Alkermes Submits NDA for Diroximel Fumarate for Relapsing Forms of Multiple Sclerosis

Craig Hopkinson, MD

A new drug application has been submitted to the FDA by Alkermes for diroximel fumarate (BIIB098), an investigational therapy in development for treatment of relapsing forms of multiple sclerosis.

The submission is backed by data from EVOLVE-MS-1 (NCT02634307), a phase 3 study evaluating the long-term safety of diroximel fumarate in approximately 700 patients with relapsing-remitting multiple sclerosis, as well as pharmacokinetic studies comparing diroximel fumarate and dimethyl fumarate.

“Diroximel fumarate was designed to provide patients with relapsing forms of multiple sclerosis a novel oral fumarate with a differentiated profile,” Craig Hopkinson, MD, chief medical officer and senior vice president, medicines development and medical affairs, Alkermes, said in a statement.¹ “The data encompassed in the regulatory package underscore diroximel fumarate’s potential to be a meaningful, new treatment option for the MS community. This NDA submission is an important step in our collaboration with Biogen for diroximel fumarate, and we look forward to working together to bring this potential new medicine to patients and healthcare providers.”

EVOLVE-MS-1 is an open-label, single-arm trial assessing the long-term safety, tolerability and treatment effect of diroximel fumarate 462 mg twice daily in approximately 935 participants.

Initial safety data from the first month of the 2-year study were presented at the ECTRIMS-ACTRIMS Meeting in 2017 which showed that among 580 participants receiving the investigational therapy, diroximel fumarate was reported safe and well-tolerated and no serious gastrointestinal adverse effects occurred.² The most common treatment-related adverse effects included flushing, pruritus and diarrhea.

More recently, exploratory interim data of annualized relapse rate (ARR) and MRI parameters were presented at the 2018 American Academy of Neurology Annual Meeting and showed that the treatment with diroximel fumarate was associated with low rates of gastrointestinal adverse effects leading to discontinuation (.5%) and no occurrence of serious gastrointestinal adverse effects.³ The data also showed that the ARR for 570 participants was .016 at 1 year. Of these patients, 152 were also assessed by MRI for changes in the number and size of gadolinium-enhancing lesions (mean: 0.3; standard deviation (SD): 1.1), new T1-hypointesnse (mean: 1.8; SD: 4.2), and new/enlarging T2 lesions (mean: 2.8; SD: 5.9) compared to baseline. The MRI analysis showed a significant reduction in the number of gadolinium-enhancing lesions and T1 and T2 compared to baseline. The number of gadolinium-enhancing lesions in 374 participants with available MRI data decreased 80% compared to baseline, from a mean 1.5 to 0.3 (P <.0001).The interim analysis suggests that diroximel fumarate may be an effective oral treatment option for patients with relapsing-remitting multiple sclerosis. The estimated study completion date is December 2020.

Alkermes is currently conducting the EVOLVE-MS-2 study (NCT03093324), a 5-week, phase 3 head-to-head gastrointestinal tolerability study comparing diroximel fumarate and dimethyl fumarate. In the study, approximately 420 patients with relapsing remitting multiple sclerosis at 65 sites in the United States and Poland will be randomized 1:1 to diroximel fumarate 462 mg twice daily or dimethyl fumarate 240 mg twice daily for 5 weeks. Researchers will assess key gastrointestinal symptoms using 2 patient-reported symptom-rating scales: the Individual GI Symptom and Impact Scale (IGISIS) and the Global GI Symptom and Impact Scale (GGISIS). The primary outcome is the number of the days that participants experience gastrointestinal adverse effects while secondary measures include other potential adverse effects. The study is expected to be completed February 2019 with data expected mid-2019.

If approved by the FDA, Biogen intends to market diroximel fumarate under the brand name Vumerity, a name that has been conditionally accepted by the FDA.

REFERENCE

1. Alkermes and Biogen Announce Submission of a New Drug Application to U.S. Food and Drug Administration for Diroximel Fumarate in Multiple Sclerosis [news release]. Dublin and Cambridge, Mass.: Alkermes plc; Dec. 17, 2018. https://www.prnewswire.com/news-releases/alkermes-and-biogen-announce-submission-of-a-new-drug-application-to-us-food-and-drug-administration-for-diroximel-fumarate-in-multiple-sclerosis-300767188.html?rel=0" ?rel=0" . Accessed Dec. 17, 2018.

2. Naismith R, Leigh-Pemberton R, Rezendes D, et al. EVOLVE-MS-1: Phase 3 Open-Label Long-Term Safety Study of ALKS 8700 in Relapsing-Remitting Multiple Sclerosis. [ECTRIMS-ACTRIMS poster P2.102]. Neurology. 2017;88 (16 Suppl).

3. Leigh-Pemberton R, Naismith R, Kandinov B, et al. MRI and Relapse Results for ALKS 8700 in Patients with

Relapsing Remitting

Multiple Sclerosis: 1-year Interim Results from the Phase 3 EVOLVE-MS-1 Study. Poster presented at the 2018 American Academy of Neurology Annual Meeting; April 24, 2018; Los Angeles, Calif. Emerging Science Abstract 006.