Vumerity (diroximel fumarate) is a new oral treatment approved by the U.S. Food and Drug Administration (FDA) for the treatment of relapsing forms of multiple sclerosis (MS). It has been developed by Alkermes in collaboration with Biogen, and is available as delayed-release capsules.
The FDA’s October 2019 decision approving Alkermes’ new drug application was based in part on data from the pivotal Phase 3 EVOLVE-1 clinical trial (NCT02634307). That study, still ongoing in the U.S. and Europe, showed the long-term safety and effectiveness of the therapy, given twice daily, in patients with RRMS.
How does Vumerity work?
MS is a progressive neurodegenerative disease in which the immune system mistakenly attacks the myelin sheath, a protective protein coat that surrounds nerve fibers. This damages the nerve cells and interferes with the transmission of nerve signals from the brain to the rest of the body and back.
Vumerity (previously BIIB098 and ALKS8700) is made of a small molecule called diroximel fumarate, which is an inactive prodrug that is converted into its active form, monomethyl fumarate (MMF), inside the body.
While MMF’s exact mechanism of action is not clearly understood, evidence suggests that it activates a protein called Nrf2, which decreases inflammation by reducing the levels of toxic molecules called reactive oxygen species (ROS) inside cells. Therefore, Vumerity should reduce damage to the nerve cells and slow down the progression of MS.
Vumerity in clinical trials
A Phase 1, randomized, double-blind, placebo-controlled clinical trial (NCT02201849) assessed the safety, tolerability, and pharmacokinetics — movement in the body — of Vumerity in 104 healthy volunteers. The trial also evaluated Tecfidera, another approved MS medication with a similar mechanism of action.
A single dose of Vumerity between 49 mg and 980 mg or Tecifidera at 240 mg was give to participants. All doses of Vumerity were well-tolerated. The participants then took part in a crossover comparison of the two treatments. Vumerity had better pharmacokinetics compared with Tecifidera. Moreover, only 4.3% of participants who received Vumerity reported gastrointestinal issues compared with 41.7% of those who received Tecifidera. The most common adverse effects with Vumerity were flushing, dizziness, and constipation; with Tecfidera, they were flushing, nausea, and diarrhea.
Alkermes, in collaboration with Biogen, then began assessing the safety, tolerability, and effectiveness of Vumerity in two Phase 3 clinical trials in patients with relapsing-remitting multiple sclerosis (RRMS). These were the EVOLVE-MS-1 trial and the EVOLVE-MS-2 trial (NCT03093324).
EVOLVE-MS-1 is a two-year, open-label study to investigate the long-term safety of Vumerity in an estimated 1,057 people with RRMS. The trial, being conducted at 107 sites across the U.S and Europe, is expected to be completed in July 2021.
The early findings, on gastrointestinal treatment-emergent adverse events (GI-TEAEs) in 696 participants, were published in the scientific journal Advances in Therapy. There were 215 GI TEAEs reported by the 696 patients (30.9%), of which 207 were mild or moderate in severity. Further, 191 out of 215 events (88.8%) were resolved within one to 87 days. Fewer than 1% of patients discontinued treatment because of GI-TEAEs.
These data suggest that the distinct chemical structure of diroximel fumarate causes fewer and less severe GI-related problems than other medicines like Tecifidera.
More interim results from the trial were presented at the 2018 American Academy of Neurology Annual Meeting. The analysis of the first 570 patients showed an annualized relapse rate (ARR) of 0.16 after one year of treatment. Of these patients, 152 also were assessed by magnetic resonance imaging (MRI) scans for changes in the number and size of lesions in their brain compared with the start of the study. The scans showed a significant reduction in lesions.
Additional interim data were presented at the 2019 Consortium of Multiple Sclerosis Centers. For newly diagnosed patients, the ARR decreased by 83% from baseline following one year of Vumerity treatment. In addition, the number of lesions visible by MRI was reduced by 96% after 48 weeks of treatment. For patients who had been treated previously, ARR decreased by 72%, and lesion number was reduced by 64% after 48 weeks of treatment with Vumerity.
EVOLVE-MS-2 was a head-to-head study that compared the gastrointestinal tolerability of 462 mg of Vumerity taken twice daily, and 240 mg of Tecfidera also taken twice daily. This five-week study was conducted in 506 patients with RRMS at 65 sites in the U.S. and Poland. The primary endpoint of the study was the number of days participants reported GI symptoms that were equal to or greater than a score of 2 on the individual gastrointestinal symptom and impact scale (IGSIS). The IGSIS scale rates symptoms from 0, or none, to 10, which indicates the most severe symptoms. Participants were evaluated twice daily to compare the intensity, frequency, and duration of common gastrointestinal symptoms, including nausea, vomiting, upper and lower abdominal pain, and diarrhea. The study was completed in June 2019.
The results showed that only 0.8% of patients treated with Vumerity discontinued treatment because of GI-related adverse events, compared with 4.8% of patients receiving Tecfidera. The most common symptom was flushing, reported by 32.8% of patients treated with Vumerity and 40.6% of those given Tecfidera. Other common symptoms were diarrhea, which affected 15.4% of those on Vumerity and 22.3% of those treated with Tecfidera, and nausea, reported by 14.6% of patients given Vumerity and 20.7% of those receiving Tecfidera.
Vumerity was originally developed by Alkermes and licensed to Biogen in 2017. Biogen has the exclusive worldwide rights to commercialize Vumerity.
Last updated: Nov. 1, 2019
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