The evolving landscape of MS John Woolmore Consultant Neurologist UHB FIN14-C173. Date of preparation: September 2014

Plan Introduction Established therapies Newer therapies, “on the horizon” MOA, pivotal trials, other efficacy data, safety NHS England Conclusion and questions

Putative targets for MS therapies Barten et al Drug Des Devel Ther. 2010;4:343-366; Linker et al, Trends Pharmacol Sci. 2008;29:558–565.129

Established therapies ABCR/BRACE Tysabri Gilenya (mitoxantrone)

Newer therapies Lemtrada, Alemtuzumab, Campath Tecfidera, Dimethyl fumarate, BG 12 Aubagio, Teriflunomide, (leflunomide)

On the horizon Daclizumab - anti IL-2 Ocrelizumab Firategast alpha4beta1 integrin Ofatumumab BAF 312 - S1P1 and S1 P5 Anti Lingo BIIB033 Copaxone/glatriamer TIW Plegridy 2 weekly IFN beta1a sub cut (Laquinimod)

Daclizumab DECIDE - Presented 11/9/14 ECTRIMS 2014, Kappos et al DAC HYP once monthly s/c vs IFNB1a 45% reduction in ARR Relapse risk reduction rate 41% T2 MRI rate 54% reduction, GAD 65% 6 month disability progression reduced by 27% Treatment discontinuation 9% - cutaneous events main AEs

Sustained-Release Dimethyl Fumarate Tecfidera Sustained-Release Dimethyl Fumarate

Inflammatory response Through Activation of Nrf2, DMF/MMF Activate Both Anti-Oxidant and Anti-Inflammatory Responses Under normal conditions, Nrf2 is sequestered in the cytoplasm via Keap1 1 DMF/MMF DMF/MMF cause Nrf2 to translocate to the nucleus (imitates physiological stress response) 2 Nrf2 Genes that code for proteins involved in ROS detoxification share a common promoter element, called the antioxidant response element (ARE). ARE-mediated gene activation is coordinated by Nrf2, which upon exposure to electrophiles or ROS, translocates to the nucleus where it binds ARE and activates antioxidant enzyme gene transcription. Activation of the Nrf2 pathway may lead to the promotion of cellular detoxification of free radicals, repair of damaged cellular proteins, and normalization of energy metabolism. Keap1 Nrf2 activates intrinsic defense mechanisms 3 Cytoplasm Antioxidant response Inflammatory response Nucleus Nrf2=nuclear factor (erythroid-derived 2)-like 2; Keap1=kelch-like ECH-associated protein. van Horssen J et al. Biochem Biophys Acta. 2011;1812:141-150; Linker RA et al. Brain. 2011;134:679-692; Scannevin R et al. J Pharmacol Exp Ther. 2012;341:274-284.

DEFINE: Proportion of Patients Relapsed (INEC-Confirmed) 0.6 0.5 0.4 0.3 0.2 0.1 HR (95% CI): BID vs placebo=0.51 (0.40, 0.66); 49% risk reduction; P<0.0001 TID vs placebo=0.50 (0.39, 0.65); 50% risk reduction; P<0.0001 0.461 0.270 0.260 Probability of Relapse Placebo (n=408) DMF 240 mg BID (n=410) DMF 240 mg TID (n=416) BL 12 24 36 48 60 72 84 96 Time on Study (weeks) Number of Patients at Risk Placebo 408 356 321 282 243 224 205 190 115 DMF BID 410 353 324 303 286 267 255 154 DMF TID 416 346 322 301 270 251 244 166 DEFINE=Determination of the Efficacy and Safety of Oral Fumarate in Relapsing-Remitting MS; INEC=independent neurology evaluation committee; HR=hazard ration; CI=confidence interval; BID=twice daily; TID=3 times daily; BL=baseline; MS=multiple sclerosis. Gold R et al. Presented at ECTRIMS; October 19–22, 2011; Amsterdam, The Netherlands. S34.

DEFINE: Annualized Relapse Rate at 2 Years (Secondary Endpoint) 53% reduction vs placebo P<0.0001 48% reduction vs placebo P<0.0001 0.364 0.189 0.172 *Annualized relapse rate calculated with negative binomial regression, adjusted for baseline EDSS score (≤2.0 vs >2.0), baseline age (<40 vs ≥40 years), region, and number of relapses in the 1 year prior to study entry. DEFINE=Determination of the Efficacy and Safety of Oral Fumarate in Relapsing-Remitting MS; CI=confidence interval; BID=twice daily; TID=3 times daily; EDSS=Expanded Disability Status Scale; MS=multiple sclerosis. Gold R et al. Presented at ECTRIMS; October 19–22, 2011; Amsterdam, The Netherlands. S34.

Integrated Safety Analysis: Common Adverse Events (≥10% in Any Group) Event, n (%) Placebo (n=836) DMF bid (n=769) DMF tid (n=823) Any adverse event 769 (92) 733 (95) 767 (93) Flushing 39 (5) 265 (34) 240 (29) MS relapse 360 (43) 221 (29) 211 (26) Nasopharyngitis 169 (20) 170 (22) 179 (22) Headache 137 (16) 133 (17) 138 (17) Diarrhea 86 (10) 107 (14) 136 (17) Urinary tract infection 96 (11) 95 (12) Upper respiratory tract infection 88 (11) 99 (13) 101 (12) Nausea 72 (9) 93 (12) 115 (14) Fatigue 91 (11) 94 (12) 103 (13) Back pain 92 (11) 84 (10) Abdominal pain upper 47 (6) 76 (10) 94 (11) Proteinuria* 59 (7) 67 (9) 85 (10) Indicates ≥3% higher incidence in either dimethyl fumarate group vs placebo. DMF 240mg BID is the licensed dose , 240mg BID and 240mg TID DMF doses were assessed for safety and efficacy in DEFINE and CONFIRM. The overall incidence of any GI event was 31%, 40%, and 43% in the placebo, dimethyl fumarate bid, and dimethyl fumarate tid groups, respectively; *no notable differences in levels of BUN and creatinine, urine β2-microglobulin, and urine microalbumin were observed across treatment groups with monitoring every 4 weeks.GI=gastrointestinal; BUN=blood urea nitrogen. Selmaj K et al. Presented at ECTRIMS; October 10–13, 2012; Lyon, France. P484.

4% discontinuation for GI events in DMF BID group Integrated Safety Analysis: Events Leading to Study Drug Discontinuation (≥1% in Any Group) Event, n (%) Placebo (n=836) DMF bid (n=769) DMF tid (n=823) Discontinued study drug due to adverse event 94 (11) 109 (14) 117 (14) MS relapse 48 (6) 11 (1) 13 (2) Flushing 1 (<1) 24 (3) GI events Diarrhea Nausea Vomiting Abdominal pain, upper Abdominal pain 2 (<1) 7 (<1) 6 (<1) 8 (1) 5 (<1) 15 (2) 14 (2) 12 (1) 10 (1) 9 (1) 4% discontinuation for GI events in DMF BID group GI=gastrointestinal. DMF 240mg BID is the licensed dose , 240mg BID and 240mg TID DMF doses were assessed for safety and efficacy in DEFINE and CONFIRM. Selmaj K et al. Presented at ECTRIMS; October 10–13, 2012; Lyon, France. P484.

Natalizumab

AFFIRM: Annualized Relapse Rate Overall Population 68% reduction in annualized relapse rate vs placebo Placebo n=315 Natalizumab n=627 1.0 0.78 0.9 68% reduction vs placebo P<0.001 70% reduction vs placebo P<0.001 0.73 66% reduction vs placebo P<0.001 0.67 0.8 0.7 0.6 Annualized Relapse Rate (95% CI) 0.5 0.4 0.27 0.23 0.20 0.3 0.2 0.1 Years 0–2 Year 0–1 Years 1–2 CI=confidence interval. Polman CH et al. N Engl J Med. 2006;354:899-910. 5

AFFIRM: Risk of Disability Progression Overall Population 3-Month Sustained* Placebo 29% Natalizumab 17% 0.1 0.2 0.3 0.4 12 24 36 48 60 72 84 96 108 120 Number of Patients at Risk Placebo Natalizumab 315 296 283 264 248 240 229 216 208 200 627 601 582 567 546 525 517 503 490 478 199 473 Proportion with Sustained Progression 42% risk reduction HR=0.58 P<0.001 Week 6-Month Sustained† 0.1 0.2 0.3 0.4 Week 12 24 36 48 60 72 84 96 108 120 Proportion with Sustained Progression Natalizumab 11% Placebo 23% Number of Patients at Risk Placebo Natalizumab 315 298 287 269 253 246 237 225 216 211 627 611 594 581 559 540 532 521 509 503 502 54% risk reduction HR=0.46 P<0.001 *Primary endpoint; †prespecified sensitivity analysis. HR=hazard ratio. Polman CH et al. N Engl J Med. 2006;354:899-910. •Updated Sept 2012 6

Natalizumab: long-term efficacy data from STRATA1 Annualized Relapse Rate STRATA is an ongoing, open-label, multinational study to evaluate the long-term safety and efficacy of natalizumab in RRMS patients who completed the feeder studies AFFIRM, SENTINEL and GLANCE. Rudick, et al. ECTRIMS 2013; P593.

Natalizumab PML Incidence Estimates by Treatment Epoch Calculations based on exposure through 31st May 2014 and 472 confirmed cases as of 4th June 2014 Biogen Idec, data on file.

Anti-JCV Antibody Status 0.1/1000 95% CI 0.01-0.35 No Yes Risk Stratification Tool: The Presence of Anti-JCV Antibodies, Prior Immunosuppressant Use, Treatment Duration* Anti-JCV Antibody Status Negative Positive Prior IS Use No Yes Natalizumab Exposure No Prior IS Use Prior IS Use 1–24 months 0.7/1000 95% CI 0.5-1.0 1.8/1000 95% CI 1.1-2.7 25–48 months 5.3/1000 95% CI 4.4-6.2 11.2/1000 95% CI 8.6-14.3 49–72 months 6.1/1000 95% CI 4.8-7.8 Insufficient data 0.1/1000 95% CI 0.01-0.35 Data beyond 4 years of treatment are limited. There are insufficient data to adequately determine PML risk in anti-JCV antibody positive patients with prior IS use and >48 months of natalizumab exposure. *Based on natalizumab exposure and 343 confirmed PML cases as of 5th March 2013. Prior IS data in overall natalizumab-treated patients based on proportion of patients with IS use prior to natalizumab therapy in TYGRIS as of May 2011; and prior IS data in PML patients as of 5th March 2013. The analysis assumes that 55% of natalizumab-treated MS patients were anti-JCV antibody positive and that all PML patients test positive for anti-JCV antibodies prior to the onset and diagnosis of PML. The estimate of PML incidence in anti-JCV antibody negative patients is based on the assumption that all patients received at least 1 dose of natalizumab . Assuming that all patients received at least 18 doses of natalizumab, the estimate of PML incidence in anti-JCV antibody negative patients was generally consistent (0.16/1000; 95% CI 0.02–0.56). Biogen Idec, data on file.

Teriflunomide

Alemtuzumab

Relapse Reduction: in RRMS and SPMS Patients Relapse Rates in RRMS Cohort Graph shows episodes reported in RRMS cohort (n=22) before and after treatment with 2 coursesa of alemtuzumab at Months 0 and 12 (red lines) Relapse frequency significantly reduced in RRMS cohort (p<0.0001) 2.21/patient/yr before treatment vs. 0.19/patient/yr after treatment 91% reduction Similar results were seen in the SPMS cohort The relapse rate fell from 0.7/patient/yr to 0.01/patient/yr (p<0.001; data not shown), which translates to a 98.5% reduction -42 -36 -30 -24 -18 -12 -6 6 12 18 24 30 36 42 48 1 2 Relapses per 3-month Period, n MS.US.PO1203.0113 – external/reactive Months Before Alemtuzumab Treatment After Alemtuzumab Treatment a Course=3 or 5 daily 20-mg intravenous administrations. Coles AJ et al. J Neurol 2006;253:98-108.

Change in EDSS: in RRMS and SPMS Patients MS.US.PO1203.0113 – external/reactive 1 year after alemtuzumab treatment, 33/36 SPMS patients had maintained their pre-treatment EDSS values However, this proportion decreased with time and this cohort showed an overall worsening of disability Note: Gradients above the equator represent increasing disability and below the equator represent reducing disability. Coles AJ et al. J Neurol 2006;253:98-108.

Fingolimod in MS: efficacy from Phase III studies RELAPSES LESIONS† DISABILITY PROGRESSION BRAIN VOLUME LOSS -82%*** (Gd+) -74%*** (T2) -30%* (3-mo conf.) -37%* (6-mo conf.) -70%*** (Gd+) -17%, NS (3-mo conf.) -28%, NS (6-mo conf.) -55%*** (Gd+) -35%** (T2) -25%, NS (3-mo conf.) – Placebo (n = 418) Fingolimod 0.5mg (n = 425) -54%*** ARR n = 357 n = 331 24 Time (months) 0.0 –0.4 –0.6 –1.4 -35%*** –0.2 –0.8 –1.2 –1.0 12 6 * ** *** Mean change in brain volume (%) FREEDOMS1 2 years, RRMS (n =1272) vs placebo Placebo (n = 355) Fingolimod 0.5mg (n = 358) -48%*** ARR Time (months) 24 0.0 –0.4 –0.6 –1.4 -33%*** –0.2 –0.8 –1.2 –1.0 12 6 * *** n = 266 n = 249 Mean change in brain volume (%) Key points The therapeutic benefit of fingolimod has been seen in three large Phase III clinical trials Fingolimod reduces the 4 key measures of disease activity: relapses MRI lesions disability progression brain volume loss Notes The primary endpoint for all three studies was ARR Fingolimod was dosed at 0.5 mg / day IFNβ-1a IM was dosed at 30 μg / week This slide is intended to provide a brief overview of the efficacy of fingolimod. Further information on fingolimod and the specific trials can be found in Section 4 of this slide module FREEDOMS II2,3 2 years, RRMS (n = 1083) vs placebo IFNβ-1a IM (n = 431) Fingolimod 0.5mg (n = 429) -52%*** ARR 24 Time (months) 0.0 –0.4 –0.6 –1.4 -32%*** –0.2 –0.8 Mean change in brain volume (%) –1.2 –1.0 12 *** n = 368 n = 359 TRANSFORMS4 1 year, RRMS (n = 1292) vs IFNβ-1a IM Data are presented from separate clinical trials Caution is required when indirectly comparing studies due to differences in trial designs and populations Changes in disability progression shown here were measured using the EDSS scale. % change is vs comparator arm. *p<0.05; **p<0.01; ***p<0.001 vs placebo. †Number of Gd+ lesions or number of new / newly enlarged T2 lesions. ARR, annualised relapse rate; conf., confirmed; IM, intramuscularly; NS, not significant; RRMS, relapsing–remitting MS. 1. From N Engl J Med; Kappos L et al. A Placebo-Controlled Trial of Oral Fingolimod in Relapsing Multiple Sclerosis, 362: 387–401. Copyright © (2010) Massachusetts Medical Society. Reproduced with permission from Massachusetts Medical Society; 2. Reproduced from Lancet Neurol 13(6) Calabresi PA, Radue EW, Goodin D, Jeffery D, Rammohan KW, Reder AT, Vollmer T, Agius MA, Kappos L, Stites T, Li B, Cappiello L, von Rosenstiel P, Lublin FD. Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind, randomised, placebo-controlled, phase 3 trial. pp545-56. ©2014 with permission from Elsevier; 3. Calabresi PA et al. Poster 015 presented at AAN 2012; 4. From N Engl J Med; Cohen JA et al. Oral Fingolimod or Intramuscular Interferon for Relapsing Multiple Sclerosis, 362: 402–415. Copyright © (2010) Massachusetts Medical Society. Reproduced with permission from Massachusetts Medical Society

Safety Profile Incidence of adverse events in FREEDOMS Safety signals of note (as per Gilenya Risk Management Plan) Fingolimod 0.5mg (n=425) Placebo (n=418) All adverse events Patients with ≥1 event 401 (94%) 387 (93%) Study drug discontinuation because of adverse event 32 (8%) Serious adverse events 43 (10%) 56 (13%) Deaths 0 (0%) 2 (<1%) Most common adverse events (increased incidence in fingolimod group vs placebo) Headache 107 (25%) 96 (23%) Elevated liver enzyme levels 67 (16%) 21 (5%) Influenza virus infection 55 (13%) 41 (10%) Diarrhoea 50 (12%) 31 (7%) Back pain 29 (7%) Fatigue 48 (11%) 45 (11%) Cough 34 (8%) Treatment initiation results in transient decreases in heart rate and may be associated with atrioventricular conduction delays In clinical trials, macular oedema occurred in 0.4% of fingolimod patients Lower respiratory tract infections were more common compared to placebo Liver enzyme elevations observed, primarily during first 12 months of treatment Vaccination may be less effective during, and for up to 2 months after, treatment Hypertension was reported for 6.1% of fingolimod patients vs 3.8% placebo patients There are very limited data on the use of fingolimod in pregnant women; pregnancy should be avoided while on treatment This is not a complete list; please refer to prescribing information for full information. Gilenya® 0.5mg/day is the only dose approved for the treatment of MS. Kappos L et al. N Engl J Med 2010; Novartis. Gilenya® Summary of Product Characteristics.

NICE/ NHSEng - Positioning First line ABCR/BRACE/Tecfidera/Aubagio/Lemtrada Second line - highly active - Gilenya/ Lemtrada n.b. Gilenya post ABCR/BRACE RES MS - Tysabri/ Lemtrada

Burden of Therapy for Patient The landscape Natalizumab JCV- Natalizumab JCV+ Burden of Therapy for Patient Alemtuzumab Fingolimod Mitoxantrone BG12 Efficacy Teriflunomide

Questions