continuous Use of GA 20 mg Endpoints GA 20 mg (N = 74) Cumulative ARR 0.2 Relapse free, % 24.3 No second relapse, % 47.3 Progression to SPMS, % 47 Mean EDSS score (SD)* 3.1 (2.2) Maintained EDSS score < 4 from GA start, % 63 Maintained EDSS score < 6 from GA start, % 79 * Mean EDSS score at GA start was 2.4 (1.4). SPMS = secondary progressive MS; EDSS = expanded disability status scale; SD = standard deviation; AEs = adverse events. Ford C, et al. [Poster 577] ECTRIMS 2013, Copenhagen 49 LTFU Interferon β-1a IM 15 years Presently on INF β-1a IM, many started in Rx group 56/122 (172 total) Mean EDSS 4.4 EDSS 6.0 = 32% NOT on INF β-1a IM, many started in Pb group 66/122 (172 total) Mean EDSS 5.7 EDSS 6.0 = 62% ie even patients doing relatively well have significant risk of significant disability (Bermel RA, et al Intramuscular interferon β-1a therapy in patients with relapsing-remitting multiple sclerosis: a 15-year follow-up study. Mult Scler 2010; 16: )

26 Newer MS Agents Natalizumab IV q 28 days; Humanized monoclonal antibody against 4-integrin Fingolimod oral daily; S1P superagonist > traps lymphocytes; potential role in CNS Teriflunomide - oral daily; dihydro-orotate dehydrogenase inhibitor > Blocks de novo pyrimidine synthesis, reducing proliferation of autoreactive T- and B-cells Dimethyl Fumarate - oral bid; MOA not really known Alemtuzumab - IV 5 days in a row and repeat for 3 days at one year; monoclonal antibody against CD52+ cells Approved by EMA 9/17/2013, pending FDA as of 11/ ARR in Newer MS Agents v Pb Natalizumab Fingolimod Dimethyl Fumarate Aubagio Alemtuzumab 62% less than Pb 50% less than Pb 50% less than Pb 33% less than Pb 55% less than IFN 52 26

27 Comparison Studies New Agents Newer Agents Generally Superior to Older TRANSFORMS: Fingolimod vs IFNβ-1a 30 µg IM COMFIRM: BG12 vs placebo and vs GA CARE-MS I and II: Alemtuzumab vs IFN β-1a 44 TIW Ocrelizumab vs placebo and vs IFN β-1a 30 µg IM TENERE: Teriflunomide equal efficacy to IFN β-1a 44 µg TIW, but with less discontinuations and greater patient satisfaction DECIDE: Daclizumab vs IFN β-1a 44 µg TIW (results pending) TRANSFORMS Trial Fingolimod vs IFNβ-1a 44 µg TIW Annualized relapse rate (ARR) at 12 months is lower, % of relapse-free patients greater, and the time to the first relapse is longer with both doses of fingolimod vs IFNβ-1a Cohen et al. N Engl J Med. 2010;362:

28 CONFIRM: Clinical and MRI Results Outcome BG mg BID* BG mg TID* Glatiramer Acetate* Annualized relapse rate 1 44% (p<.0001) 51% (p<.0001)** 29% (p<.02) Proportion of patients with relapses 1 34% (p<.003) 45% (p<.0001) 29% (p<.01) 12-week confirmed EDSS progression 1 21% (NS) 24% (NS) 7% (NS) Mean # of new/enlarging T2 lesions 2 71% ** (p<.0001) 73% ** (p<.0001) 54% (p<.0001) Mean # of new T1-hypointense lesions 2 57% (p<.0001) 65% ** (p<.0001) 41% (p<.0001) *Compared with placebo. ** significantly favors BG12 vs GA** Fox et al. N Engl J Med. 2012;367: CARE-MS I: Annualized Relapse Rate 55%; P<.0001 Cohen et al Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial. Lancet Volume 380, Issue 9856, November 2012, Pages

29 CARE-MS I: MRI Outcomes for Alemtuzumab vs IFNβ-1a % of Patients with Gd-Enhancing Lesions % of Patients with New/Enlarging T2 Lesions -44% P= % P=.035 Cohen et al Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial. Lancet Volume 380, Issue 9856, November 2012, Pages CARE-MS I: MRI Outcomes for Alemtuzumab vs IFNβ-1a Change in Brain Parenchymal Fraction P =.0052 P <.0001 P <.0001 Cohen et al Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial. Lancet Volume 380, Issue 9856, November 2012, Pages

30 Figure 2 Clinical efficacy outcome measures Kaplan-Meier estimates of time to first relapse (A) and 6 month sustained accumulation of disability (B). Alasdair J Coles, Cary L Twyman, Douglas L Arnold, Jeffrey A Cohen, Christian Confavreux, Edward J Fox, Hans... Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial. The Lancet Volume 380, Issue CARE-MS II: Key Disability Data Mean change in EDSS score (P<.0001): Alemtuzumab: IFNβ-1a: month sustained reduction in disability (P=.0002): Alemtuzumab: 29% IFNβ-1a: 13% Coles et al Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial. The Lancet Volume 380, Issue

31 CARE-MS Cautions Neither study showed reduction in accumulation of new T2 lesion burden CARE-MS1 did not show greater effect on slowing sustained accumulation of disability (SAD), a primary endpoint On 11/8/2013, the FDA raised concerns about trial design (was not double dummy), blinding in CARE-MS2 (resulting in high IFN dropout and potential effect on SAD), and safety 61 Potential Safety Issues with Alemtuzumab These include the incidence of an array of autoimmune diseases including immune thrombocytopenia (ITP), autoimmune hemolytic anemia, immune pancytopenia, anti-glomerular basement membrane (Anti-GBM) disease, membranous glomerulonephritis, thyroid disorders, endocrine ophthalmopathy, acquired hemophilia A, type 1 diabetes mellitus, acute epitheliopathy of the retina, autoimmune skin disease, and undifferentiated connective tissue disorders, along with the incidence of malignancies, notably including thyroid cancer and melanoma. FOOD AND DRUG ADMINISTRATION (FDA) Center for Drug Evaluation and Research (CDER) Peripheral and Central Nervous System Drugs Advisory Committee Meeting Alemtuzumab (BLA \5139) Background Package November 13,

32 HERMES Trial: Gadolinium-Enhancing Lesions in Each Study Group from Baseline to Week 48 A Mean total # gad lesions by week B Mean total # of new gad lesions by week Two doses Rituximab 1000mg IV each over two weeks in RRMS(green treated, gray placebo) produced profound and persistent reduction in gad lesions. Less relapses in treated group at weeks 24, 48. Hauser S et al. N Engl J Med 2008;358: Phase II Trial of Ocrelizumab in RRMS: Week 144 Results Study Design Time Patient Dosing Cohorts 0 Week 24 Placebo OCR 600 mg OCR 2,000 mg IFNβ-1a 30 mcg IM Weeks OCR 600 mg OCR 600 mg OCR 1,000 mg OCR 600 mg Weeks OCR 600 mg OCR 600 mg OCR 1,000 mg OCR 600 mg Weeks OCR 600 mg OCR 600 mg OCR 600 mg OCR 600 mg Weeks Treatment-free F/U Treatment-free F/U Treatment-free F/U Treatment-free F/U 166 of original 220 patients in current analysis ARR remains low in all groups (reduced by 73% overall), even though patients have not received drug for 18 months Only 3 patients have had new lesions on MRI Phase III program in RRMS (OPERA I and II trials) recruiting ~ 1,600 patients (data expected in 2015) ORATIO trial in PPMS also ongoing Hauser S, et al. Presented at AAN 2013; March 16 23, 2013; San Diego, CA. Abstract S

33 The Reduction in Gd-Enhancing T1 Lesions by OCR is Maintained Through 144 Weeks Primary endpoint: OCR vs Placebo 1 Patients with baseline MRI Placebo (n=54) OCR 600 mg dose regimen (n=55) OCR 1000 mg dose regimen (n=55) IFN-β1a (n=54) - Core Study' (0 96 weeks) - Follow Up' ( weeks) a * Weeks *p< for both OCR doses vs placebo, N (for primary analysis): Placebo=54, OCR 600 mg=51, OCR 1000mg=52, IFN-β1a=52 2 a Patients who withdrew during earlier treatment cycles were also included in the follow-up periods 1. Kappos L, et al. Lancet. 2011;378(9805): ; 2. Kappos L, et al. Abstract presented (P362) ECTRIMS 2012, October 12 Figure 2. Time to failure.the Kaplan Meier method was used to derive estimated rates of failure at Weeks 24, 48 and 96. IFN patients fail mostly due to adverse events/tolerance TFL patients fail mostly due to relapses, esp at 7 mg Vermersch P et al. Mult Scler 2013; Copyright by SAGE Publications 33

34 Table 2. Analysis of primary and secondary endpoints at 48 weeks, ITT population. Copyright by SAGE Publications Vermersch P et al. Mult Scler 2013; Natalizumab Compared to Itself?! Tysabri Observational Program As of 12/11, 3796 patients in 15 countries 366 (9%) treatment-naïve (TN) TN a little younger (35.7 vs 37.4, ns), with shorter disease duration (1.9 y vs 7.8 y), lower EDSS (3.3 vs 3.5) but similar ARR (2.0) TN compared to previously treated ARR decreased for both, to 0.23 in TN vs 0.28 (ns) Probability of relapse by year 3, 31% vs 43% (p=.002) EDSS lower over time in TN and differences increased Risk of EDSS IMPROVEMENT 30% in TN vs 20% (p=.024) Butzkueven et al. Abstract P Presented at: American Academy of Neurology 64th Annual Meeting; April 21-28, Preliminary data. 34

35 Issues for New Studies/Agents Challenge of designing studies in a world with many approved agents Unethical to do placebo controls in RRMS Need more/all comparator trials for RRMS Double dummy more acceptable from a blinding point of view, but more challenging for the patient and more expensive Higher reward with higher risk with newer agents Management of risk requires more testing and time for patient and MD 69 Time to Flip the Approach? Treat with most effective therapy at time the disease is most active (ie, early) Transition, as necessary, to safer therapies when risk of disease itself is similarly lower (ie, later) Use a more directed approach to therapy 35

36 Biomarkers and the Advent of Personalized Medicine Disease severity Risk of therapy Futility of therapy Predicting response to therapy Monitoring response to therapy Risk of Therapy Natalizumab and PML (Progressive Multifocal Leukoencephalopathy) JCV status Duration of use Prior chemotherapy/immunosuppression Autoimmunity with alemtuzumab IL-21 levels predictive of risk Remains to be verified IL = interleukin; JCV = JC virus; PML = progressive multifocal leukoencephalopathy. 36

37 Natalizumab and PML As of June 2013, patients with PML 372/115,000+ treated patients, ~ 1/310 overall Risk related to several factors Prior exposure to JCV 56% exposed; with time Natalizumab doesn t alter shedding of virus in blood/urine Duration of use, esp after 2 years of use Prior use of IS drugs, esp Mitoxantrone > 4x risk May explain 2 x risk in European vs US patients?antibody Index higher v lower index may increase risk 25x (index,0.9 vs index > 1.5)? Low body mass? Low L-Selectin levels Schwab N et al. Neurology 2013;81: ? Absence of lipid-specific IgM OCBs ( ECTRIMS 2013) PML Risk with Tysabri by Epoch of Use From: Biogen Idec, June

38 Estimated Incidence of Natalizumab-Associated PML Stratified by Risk Factors * Biogen IDEC October, 2013 * risk as high as year 1 ~ 1/8,333, year 2 ~ 1/1163 PML risk can be estimated by index threshold in anti-jcv antibody-positive patients PML risk estimates (95% CI) per 1000 patients (anti-jcv antibody positive ) (no prior IS use) Index threshold > months 0.1 (0 0.41) 0.1 (0 0.34) 0.1 ( ) 0.1 ( ) 1.0 ( ) months 0.3 ( ) 0.7 ( ) 1.0 ( ) 1.2 ( ) 8.1 ( ) months 0.4 ( ) 0.7 ( ) 1.2 ( ) 1.3 ( ) 8.5 ( ) PML risk estimates for anti-jcv antibody index thresholds were calculated based on the current PML risk stratification algorithm (from September 2012) and predicted probabilities for the population at or below that particular index ( ) and for the population above an index of 1.5. For index thresholds below 0.9, patient numbers were insufficient to allow for calculation of risk estimates. SOURCE BIOGEN Idec 2013 Consortium of MS Centers, May 2013, Poster DX51 38

39 PML risk can be estimated by index threshold in anti-jcv antibody-positive patients PML risk estimates (95% CI) per 1000 patients (anti-jcv antibody positive ) (no prior IS use) Index threshold > months 0.1 (0 0.41) 0.1 (0 0.34) 0.1 ( ) 0.1 ( ) 1.0 ( ) months 0.3 ( ) 0.7 ( ) 1.0 ( ) 1.2 ( ) 8.1 ( ) months 0.4 ( ) 0.7 ( ) 1.2 ( ) 1.3 ( ) 8.5 ( ) PML risk estimates for anti-jcv antibody index thresholds were calculated based on the current PML risk stratification algorithm (from September 2012) and predicted probabilities for the population at or below that particular index ( ) and for the population above an index of 1.5. For index thresholds below 0.9, patient numbers were insufficient to allow for calculation of risk estimates. SOURCE BIOGEN Idec 2013 Consortium of MS Centers, May 2013, Poster DX51 Figure 1 Surface expression of CD62L and its correlation to progressive multifocal leukoencephalopathy development in multiple sclerosis patients receiving natalizumab therapy(a, B) The percentage of CD62L surface expressing CD3+ CD4+ T cells, gated as shown in figure 2. Schwab N et al. Neurology 2013;81: American Academy of Neurology 39

40 Prevalence of JCV Antibody: STRATIFY-1 Seropositivity Increases with Age Numbers at lower end of each bar indicate number of patients; error bars represent 95% CI. Bozic et al. Abstract P Presented at: American Academy of Neurology 63 rd Annual Meeting; April 9-16, 2011; Honolulu. Preliminary data. Figure 2. DR15-DQ6 positive but DR17-DQ2 negative combination was strongly predictive of a favorable clinical response (71%) Suhayl Dhib-Jalbuta, et al 2013 HLA DR and DQ alleles and haplotypes associated with clinical response to glatiramer acetate in multiple sclerosis Multiple Sclerosis 80 40

41 New Paradigms/Algorithms Assumes approval of multiple medications Assumes confirmation of test utility Assumes availability of screening tests Assumes insurance company agreement Will change as we gain more information, especially with comparison trials Following is one possible alternative approach, with qualitative conclusions; there are undoubtedly many others Diagnosed with RRMS 2013 Low-Risk Medications IFN, GA; or Watch/Wait Do Well Do Poorly Continue Indefinitely If GA Try IFN Do Poorly If IFN Try GA Do Well Pos JCV status Neg Do Well Continue Indefinitely Fingolimod Teriflunomide? Natalizumab x mo if JCV+ Natalizumab Continue Indefinitely 41

42 vs More Severity Less Neg Natalizumab Rituximab/ Ocrelizumab JCV Status Pos IL-21 Autoimmune Risk Low Alemtuzumab High Low-Risk Medications Fingolimod/DMF Teriflunomide/Laquinimod Daclizumab If Fail JCV/IL-21 Risk Do well Do Well Continue Indefinitely Do Poorly Need Alternative Low Natalizumab Alemtuzumab Rituximab/Ocrelizumab GA responder Pregnancy GA High IFN responder Interferon Continue 42

43 Thank You 43