DXT42 Efficacy of Diroximel Fumarate in Relapsing-Remitting MS Patients Who Are Newly Diagnosed or Previously Treated With Interferons or Gudesblatt M,1 Wray S,2 Miller C,3 Hanna J,4 Lopez-Bresnahan M,5 Kandinov B,5 Chen H,3 Yang L,3 Leigh-Pemberton R5 1South Shore Neurologic Associates, PC, Patchogue, NY, USA; 2Hope Neurology Center, Knoxville, TN, USA; 3Biogen, Cambridge, MA, USA; 4Biogen, Maidenhead, UK; 5Alkermes, Waltham, MA, USA

Figure 1. EVOLVE-MS-1 Study Design Table. Baseline Demographics and Disease Characteristics in EVOLVE-MS-1 Conclusions Overall Newly Diagnosed Prior IFN/GA Screeninga DRF 462 mg BID (96 weeks, open label) Follow-upb Population Subgroup Subgroup • In newly diagnosed and prior IFN/GA patients treated with DRF for a median of ~1 year, DRF demonstrated improvement from n = 696 n = 82 n = 361 baseline in clinical and radiological measures of disease activity. Mean (SD) age, y 41.9 (11.0) 37.1 (11.3) 43.7 (10.6) –– Significant reductions were observed in ARR, and more patients were relapse free compared with baseline. Study –– Patients had significantly fewer Gd+ lesions compared with baseline. week –4 12 4812 16 20 24 36 48 60 72 84 96 98 Female, n (%) 505 (73) 54 (66) 276 (77) –– Outcomes in newly diagnosed and prior IFN/GA patients were similar to those observed in the overall EVOLVE-MS-1 study population. US region, n (%) 283 (41) 30 (37) 197 (55) • DRF may be an effective treatment option in patients who are newly diagnosed with MS and DMT naive, as well as in those with BID = twice daily; DRF = diroximel fumarate aThe EVOLVE-MS-1 study population includes patients who rolled over from the randomized, double-blind, Phase 3 EVOLVE-MS-2 (NCT03093324) study after a greater time since diagnosis and prior IFN or GA use. completing the 5-week treatment period and those who were newly enrolled to the DRF clinical trial program. Prior DMT, n (%) 452 (65) 0 361 (100) b All patients completed a 2-week safety follow-up; in addition, patients who discontinued or completed treatment with a last measured absolute lymphocyte b count of < 0.8 × 109/L were required to complete lymphocyte follow-up visits for up to 6 additional months. IFN 274 (39) 0 274 (76) GAb 178 (26) 0 178 (49) Introduction Results Mean (SD) time since diagnosis, y 7.6 (7.3) 0.4 (0.5) 9.8 (7.4) • Diroximel fumarate (DRF; ALKS 8700, BIIB098) is a novel oral • As of 30 March 2018, 82 newly diagnosed and 361 prior IFN/GA Figure 2. Patients Treated With DRF in EVOLVE-MS-1 Experienced Reduction From Baseline in ARR Mean (SD) no. of relapses in fumarate in development for patients with relapsing forms of patients were enrolled in EVOLVE-MS-1. 0.8 (0.8) 1.1 (0.7) 0.6 (0.8) previous year multiple sclerosis (MS). • Median (range) DRF exposure was 15.0 (0.4–24.2) months in newly (A) Rate ratio (95% CI) Mean (SD) EDSS score 2.7 (1.5) 2.1 (1.2) 2.86 (1.6) • DRF undergoes rapid, presystemic conversion to monomethyl diagnosed and 14.9 (0.0–24.3) months in prior IFN/GA patients. 0.17 (0.09–0.30) 83.3% reduction + fumarate (MMF), the same pharmacologically active metabolite • Newly diagnosed patients were on average 37 years of age, with Mean (SD) no. of Gd lesions 1.2 (4.0) 2.1 (5.8) 1.0 (3.0) 1 p < 0.0001 as the approved drug, delayed-release (DMF). + 2.1 Gd lesions and 0.4 years since diagnosis; prior IFN/GA patients Rate ratio (95% CI) Patients with Gd+ lesions, n (%) 208 (30) 37 (45) 82 (23) • DRF is differentiated from DMF based on its distinct chemical were on average 44 years of age, with 1.0 Gd+ lesion and 9.8 years 1.5 0.21 (0.16–0.26) Rate ratio (95% CI) DMT = disease-modifying therapy; EDSS = Expanded Disability Status Scale; GA = glatiramer acetate; Gd+ = gadolinium-enhancing; IFN = interferon structure, but is expected to have an efficacy and safety profile since diagnosis (Table). 79.5% reduction 1.11 0.28 (0.20–0.39) aPrior DMT use was permitted with restrictions: patients who were newly enrolled in the diroximel fumarate clinical trial program were not eligible to participate in EVOLVE-MS-1 if they received within 2 years of Visit 2, within 2 months of Visit 2, within 90 days of Visit 2, and within 6 months of Visit 2. similar to DMF when given at the investigated dose because • Overall, 17.1% of newly diagnosed and 19.4% of prior IFN/GA p < 0.0001 (0.98–1.26) 71.9% reduction bSome patients may have received both IFN and GA treatment prior to therapy. both compounds produce bioequivalent levels of systemic MMF patients discontinued DRF treatment. p < 0.0001 upon oral administration. Newly Diagnosed Patients • EVOLVE-MS-1 (NCT02634307) is an ongoing, global, open-label, + a • Adjusted ARR (95% CI) was 0.19 (0.10–0.33) at Week 48, Figure 3. Patients Treated With DRF in EVOLVE-MS-1 Had Reduction From Baseline to Week 48 in Number of Gd Lesions single-arm, Phase 3 study assessing long-term safety, tolerability, 1.0 0.78 and treatment effect of DRF 462 mg twice daily over 96 weeks representing an 83.3% risk reduction compared with the 12 months (0.72–0.84) 0.63 (A) (B) before study start (1.11 [0.98–1.26]; rate ratio [95% CI], 0.17 0 lesions in adults with relapsing-remitting MS (RRMS). (0.55–0.72) 96% lower [0.09–0.30]; p < 0.0001; n = 82; Figure 2A). + 1–4 lesions • Post hoc subgroup analyses were performed to evaluate DRF Gd lesion count • Estimated proportion of patients with a relapse at Week 48 was 5–8 lesions efficacy in 2 MS patient populations: those who were newly p = 0.0051 14% (Figure 2B). ≥ 9 lesions diagnosed with MS and naive to disease-modifying therapies 0.5 0.19 • Mean (SD) EDSS and T25FW scores remained stable over the 2.2 (0.7) (DMTs), and those with greater time since diagnosis and prior Adjusted ARR (95% CI) 3 100 first year of treatment: (0.10–0.33) 0.18 interferon (IFN) beta or glatiramer acetate (GA) use. 0.16 64% lower 90 89 89

(0.13–0.25) % –– EDSS: baseline, 2.10 (1.15), n = 81; Week 48, 2.25 (1.10), n = 70 + b (0.13–0.20) 77% lower Gd lesion count –– T25FW: baseline, 5.78 (2.11), n = 81; Week 48, 6.06 (3.79), n = 70. Gd+ lesion count p < 0.0001 80 75 p < 0.0001 67 Objective • By Week 48, 71 (87%) patients were relapse free, compared with 2 • To explore efficacy outcomes in DRF-treated patients with RRMS 12 (15%) patients in the 12 months before study start. 0.0 60 56

Lesion Count 1.3 (0.2)

from the ongoing EVOLVE-MS-1 study who were newly diagnosed + + Baseline Baseline Week 48 Baseline Week 48 1.1 (0.2) Lesion Count, • Mean (SE) Gd lesion count was 2.2 (0.7) at baseline and 0.1 (0.1) Week 48 + with MS or previously treated with IFN or GA. at Week 48 (96% reduction; p = 0.0051; Figure 3A). 40 Overall Populationa Newly Diagnoseda Prior IFN/GAa 33 –– A greater percentage of patients had no Gd+ lesions at Week 48 1 (n = 696) (n = 82) (n = 361) 25 compared with baseline (Figure 3B). Methods 0.4 (0.1) 20 18

(B) Mean (SE) Gd 0.3 (0.1) 11 • Patients enrolled in EVOLVE-MS-1 were 18–65 years of age, had a • Mean (SE) numbers of new/newly enlarging T2 hyperintense and 0.1 (0.1) 9 9 Patients by Gd 6 6 5 4 3 2 new T1 hypointense lesions from baseline to Week 48 were 0.3 3 0 1 00 0 1 confirmed RRMS diagnosis, and were neurologically stable with 0 0 no evidence of relapse in the 30 days before screening. 3.0 (0.7) and 2.8 (0.7), respectively (Figure 3C, D). Baseline Week Baseline Week Baseline Week BaselineWeek 48 Baseline Week 48 Baseline Week 48 –– Patients in the newly diagnosed group were diagnosed with Prior IFN/GA Patients 48 48 48 RRMS within 1 year of study entry and were naive to DMTs. Overall Population Newly Diagnosed Prior IFN/GA • Adjusted ARR (95% CI) was 0.18 (0.13–0.25) at Week 48, Overall Population Newly Diagnosed Prior IFN/GA (n = 503) (n = 70) (n = 242) –– Patients in the prior IFN/GA group had prior IFN or GA use representing a 71.9% reduction from the 12 months before study (n = 503) (n = 70) (n = 242) at any time since diagnosis. start (0.63 [0.55–0.72]; rate ratio [95% CI] 0.28 [0.20–0.39]; 0.2 • Patients received DRF 462 mg twice daily over the 96-week p < 0.0001; n = 361; Figure 2). open-label treatment period; patients newly enrolled in the DRF • Estimated proportion of patients with a relapse at Week 48 clinical trial program initiated treatment with a 1-week titration was 13.4%. (C) (D) period (Figure 1). • By Week 48, 321 (89%) patients were relapse free, compared with 4 3.0 (0.7) 4 • Efficacy endpoints were exploratory; the following endpoints 185 (51%) patients in the 12 months before study start. 2.8 (0.7) were included in these analyses: 0.1 2.7 (0.6) • Mean (SD) EDSS and T25FW scores remained stable over the 2.8 (0.3) –– Clinical: annualized relapse rate (ARR), estimated proportion first year of treatment: 3 3 of patients with relapse at Week 48, disability progression –– EDSS: baseline, 2.84 (1.57), n = 347; Week 48, 2.86 (1.63), n = 240 Overall population (n = 696) Proportion of Patients With Relapse 2.0 (0.2) assessed by the Expanded Disability Status Scale (EDSS), Newly diagnosed (n = 82) Timed 25-Foot Walk (T25FW) test –– T25FW: baseline, 7.46 (5.53), n = 347; Week 48, 7.74 (8.86), n = 237. 1.7 (0.3) + Prior IFN/GA (n = 361) 2 2 ▪▪Adjusted ARR (95% CI) was based on a Poisson regression model • Mean (SE) Gd lesion count was 1.1 (0.2) at baseline and 0.4 (0.1) that included patient-reported relapses in the 12 months before at Week 48 (64% reduction; p < 0.0001; n = 242; Figure 3A). 0.0 study start (baseline value) or protocol-defined relapses occurring –– A greater percentage of patients had no Gd+ lesions at Week 48 012243648 60 compared with baseline (Figure 3B). Time on Study, wk Mean (SE) New/Newly 1 1

on or before 48 weeks (Week 48 value) Enlarging T2 Lesion Count From Baseline to Week 48 –– Radiological: gadolinium-enhancing (Gd+), new/newly enlarging • Mean (SE) numbers of new/newly enlarging T2 hyperintense and No. of Patients at Risk From Baseline to Week 48 Overall Mean (SE) New T1 Lesion Count T2 hyperintense, and new T1 hypointense lesion counts. new T1 hypointense lesions from baseline to Week 48 were 2.7 (0.6) 0 0 and 1.7 (0.3), respectively (Figure 3C, D). population 696 630 529 468 424 293 • Relapses were analyzed in patients who received ≥ 1 dose of DRF. Newly Overall Newly Prior IFN/GA Overall Newly Prior IFN/GA • All other efficacy endpoints (magnetic resonance imaging lesions, diagnosed 82 76 69 63 59 36 Population Diagnosed (n = 242) Population Diagnosed (n = 242) (n = 503) (n = 70) (n = 503) (n = 70) EDSS, T25FW) were analyzed in patients who received ≥ 1 dose of Prior IFN/GA 361 321 264 230 203 144 DRF and completed ≥ 1 postbaseline efficacy assessment. DRF = diroximel fumarate; GA = glatiramer acetate; Gd+ = gadolinium-enhancing; IFN = interferon • Outcome visualizations include the overall study population for ARR = annualized relapse rate; DRF = diroximel fumarate; GA = glatiramer acetate; IFN = interferon aMagnetic resonance imaging outcomes were evaluated in patients who received ≥ 1 dose of DRF and completed ≥ 1 postbaseline efficacy assessment. comparison. aRelapse was evaluated in patients who received ≥ 1 dose of DRF. bCombined percentages for baseline or Week 48 may not equal 100 due to rounding.

References 1. Tecfidera [prescribing information]. Cambridge, MA: Biogen; 2017. 2. Polman CH, et al.Ann Neurol. 2011;69(2):292-302. Disclosures MG: consulting fees from Biogen, EMD Serono, Novartis, and Sanofi-Genzyme; research support from Alkermes; speaker bureaus for Biogen, EMD Serono, Genentech-Roche, and Sanofi-Genzyme; SW: consulting fees from Biogen, EMD Serono, Genentech-Roche, and Sanofi-Genzyme; research support from Alkermes, Biogen, Celgene, Genentech-Roche, Novartis, Sanofi-Genzyme, and TG Therapeutics; speaker bureaus for Biogen, EMD Serono, Genentech-Roche, and Sanofi-Genzyme; CM, JH, HC, and LY: employees of and hold stock/stock options in Biogen; ML-B, BK, and RL-P: employees of and hold stock/stock options in Alkermes. Acknowledgments This study was sponsored by Biogen (Cambridge, MA, USA) and Alkermes (Waltham, MA, USA). Writing and editorial support for the preparation of this poster was provided by Excel Scientific Solutions (Southport, CT, USA): funding was provided by Biogen. Consortium of Multiple Sclerosis Centers I‌ May 28 – June 1, 2019 I‌ Seattle, WA