Dimethyl Fumarate and Peginterferon b-1a: New Insights Into the Pivotal Trials Pavan Bhargava, MD Johns Hopkins University School of Medicine, Baltimore, Maryland A REPORT FROM THE 66TH ANNUAL MEETING OF THE AMERICAN ACADEMY OF NEUROLOGY (AAN 2014) © 2014 Direct One Communications, Inc. All rights reserved. 1

Introduction The armamentarium of medications approved by the US Food and Drug Administration (FDA) to treat patients with multiple sclerosis (MS) continues to expand. Treatment decisions must balance the efficacy of a disease-modifying therapy with its adverse effects. Other factors, such as impact on quality-of-life measures, are also becoming an important part of this decision, since they may play a role in determining the real-world effectiveness of a medication. © 2014 Direct One Communications, Inc. All rights reserved. 2

Dimethyl Fumarate © 2014 Direct One Communications, Inc. All rights reserved. 3

Pharmacology Dimethyl fumarate is an oral second-generation fumarate ester that was approved by the FDA for the treatment of relapsing-remitting MS in 2013. Dimethyl fumarate appears to exert its effects primarily through the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway, which is involved in cellular defense against oxidative stress and also in immune homeostasis. The efficacy of dimethyl fumarate was demonstrated in two pivotal phase 3 randomized, controlled clinical trials—DEFINE and CONFIRM. Gold R et al. N Engl J Med. 2012;367:1098; Fox RJ et al. N Engl J Med. 2012;367:1087 © 2014 Direct One Communications, Inc. All rights reserved. 4

Inclusion and Exclusion Criteria Major inclusion and exclusion criteria in the DEFINE and CONFIRM studies Gold R et al. N Engl J Med. 2012;367:1098; Fox RJ et al. N Engl J Med. 2012;367:1087 © 2014 Direct One Communications, Inc. All rights reserved. 5

Efficacy in Highly Active Disease In all, 136 RRMS patients with highly active disease (two or more relapses in the year prior to study plus one or more gadolinium-enhancing MRI lesions at baseline) were identified in DEFINE and CONFIRM. Dimethyl fumarate twice daily reduced the annualized relapse rate (ARR) by 60.3% (P = 0.0018) versus placebo. Dimethyl fumarate twice daily also reduced the risk of relapse (HR = 0.368; P = 0.003) versus placebo. These data show that dimethyl fumarate twice daily is effective in MS patients with highly active disease. Hutchinson M et al. AAN 2014, Poster P3.189 © 2014 Direct One Communications, Inc. All rights reserved. 6

Efficacy in Highly Active Disease Annualized relapse rate in RRMS patients with highly active disease Hutchinson M et al. AAN 2014, Poster P3.189 © 2014 Direct One Communications, Inc. All rights reserved. 7

Efficacy in Minority Populations A total of 29 patients of African, 54 of Hispanic, and 136 of Asian decent were identified in the DEFINE and CONFIRM populations. Patients on dimethyl fumarate twice daily in all three minority subgroups showed a reduction in ARR and in the proportion of patients who relapsed at 2 years. Similar trends were noted in disability progression. The small sample size, however, limits definite conclusions. Hutchinson M et al. AAN 2014, Poster P3.171 © 2014 Direct One Communications, Inc. All rights reserved. 8

Health-Related Quality of Life (HRQoL) In all, 464 patients were analyzed, of which 136 were on placebo, 128 on dimethyl fumate (DMF) bid, 135 on DMF tid, and 65 on glatiramer acetate (GA). Physical component scores on the SF-36 improved significantly in patients taking DMF bid or tid compared with those on GA or placebo. Mental component scores on the SF-36 improved significantly in the DMF bid group but not in the other treatment groups. EQ-5D scores also improved in patients taking DMF bid or tid compared with those on GA or placebo. Kita M et al. AAN 2014, Poster P4.176 © 2014 Direct One Communications, Inc. All rights reserved. 9

Measures of HRQoL Description of patient-reported outcome measures Kita M et al. AAN 2014, Poster P4.176 © 2014 Direct One Communications, Inc. All rights reserved. 10

HRQoL: Effect of Previous Treatment Effects on HRQoL measures were analyzed based on treatment (none, interferon or GA, other treatment) prior to entry into DEFINE and CONFIRM. In the treatment-naïve subgroup, a significantly greater proportion of patients on DMF bid or tid showed either no change or improvement, compared with placebo, in the SF-36 physical scores but not mental scores. In the prior interferon/GA treatment group, a significant proportion of patients on DMF bid or tid showed no change or improvement, compared with placebo, in the SF-36 physical and mental scores. Kappos L et al. AAN 2014, Poster P3.162 © 2014 Direct One Communications, Inc. All rights reserved. 11

Freedom from Disease Activity A larger proportion of patients taking DMF bid (69%) or tid (71%) had no measurable clinical disease activity at 2 years than those on placebo (53%; P = 0.0001). Similarly, a larger proportion of patients on DMF bid (34%) or tid (35%) at 2 years showed no measurable neuroradiologic disease activity on MRI than those on placebo (20%; P = 0.0001). The proportion of patients with no measurable overall disease activity at 2 years was larger in the DMF bid (23%) and tid (23%) groups than in the placebo group (11%; P = 0.0001). Havrdova E et al. AAN 2014, Poster P3.159 © 2014 Direct One Communications, Inc. All rights reserved. 12

ENDORSE Study: Clinical Efficacy ENDORSE is a 5-year extension study of the DEFINE and CONFIRM trials designd to evaluate the long-term safety and efficacy of DMF. Among the patients continuing on DMF bid, the ARR was 0.142 after 2 years of treatment and 0.198 after 4 years of treatment, suggesting continued clinical efficacy of DMF. Among the patients switching from placebo or glatiramer acetate to DMF bid or tid, the ARR at the end of 2 years of treatment with DMF was similar to that noted at the end of 2 years of DMF treatment in the DEFINE and CONFIRM studies. Gold R et al. AAN 2014, Poster P3.173 © 2014 Direct One Communications, Inc. All rights reserved. 13

ENDORSE Study: Clinical Efficacy Changes in annualized relapse rate Hutchinson M et al. AAN 2014, Poster P3.189 © 2014 Direct One Communications, Inc. All rights reserved. 14

ENDORSE Study: MRI Outcomes The MRI cohort in the DEFINE and CONFIRM studies consisted of 1,221 patients with RRMS, of whom 718 went on to the ENDORSE study. Among patients who continued on DMF bid, 68% were free of new/enlarging T2 lesions, 76% were free of new T1 hypointense lesions, and 88% were free of gadolinium-enhancing lesions at year 2 in the ENDORSE study. At year 2 in the ENDORSE study, patients who had switched from placebo or glatiramer acetate to DMF seemed to have similar MRI activity to that seen in the parent DEFINE and CONFIRM studies. Arnold D et al. AAN 2014, Poster P3.160 © 2014 Direct One Communications, Inc. All rights reserved. 15

ENDORSE Study: MRI Outcomes Number of new and/or enlarging T2 lesions Hutchinson M et al. AAN 2014, Poster P3.189 © 2014 Direct One Communications, Inc. All rights reserved. 16

Conclusions Dimethyl fumarate is an important oral disease-modifying therapy option for the treatment of MS. Evidence suggests continued clinical and radiological efficacy, in addition to a benefit in terms of HRQoL, beyond the original DEFINE and CONFIRM trial periods. Further data from the ENDORSE study will help elucidate the long-term efficacy and safety of this medication. © 2014 Direct One Communications, Inc. All rights reserved. 17

Peginterferon b-1a © 2014 Direct One Communications, Inc. All rights reserved. 18

Pharmacology and Clinical Efficacy Peginterferon b-1a is a modified form of interferon b-1a that has a polyethylene glycol (PEG) group attached to interferon b-1a. The attachment of PEG to interferon b-1a prolongs its half-life, reducing the frequency of dosing. The ADVANCE trial was a phase 3 study comparing placebo to subcutaneous peginterferon b-1a 125 µg every 2 or 4 weeks for 1 year. Patients taking peginterferon b-1a every 2 or 4 weeks showed a reduction in ARR, disability progression, and MRI measures of disease activity compared with those on placebo at 48 weeks. Calabresi PA et al. Lancet Neurol. 2014;13:657 © 2014 Direct One Communications, Inc. All rights reserved. 19

Pharmacology and Clinical Efficacy Design of the ADVANCE study Calabresi PA et al. Lancet Neurol. 2014;13:657 © 2014 Direct One Communications, Inc. All rights reserved. 20

Pharmacokinetics and Pharmacodynamics Maximum serum level of peginterferon b-1a was reached at 1.0–1.5 days after injection, and the terminal half-life was 2–5 days for both the every-2-week and every-4-week regimens. By doubling the frequency of dosing, the every-2-week regimen provided twice the exposure to peginterferon b-1a than the every-4-week regimen. Anti-PEG antibodies had no effect on the pharmaco-kinetics of peginterferon b-1a. Neopterin levels (marker of IFN receptor activation) reached a peak elevation at 3 days post peginterferon b-1a injection and remained elevated for 10–14 days. Hu X et al. AAN 2014, Poster P3.194 © 2014 Direct One Communications, Inc. All rights reserved. 21

Pharmacokinetics and Pharmacodynamics Serum peginterferon b-1a and neopterin levels Hu X et al. AAN 2014, Poster P3.194 © 2014 Direct One Communications, Inc. All rights reserved. 22

Effect on Relapse-Associated Costs The cost of multiple sclerosis per year in the US is estimated to range from $44,000 to $88,000 per patient in 2006 dollars. Treatment with peginterferon b-1a every 2 weeks for 1 year reduced the cost of hospitalization by $1,297 (95% CI: 288, 2,173), the cost of IV corticosteroids by $62 (95% CI: 20, 99), and the cost of MS relapse by $1,941 (95% CI: 877, 2,931) compared with placebo. Every-2-week administration of peginterferon b-1a had a high probability of reducing relapse-related costs as compared with every-4-week dosing. Kobelt G et al. Neurology. 2006;66:1696; O’Day K et al. AAN 2014, Poster P4.146 © 2014 Direct One Communications, Inc. All rights reserved. 23

Impact on HRQoL As compared with placebo, disability progression was associated with a lower worsening in MSIS-29 physical scores in patients taking peginterferon b-1a every 2 weeks. Similarly, the worsening of MSIS-29 psychological scores associated with a relapse in the placebo group was greatly attenuated in the group receiving peginterferon b-1a every 2 weeks. These results suggest that peginterferon b-1a every 2 weeks not only reduces the occurrence of relapse and disability progression but also reduces the impact of these events on HRQoL. Kinter E et al. AAN 2014, Poster P4.177 © 2014 Direct One Communications, Inc. All rights reserved. 24

Conclusions Results from the pivotal ADVANCE study help establish the efficacy and safety of peginterferon b-1a given every 2 weeks. Pegylated interferon b-1a will be an important addition to the MS therapeutic armamentarium, since it preserves the efficacy of previous interferon b-1a formulations with markedly fewer injections and potentially could translate into better adherence. In addition, these findings demonstrate possible cost savings related to relapse-associated healthcare costs and a reduction in the impact of relapses and disability progression on HRQoL. © 2014 Direct One Communications, Inc. All rights reserved. 25