How BIIB098 works
BIIB098 is a small molecule called diroximel fumarate, a prodrug that, once in the body, is rapidly and efficiently converted into monomethyl fumarate (MMF).
While the exact mechanism of action for BIIB098 is not clearly understood, MMF is known to activate a protein called Nrf2. Among other effects, Nrf2 is thought to have antioxidant properties, and when activated should reduce damage from oxidative stress.
In MS, inflammation and oxidative stress contribute to damage to nerve cells and the myelin sheath that insulates nerve fibers (axons). By activating the Nrf2 pathway, BIIB098 may reduce or slow the progressive damage to nerve cells.
MMF is the active metabolite of dimethyl fumarate (Tecfidera), Biogen’s approved oral therapy for relapsing forms of MS. Tecfidera and BIIB098 have a similar mechanism of action, but BIIB098 may have fewer gastrointestinal side effects than the approved medication.
BIIB098 in clinical trials
A Phase 1, randomized, double-blind clinical trial (NCT02201849), conducted in 2015, assessed the safety, tolerability, and pharmacokinetics (movement in the body) of a single dose of either BIIB098 or Tecfidera in 35 healthy participants. The treatment was then changed to enable crossover comparison. Results showed that BIIB098 met the standards for being a bioequivalent therapy to Tecfidera. The most common adverse effects were flushing, dizziness, and constipation forBIIB098, and flushing, nausea, and diarrhea for Tecfidera.
Alkermes is currently assessing the safety and effectiveness of BIIB098 in two Phase 3 studies in patients with relapsing-remitting multiple sclerosis (RRMS) — the EVOLVE-MS-1 trial (NCT02634307) and the EVOLVE-MS-2 trial (NCT03093324).
EVOLVE-MS-1 is a two-year, open-label study to investigate the long-term safety of BIIB098 in an estimated 935 patients with RRMS, at 107 sites across the U.S and Europe. The trial is expected to finish in December 2020.
Interim trial results were presented at the 2018 American Academy of Neurology (AAN) Annual Meeting. The analysis of the first 520 patients showed an annualized relapse rate (ARR) of 0.16 after one year of treatment. Of these patients, 152 were also assessed by MRI for changes in the number and size of lesions compared to baseline, or the study’s start. The scans showed a significant reduction in their brain lesions.
EVOLVE-MS -2 is a head-to-head study comparing the gastrointestinal tolerability of BIIB098 at 462 mg twice daily, and Tecfidera at 240 mg twice daily. This five-week study will involve around 420 people with RRMS at 65 sites in the U.S. and Poland. The study is still recruiting (site locations can be viewed here) and is expected to be completed in February 2019.
The study will compare the intensity, frequency, and duration of common gastrointestinal symptoms, including nausea, vomiting, upper and lower abdominal pain, and diarrhea.
BIIB098 was originally developed by Alkermes and was licensed to Biogen in 2017. Biogen will have the exclusive worldwide rights to commercialize BIIB098, should the therapy be approved by the U.S. Food and Drug Administration (FDA) and other regulatory agencies.
Alkermes is planning to file a new drug application for BIIB098 with the FDA by the end of 2018.
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