Bruce Cree, MD, PhD, MCR. BG-12 Has Shown Nrf2 Pathway. Activation. DEFINE (BG-12/Dimethyl Fumarate) : Study Design

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1 MS Therapies Update 212 Bruce Cree, MD, PhD, MCR BG12 Alemtuzumab Daclizumab BAF312 Erythropoetin Outline Fingolimod IFN β-1a Natalizumab Oral solumedrol Duloxetine O BG-12 Has Shown Nrf2 Pathway O OH Activation O OR O DMF (BG-12) O O MMF O DEFINE (BG-12/Dimethyl Fumarate) : Study Design Year 1 Year 2 Keap1 Nrf2 ARE Cytoplasm Maf Jun ATF4 Nucleus - Detoxification enzymes - Antioxidant enzymes - NADPH generating enzymes - GSH biosynthesis enzymes - Chaperones - Ubiquitination/proteasome - Detoxification - Normalization of energy metabolism - Repair/degradation of damaged proteins Randomization 1:1:1 N = 1237 MRI N = 54 EDSS/MSF/VFT SF-36/EQ-5D BG mg BID BG mg TID DMF=dimethyl fumarate; MMF=monomethyl fumarate. Scannevin R, et al. Poster presented at ECTRIMS October 13 16, 21. Gothenburg, Sweden. P887. Feinstein D, et al. Poster presented at ECTRIMS October 13 16, 21. Gothenburg, Sweden. P879. Study Week Gold R, et al. Presented at ECTRIMS / ACTRIMS 211; Amsterdam, Netherlands. [Abstract 95] 1

2 DEFINE: Cumulative Probability of Relapse (1 o Endpoint) DEFINE: Annualized Relapse Rates Probability of Relapse Hazard Ratio: BG-12 BID vs placebo =.51 (P <.1) BG-12 TID vs placebo =.5 (P <.1) (n = 48).1 BG-12 BID (n = 41) BG-12 TID (n = 416) BL Time (weeks) Number of Patients at Risk: BG-12 BID BG-12 TID Patients were censored if they withdrew from study or switched to alternative MS medication without a relapse. Gold R, et al. Presented at ECTRIMS / ACTRIMS 211; Amsterdam, Netherlands. [Abstract 95] ARR % Reduction vs placebo P < (n = 48) BG-12 BID (n = 41) BG-12 TID (n = 416) Gold R, et al. Presented at ECTRIMS / ACTRIMS 211; Amsterdam, Netherlands. [Abstract 95] 48% Reduction vs placebo P <.1 DEFINE: Time to 12-Week Confirmed Disability Progression DEFINE: 2 Years MRI Outcomes Proportion Pts with 12 Weeks Disability Progression Hazard Ratio: BG-12 BID vs placebo =.62 (P =.5) BG-12 TID vs placebo =.66 (P =.128) BL Time (weeks) (n = 48) BG-12 BID (n = 41) BG-12 TID (n = 416) Number of Patients at Risk: BG-12 BID BG-12 TID Mean Number of GD+ Lesions Gd-enhancing lesions (n = 165) 9% reduction* P < % reduction* P <.1.5 BG-12 BID BG-12 TID (n = 152) (n = 152) New or newly enlarging T2 lesions Adjusted Mean Number of New or Newly Enlarging T2 Lesions (n = 165) 85% reduction* P < % reduction* P < BG-12 BID BG-12 TID (n = 152) (n = 152) Gold R, et al. Presented at ECTRIMS / ACTRIMS 211; Amsterdam, Netherlands. [Abstract 95] Arnold DL, et al. Presented at ECTRIMS / ACTRIMS 211; Amsterdam, Netherlands. [P831] 2

3 AE n (%) DEFINE: Adverse Events Any event Flushing* MS relapse Nasopharyngitis Headache Diarrhea* Fatigue Upper respiratory tract infection Urinary tract infection Nausea* Back pain Upper abdominal pain* Proteinuria* Abdominal pain* Arthralgia Influenza Pruritus* Vomiting* (n = 48) 387 (96) 2 (5) 189 (46) 11 (25) 8 (2) 55 (13) 54 (13) 53 (13) 53 (13) 38 (9) 57 (14) 28 (7) 34 (8) 22 (5) 39 (1) 39 (1) 19 (5) 24 (6) *Indicates an incidence 3% higher in either BG-12 group. BG mg BID (n = 41) 395 (96) 154 (38) 111 (27) 18 (26) 81 (2) 62 (15) 57 (14) 63 (15) 55 (13) 53 (19) 59 (14) 4 (1) 38 (9) 46 (11) 46 (11) 34 (18) 42 (1) 4 (1) Selmaj K, et al. Presented at ECTRIMS / ACTRIMS 211; Amsterdam, Netherlands. [P994] BG mg TID (n = 416) 396 (95) 132 (32) 114 (27) 19 (26) 8 (19) 78 (19) 63 (16) 51 (12) 54 (13) 54 (13) 46 (11) 52 (13) 5 (12) 37 (9) 37 (9) 48 (12) 34 (8) 3 (7) CONFIRM: A Phase 3 Trial of BG-12 with An Active Comparator in Patients with MS N = 1232 RRMS EDSS score. to 5. Endpoint ARR New/Enlarging T2 Lesions New T1 Lesions 12-wk CDP R BG-12 BID (vs ) -44% (P <.1) -71% (P <.1) -57% (P <.1) -21% (NS) BG-12 TID (vs ) -51% (P <.1) -73% (P <.1) -65% (P <.1) -24% (NS) Biogen Idec. Press Release, October 26, details.aspx?id=5981&reqid = Accessed January 24, 212. BG mg BID BG mg TID Glatiramer Acetate 2 mg/day GA (vs ) -29% (P <.2) -54% (P <.1) -41% (P <.3) -7% (NS) BG12 Summary Compared to placebo BG12 showed significant reductions with respect to the probability of experiencing a relapse, the annualized relapse rate, disability progression and accumulation of gadolinium enhancing or new T2 lesions on MRI There did not appear to be any difference between the BID and TID treatment arms Data on brain volume loss was not presented TEMSO: Phase 3 -Controlled Trial of the Pyrimidine Synthesis Inhibitor, in MS N = 1,88 RRMS R 14 mg/day Additional Outcomes Both teriflunomide doses superior to placebo in terms of MRI outcomes 3% in 12-wk CDP with 14 mg teriflunomide dose (P =.3 vs ) Both doses were well-tolerated 7 mg/day ARR % Reduction P = mg 31.5% Reduction P =.5 14 mg O Connor P, et al. ECTRIMS 21. Abstract 79. 3

4 Long-Term Follow-Up Data on Efficacy and Tolerability of in Patients with MS No difference in serious opportunistic infections or liver enzyme elevations >3X ULN observed in pts treated with teriflunomide compared with placebo in TEMSO trial 1 Open-label extension study of TEMSO trial has shown clinical benefits of teriflunomide maintained for up to 5 years 2 Both doses of teriflunomide were well tolerated with favorable safety profile with up to 4 years' follow-up 3 Similar results with respect to the tolerability and safety of teriflunomide were reported after up to 9 years of follow-up of a phase 2 study 4 Reductions in disease activity observed in phase 2 trial maintained for up to 8 years 5 TENERE: Phase 3 Trial Comparing with IFN β-1a in Patients with MS 1 N = 324 RRMS Preliminary Results Endpoint R 7 mg/day 14 mg/day IFN β-1a 44 µg TIW 7 mg Risk of Treatment Failure Confirmed relapse Or Any cause treatment discontinuation 14 mg IFN β-1a Risk of treatment failure 48.6% 37.8% 42.3% ARR Treatment discontinuation 8.2% 1.9% 21.8% 1. O Connor P, et al. ECTRIMS 21. Abstract O Connor P et al. ECTRIMS/ACTRIMS 211. Abstract P Comi G et al. ECTRIMS/ACTRIMS 211. Abstract P Confavreaux C et al. ECTRIMS/ACTRIMS 211. Abstract P Li DKB et al. ECTRIMS/ACTRIMS 211. Abstract P Genzyme, a Sanofi company. Press Release, December 2, Accessed January 24, 212. Proposed Mechanisms: Modulates TH1/TH2 activity by: Inhibiting proinflammatory pathways Enhancing anti-inflammatory pathways Suppresses pathways involved in antigen presentation to naïve T cells Increased levels of transcripts encoding: Insulin-like growth factor-1 by > than 2 fold Brain-derived neurotrophic factor (BDNF) by 3 fold Pro-inflammatory IL-12 TNF-α Gurevich M, et al. J Neuroimmunol. 21;221: Silva C, et al. Presented at ECTRIMS 21; October 13-16, 21; Gothenburg, Sweden. [Poster 882] Anti-inflammatory IL-4 IL-1 ALLEGRO Subjects with RRMS (N = 116) BRAVO Subjects with RRMS (N = 1332) Evaluations (baseline) : Ongoing Phase III Studies Oral laquinimod.6 mg qd Oral matching placebo Oral laquinimod.6 mg qd IFNβ-1a 3 mcg/wk IM injection Oral matching placebo Open-label extension Open-label extension months ClinicalTrials.gov. Accessed 12/1/1. 4

5 ALLEGRO (): Updated Efficacy Outcomes EDSS progression after 2 years (%).6 mg P-value ARR requiring IV steroids <.1 ARR requiring hospitalization 27% in laquinimod group % in laquinimod group Relapse-free during study (%) Risk of EDSS score progression 3 month 36% in laquinimod group 6 month 48% in laquinimod group Comi G, et al. Presented at ECTRIMS / ACTRIMS 211; Amsterdam, Netherlands. [P934] Mean cumulative number of T1 hypointense lesions ALLEGRO: Updated MRI Outcomes Mean New Hypointense T1 Lesions (n = 556) 26.7% reduction P = (n = 55) % change in brain atrophy from baseline.% -.5% -1.% -1.5% 12 months 24 months -.76% -.36% (.6 mg) Filippi M, et al. Presented at ECTRIMS / ACTRIMS 211; Amsterdam, Netherlands. [P363] Brain Atrophy Outcomes 51.7% lower; P <.1-1.3% -.87% 32.8% lower; P <.1 Annualized Relapse Rate* BRAVO: ARR (1 Endpoint) 21% Reduction P = mg 29% Reduction P =.2 IFNβ-1a IM 3 mcg *Adjusted for baseline EDSS, number of relapse in 2 year pre-study period, country, baseline T2 lesion volume and Gd-enhancing T1 status at baseline Vollmer TL, et al. Presented at ECTRIMS / ACTRIMS 211; Amsterdam, Netherlands. [Abstract 148] Cumulative Number of GdE-T1 Lesions (Months 12 & 24) 1.14 BRAVO: MRI Results Gd-enhancing T1 lesions % Reduction P = mg 6% Reduction P <.1.45 IFNβ-1a IM Cumulative Number of New T2 Lesions (Months 12 & 24) New T2 lesions 19% Reduction P = mg Vollmer TL, et al. Presented at ECTRIMS / ACTRIMS 211; Amsterdam, Netherlands. [Abstract 148] 52% Reduction P < IFNβ-1a IM 5

6 BRAVO: Confirmed Disease (EDSS) Progression BRAVO: Effects on Brain Volume Patients with Confirmed Progression* (%) Month vs pbo: 33.5% Reduction, P =.4 IFNß-1a IM vspbo: 28.7% Reduction, P = Day.6 mg IFNβ-1a IM Month vs pbo: 4.6% Reduction, P =.4 IFNß-1a IM vspbo: 28.3% Reduction, P = Day Percent Brain Volume Change* (Months 24) mg -27.4% Improvement P <.1 IFNβ-1a IM 3 mcg +9% Deterioration P =.14 *A confirmed progression was defined as at least a 1 point increase from baseline on EDSS score if baseline EDSS was between and 5., or at least.5 point increase if baseline EDSS was 5.5 Vollmer TL, et al. Presented at ECTRIMS / ACTRIMS 211; Amsterdam, Netherlands. [Abstract 148] *Using SIENA; adjusted for baseline normalized brain volume, T2 lesion volume and Gd-T1 status Vollmer TL, et al. Presented at ECTRIMS / ACTRIMS 211; Amsterdam, Netherlands. [Abstract 148] BRAVO: Adverse Events.6 mg (N = 433) (N = 449) IFNβ-1a IM 3 mcg (N = 442) Risk Ratio Laq/ Risk Ratio IFN/placebo Headache 54 (12.5%) 54 (12%) 6 (13.6%) Back Pain 44 (1.2%) 32 (7.1%) 15 (3.4%) Nasopharyngitis 4 (9.2%) 35 (7.8%) 29 (6.6%) Upper Respiratory Tract Infection 34 (7.9%) 36 (8%) 22 (5%).9.6 Influenza 27 (6.2%) 29 (6.5%) 2 (4.5%) 1..7 Arthralgia 24 (5.5%) 18 (4%) 18 (4.1%) Depression 22 (5.1%) 12 (2.7%) 21 (4.8%) Pyrexia 6 (1.4%) 7 (1.6%) 52 (11.8%) Flu-like illness 5 (1.2%) 7 (1.6%) 26 (46.6%) Vollmer TL, et al. Presented at ECTRIMS / ACTRIMS 211; Amsterdam, Netherlands. [Abstract 148] BRAVO: Summary Data consistent with Phase III ALLEGRO study Apparently disproportionate effect of laquinimod on parameters of neurodegeneration (progression of disability, brain volume loss) relative to inflammation (relapses and new lesions) Interferon beta-1a had similar effects on relapses and lesion accumulation as was observed in the MSCRG pivotal trial Significant effects on brain volume were not observed Vollmer TL, et al. Presented at ECTRIMS / ACTRIMS 211; Amsterdam, Netherlands. [Abstract 148] 6

7 Proposed Mechanisms: Alemtuzumab Humanized mab directed against Alemtuzumab CD52 (expressed on leukocyte surface) Rapidly and profoundly depletes T cells, B cells, and monocytes CD52 through: Antibody-dependent cellmediated cytotoxicity (ADCC) Complement-mediated cytotoxicity (CDC) CD4+ cells may take ~5 years to fully recover B cell Reconstituted lymphocytes appear to have regulatory properties Jones JL, Coles AJ. Int MS J. 29;16: T cell CARE-MS I (Alemtuzumab): Study Design Alemtuzumab 12 mg IV IFNβ-1a 44 mcg SC Study duration (months) Daily 5 Daily 3 3 / Week Entry criteria: age 18-5 years; MS symptom onset 5 years, baseline EDSS 3; 2 or more relapses in 24 months prior to study entry; and at least 1 attack in the 12 months prior to study entry Both treatment arms received 1 gram methylprednisolone once daily 3 days at Months and 12 EDSS performed quarterly and MRI annually Coles A, et al. Presented at ECTRIMS / ACTRIMS 211; Amsterdam, Netherlands. [Abstract 151] CARE-MS I: Annualized Relapse Rates CARE-MS I: Patients with Gd-enhancing Lesions P <.1 P <.2 55% Rate Reduction P <.1 Patients (%) P = P = SC IFNβ-1a Alem 12 mg/day P = Baseline Year 1 Year 1 2 Years 2 Coles A, et al. Presented at ECTRIMS / ACTRIMS 211; Amsterdam, Netherlands. [Abstract 151] Coles A, et al. Presented at ECTRIMS / ACTRIMS 211; Amsterdam, Netherlands. [Abstract 151] 7

8 Proportion of Patients with New and Enlarging T2-Hyperintense Lesions SC IFNβ-1a Alem 12 mg/day Proportion of Patients with New T1-Hypointense Lesions CARE-MS I: Additional MRI Outcomes SC IFNβ-1a Alem 12 mg/day P =.65 P < Year 1 Year 1 2 Years P = P = Coles A, et al. Presented at ECTRIMS / ACTRIMS 211; Amsterdam, Netherlands. [Abstract 151] 6.8 P =.35 P = Year 1 Year 1 2 Years 2 Median Change (%) CARE-MS I: Change in Brain Parenchymal Fraction Year 1 Year 1 2 Years P <.1 SC IFNβ-1a Alem 12 mg/day P = Coles A, et al. Presented at ECTRIMS / ACTRIMS 211; Amsterdam, Netherlands. [Abstract 151] -.87 P <.1 CARE-MS I: Key Safety Issues Autoimmune Thyroid Disease Thyroid disorders more common with alemtuzumab treatment 18.1% alemtuzumab vs 6.4% SC IFNβ-1a Hyperthyroidism most common Mostly mild-moderate in severity 1.1% with serious alemtuzumab-associated thyroid events 1 (.3%) ophthalmopathy, 1 (.3%) thyrotoxicosis in the same patient SC IFNβ-1a Alemtuzumab N = 187 N = 376 n (%) n (%) Immune Thrombocytopenia Platelet-based* or AE-based definition 3 (1.6) 3 (.8) Platelet-based *definition 3 (1.6) 3 (.8) AE-based definition 1 (.5) 3 (.8) *Alemtuzumab-related cases were SAEs Coles A, et al. Presented at ECTRIMS / ACTRIMS 211; Amsterdam, Netherlands. [Abstract 151] CARE MS-1 Summary Compared to interferon beta-1a, alemtuzumab significantly reduced the annualized relapse rate, number of contrast enhancing lesions and slowed brain volume loss Effects on accumulation of new T2 lesions and T1esions were less robust There was no difference with respect to disability progression (11% versus 8% p=.22) 8

9 SELECT (Daclizumab HYP) Phase II: Efficacy Outcomes (n = 196) DAC HYP 15 mg (n = 21) DAC HYP 3 mg (n = 23) ARR *.46.21*.23* Relapse-free patients * 64% 81%* 8%* New or newly enlarging T2 lesions (1-year) * * 1.7* New Gd+ lesions (wks 8 24) * * 1.* Risk of 3-month sustained disability progression at 1-year vs placebo *P <.1 for both doses of DAC HYP compared with placebo DAC = daclizumab; HYP = high yield process 57% P =.2 Giovannoni G, et al. Presented at ECTRIMS / ACTRIMS 211; Amsterdam, Netherlands. [Abstract 149] 43% P =.9 SELECT: Adverse Events Adverse Event (%) (n = 196) DAC HYP 15 mg (n = 21) DAC HYP 3 mg (n = 23) MS relapse Nasopharyngitis Upper respiratory tract infection Headache Pharyngitis Serious infections 3 1 Serious cutaneous events 1 1 Death, n 1* * One subject who was recovering from a serious cutaneous event died due to a complication of a psoas abscess. Giovannoni G, et al. Presented at ECTRIMS / ACTRIMS 211; Amsterdam, Netherlands. [Abstract 149] BAF312 (Selective S1-P Receptor Modulator): Phase II Study in RRMS BAF312: Active Lesions and ARR Interim Analysis st Patient Group Period 1 Month Month 3 Month 6 Randomization (N = 188), 1:1:1:1 BAF312 1 mg/d BAF312 2 mg/d BAF312.5 mg/d BAF312 1 mg/d BAF312 2 mg/d BAF312.5 mg/d Period 2 doses selected based on the interim analysis results to optimally inform the final dose-response curve Patients on placebo equally randomized to BAF312 doses Mean CUAL at Month ARR at 6 Months ND Patient Group Period 2 BAF mg/d BAF mg/d Selmaj K, et al. Presented at ECTRIMS / ACTRIMS 211; Amsterdam, Netherlands. [P117] Randomization (N = 188), 1:4:4 (N=61) BAF.25 mg (N=51) BAF.5 mg (N=43) BAF 1.25 mg (N=42) BAF 2 mg (N=29) BAF 1mg (N=5) (N=45) BAF.5 BAF 2 mg mg (N=43) (N=49) CUAL: defined as new Gd+ T1 lesions or new or enlarging T2 lesions, without double counting Selmaj K, et al. Presented at ECTRIMS / ACTRIMS 211; Amsterdam, Netherlands. [P117] BAF 1 mg (N=5) 9

10 BAF312: Phase II Safety Erythropoietin Add-On Treatment To Methylprednisolone For Optic Neuritis BAF312 Adverse Event (%).25 mg.5 mg 1.25 mg 2. mg 1. mg Headache Bradycardia Dizziness Nasopharyngitis Nausea Fatigue Lymphopenia ALT increase Somnolence Selmaj K, et al. Presented at ECTRIMS / ACTRIMS 211; Amsterdam, Netherlands. [P117] Randomized, double-blind, placebocontrolled, phase II Patients w/ first episode of ON (visual acuity.5) 33, IU Epo daily x3 days or placebo, and 1 mg of MP Primary outcome: change in RNFL thickness No safety issues noted in RNFL (µm) Epo Median Mean Difference of RNFL Thickness to Baseline (µm) Mean RNFL Thickness (µm) * 35 P = Week 4 Week 8 Week ON = optic neuritis; IU = international unit; Epo = erythropoietin; RNFL retinal nerve fibre layer P =.961 Sühs KW, et al. Presented at ECTRIMS / ACTRIMS 211; October 1-22,211; Amsterdam, Netherlands. [Abstract 96] Fingolimod: The First Orally Administered DMT for Patients With MS Study Treatment Arms Outcomes Outcome Fingolimod New Data on Existing Therapies for MS TRANSFORMS 1 N = 1,292; RRMS Aged years EDSS mo study (1) Fingolimod.5 mg (2) Fingolimod 1.25 mg (3) IFN β-1a 3 µg Reduction (vs IFN).5 mg 1.25 mg ARR 52% (P <.1) 38% (P <.1) Active T2 35% (P =.4) 42% (P <.1) GdE lesions 55% (P <.1) 73% (P <.1) DP 25% (P, NS) 15% (P, NS) Outcome Fingolimod FREEDOMS 2 N = 1,272; RRMS Aged years EDSS mo study (1) Fingolimod.5 mg (2) Fingolimod 1.25 mg (3) Reduction (vs PBO).5 mg 1.25 mg ARR 54% (P <.1) 6% (P <.1) Enlarging T2 74% (P <.1) 74% (P <.1) GdE lesions 82% (P <.1) 82% (P <.1) CPDP a 26% (P <.3) 31% (P <.1) a Confirmed at 3 mo. 1. Cohen J et al. N Engl J Med. 21;362: Kappos L et al. N Engl J Med. 21;362:

11 Initial Experience with Switching From Natalizumab to Fingolimod 25-month observational study (N =14) Compared switching to either fingolimod or no alternative treatment after natalizumab withdrawal Results ARR No Treatment 1.2 Fingolimod No severe adverse effects have been observed in patients who switched to fingolimod, thus far Although limited enrollment in this trial renders results inconclusive, study does provide preliminary evidence that patients treated with natalizumab can be switched to fingolimod Havia J, et al. ECTRIMS/ACTRIMS 211. Abstract P522. Adverse Events 1,2 Fingolimod: What Are the Risks? Bradyarrhythmia/ATV block Macular edema Infection FEV1 and DLCO Pregnancy Risk Category C Elevated liver enzymes Required Precautions 3 All pts must be observed for 6 h after initial dose for signs and symptoms of bradycardia If pts go off medication for prolonged time period, they must be observed when restarting therapy Ophthalmologic at baseline and 3-4 mo after treatment initiation Patients should be vaccinated for VZV Consider stopping therapy if serious infection develops Avoid live attenuated vaccines for at least 2 mo after stopping therapy Spirometric Evaluation when indicated Counsel patients about fetal risks Use effective contraception on treatment and for at least 2 mo after stopping therapy Monitor regularly, as needed FEV1, forced expiratory volume over 1 second; DLCO, diffusion capacity of the lung for carbon monoxide 1. Cohen J et al. N Engl J Med. 21;362: Kappos L et al. N Engl J Med. 21;362: Gilenya (Fingolimod).5 mg capsules. Risk Evaluation and Mitigation Strategy. /downloads/drugs/drugsafety/ PostmarketDrugSafetyInformationforPatientsandProviders/UCM pdf. Accessed June 23, 211. Should Initial Cardiac Monitoring Period for Patients Receiving First Dose of Fingolimod Be Extended? 1 1 patient death (out of approximately 28, patients) within 24 hr of receiving first fingolimod dose Patient was monitored for required 6 hr after taking first dose without incident Exact cause of the death hasn t been established Should initial monitoring period be extended to 24 hr? Randomization [1:1:1] REFLEX: Trial Design Day -28 n = 171 IFNβ-1a, 44µg sc tiw n = 175 IFNβ-1a, 44µg sc qw n = 171 Study Day 1 McDonald 26 MS McDonald 26 MS McDonald 26 MS CDMS CDMS CDMS IFNβ-1a, 44µg sc tiw IFNβ-1a, 44µg sc tiw IFNβ-1a, 44µg sc tiw Months Neurological examination MRI 1. Accessed January 24, 212 Kappos L, et al. Presented at ECTRIMS / ACTRIMS 211; Amsterdam, Netherlands. [P911] 11

12 REFLEX: IFNβ-1a SC in FCDE Patients: Disease Progression and MRI Outcomes Updated Natalizumab-Associated PML Incidence by Treatment Duration Incidence of McDonald MS 25 at 2 yrs Median time to McDonald MS 25 Risk of conversion (n = 171) 85.8% 97 days IFNβ-1a 44 mg TIW (n = 171) 62.5% 31 days IFNβ-1a 44 mg QW (n = 175) 75.5% 182 days Risk reduction (P-value) 51% (<.1) 31% (<.1) Cumulative incidence of CDMS (Pvalue) Mean # CUA lesions/patient/scan vs placebo (P-value) 37.5% 2.6% (<.1) 21.6% (.2) 81% reduction* (<.1) 63% reduction (<.1) Note: MRI lesion volumes decreased or remained stable for both active treatment groups, but increased in placebo group *Reduction in CUA lesions was also significantly greater with tiw vs qw dosing FCDE = first clinical demyelinating event; SC = subcutaneous; TIW = 3 times/week; QW = every week; CUA = combined unique active Kappos L, et al. Presented at ECTRIMS / ACTRIMS 211; Amsterdam, Netherlands. [P911] Number of infusions 17 cases of PML have been documented in patients treated with natalizumab as of October 28, 211. Available at: Bloomgren G, et al. Presented at ECTRIMS / ACTRIMS 211; Amsterdam, Netherlands. [P995] Estimated Incidence of Natalizumab- Associated PML Stratified by Risk Factors Negative.11/1 95% CI:.56 (based on 1 hypothetical anti-jcv antibody negative PML case) IS = immunosusppressant Anti-JCV Antibody Status Natalizumab exposure No Prior IS Use Prior IS Use 1 24 months months.53/1 95% CI: /1 95% CI: Positive Prior IS Use Bloomgren G, et al. Presented at ECTRIMS / ACTRIMS 211; Amsterdam, Netherlands. [P995] No Yes 1.5/1 95% CI: /1 95% CI: RESTORE Study: Natalizumab Background: NTZ efficacy in RRMS based on SENTINEL and AFFIRM phase III trials Associated with PML (opportunistic infection of CNS) caused by JC virus Risk increases with anti-jcv antibody (+) status, prior immunosuppressant use, and duration of NTZ treatment RESTORE Overview: Randomized study evaluating effect of 24-week NTZ treatment interruption on immune parameters and disease activity Patients treated with NTZ for 12 months (N = 175) randomized (1:1:2) to: NTZ Other immunomodulatory therapy (IM IFNβ-1a, GA, or MP; investigator determined) Fox R, et al. Presented at ECTRIMS / ACTRIMS 211; Amsterdam, Netherlands. [Abstract 15] 12

13 RESTORE: Study Design Screening Randomized Treatment Period Follow-up Period Double-blind NTZ infusions Double-blind placebo infusions Other open-label therapies IM IFNβ-1a, GA, or MP Rescue Fox R, et al. Presented at ECTRIMS / ACTRIMS 211; Amsterdam, Netherlands. [Abstract 15] Open-label NTZ infusions Week -4 Week Week 28 Week 52 If patient developed evidence of MS disease activity, investigators could administer high-dose corticosteroids and/or restart NTZ as rescue treatment Clinical disease activity: defined by change in overall EDSS or functional system subscale scores MRI disease activity: defined as 1 new Gd+ lesion of >.8 cm or 2 or more new GD+ lesions of any size Study not designed or powered to determine effect on development of PML Patients with Clinical Relapses or Meeting MRI Rescue Criteria After Randomization* Patients, n/n Clinical Relapses a Rescue Criteria b MRIs Meeting Total 25/167 (15%) 48/167 (29%) Natalizumab 2/45 (4%) /45 (%) 7/41 (17%) 18/41 (44%) Other therapies IM IFNβ-1a 4/14 (29%) 1/14 (7%) GA 4/15 (27%) 8/15 (53%) MP 8/52 (15%) 21/52 (4%) *Interim results a 11 relapses (44%) occurred by 16 weeks, and 14 (56%) occurred between weeks b 36 of 48 patients (75%) who met rescue criteria did so at week 16 or 2 Fox R, et al. Presented at ECTRIMS / ACTRIMS 211; Amsterdam, Netherlands. [Abstract 15] RESTORE: Summary NTZ interruption resulted in a high rate of recurrence of MRI and clinical MS disease activity (starting clinically at ~ week 8, radiographically ~ week 12) IM IFNβ-1a appeared to suppress MRI activity more than other open-label treatments, although this group had lower disease activity prior to start of NTZ However, study was not designed or powered to compare efficacy of alternative immunomodulatory therapies Monthly MP (1g IV, started 1 month after last NTZ dose) did not appear to be effective in disease suppression Fox R, et al. Presented at ECTRIMS / ACTRIMS 211; Amsterdam, Netherlands. [Abstract 15] IV vs Oral Methylprednisolone for Treating Relapse Patients randomized to 3-day treatment with: 1 mg/day IV MP (n = 24) or 125 mg/day oral MP (n = 24) 4-week EDSS improvement was exactly the same across groups Mean reduction for both arms = 1.1 (95% CI =.7-1.5; P <.1 relative to baseline) No significant differences between groups in: Number or volume of Gd+ lesions Black holes No serious adverse event reported for either treatment Conclusion: 125 mg oral MP is not inferior to 1 mg IV MP in reducing EDSS score and avoiding brain lesions at 4 weeks Ramo-Tello C, et al. Presented at ECTRIMS / ACTRIMS 211; Amsterdam, Netherlands. [Abstract 243] 13

14 Duloxetine for Central Neuropathic Pain (CNP) in MS CNP-MS patients (n = 239) randomized to duloxetine (DLX) 6 mg/day or placebo (PBO) for 6 weeks Baseline mean score on average pain intensity (API) scale: 6.4 (no pain) 1 (worst possible pain) Greater improvement in API in DLX vs PBO (-1.8 vs -1.1, P =.1) Reduction of API by 3% was greater in DLX vs PBO group (4.9% vs 26.9%, P =.27) Significantly more discontinuations due to adverse events in DLX vs PBO (13.6% vs 4.1%, P =.12) Conclusion: DLX is effective for managing CNP in MS patients; no new safety risks were observed Unmet Challenges MS treatment algorithm Sequencing of therapies Secondary and primary progressive MS Restoration of neurological function Fatigue Cognitive impairment Vollmer T, et al. Presented at ECTRIMS / ACTRIMS 211; Amsterdam, Netherlands. [Abstract 144] 14