Vumerity® (diroximel fumarate)

FDA-Approved Medications: Medications Recently Approved

Company: Biogen Inc. and Alkermes plc

• Starting dose: 231 mg twice a day, orally, on Days 1-7
• Maintenance dose after seven days: 462 mg (administered as two 231-mg capsules) twice a day, orally
• Approved in October 2019 for relapsing forms of MS, including clinically isolated syndrome, relapsing-remitting disease, and active secondary-progressive disease, in adults

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Vumerity^® (diroximel fumarate) is a fumarate agent, as is Biogen’s Tecfidera^® (dimethyl fumarate). However, it has a chemical structure that is distinct from Tecfidera, and has been shown to cause fewer gastrointestinal (GI) side effects – such as diarrhea, nausea, vomiting, and abdominal pain – than Tecfidera. The exact mechanism of action by which diroximel fumarate exerts its therapeutic effect in MS is not completely understood. However, upon entering the body, the medication is rapidly converted into the molecule monomethyl fumarate. The converted molecule is thought to activate an antioxidant protein that reduces oxidative stress, which in turn slows damage to protective nerve fibers in the brain.⁶

The FDA’s October 2019 approval of Vumerity was based on a new drug application (NDA) that included data from pharmacologic studies comparing Vumerity and Tecfidera. By demonstrating that the two agents were similar in many key respects, or had “bioequivalence,” Biogen and Alkermes were able to ask the FDA to consider findings on the safety and efficacy of Tecfidera as part of the evidence supporting Vumerity.⁶

The application also included interim exposure and safety findings from EVOLVE-MS-1, an ongoing, Phase III, single-arm, open-label, two-year safety study evaluating Vumerity in patients with relapsing-remitting MS. Interim results from EVOLVE-MS-1 at the time the application was submitted included a low overall rate of Vumerity treatment discontinuation due to adverse events (6.3%), which included less than 1% of patients discontinuing Vumerity due to gastrointestinal (GI) adverse events. Additional exploratory efficacy endpoints in the ongoing EVOLVE-MS-1 study showed changes in clinical and radiological measures compared to baseline.⁶

A few weeks after the FDA approved Vumerity, Biogen presented data from another Phase III study, EVOLVE-MS-2, that directly compared the GI tolerability of Vumerity with that of Tecfidera.²⁴

EVOLVE-MS-2 was a multi-center, double-blind, active-controlled, five-week study involving 506 patients with relapsing forms of MS. The primary endpoint was the number of days patients reported GI symptoms with a symptom intensity score ≥2 on the Individual Gastrointestinal Symptom and Impact Scale (IGISIS) rating scale. Secondary endpoints included the number of days (relative to exposure) that patients reported GI symptoms with IGISIS intensity scores of ≥1 or ≥3 in the overall population. Patients who completed the five-week treatment period were eligible to enroll in EVOLVE-MS-1, the 96-week, open-label, safety study referenced above.

Results for the primary endpoint showed that patients treated with Vumerity reported 46% fewer days with intensity scores of ≥2 on the IGISIS, compared to Tecfidera.

The EVOLVE-MS-2 results also found that compared to people taking Tecfidera, patients receiving Vumerity had:

• Lower discontinuations due to GI adverse events (0.8% vs. 4.8%).
• Fewer days with IGISIS intensity scores of ≥1 and ≥3 (29% relative reduction and 44% relative reduction, respectively).
• Fewer days with a self-reported intensity score of ≥1 (30% reduction on the Global Gastrointestinal Symptom and Impact Scale [GGISIS], which assessed the overall intensity of GI symptoms, their impact on daily activities and how bothersome they were). Fewer days with GGISIS intensity scores of ≥2 and ≥3 were also observed.
• A gradual decline in worst IGISIS intensity scores over the five-week treatment period.

These findings that use the patient-assessed symptom intensity scales were supported by lower investigator-reported incidences of GI adverse events with Vumerity (34.8%) compared to Tecfidera (49.0%). Overall, adverse events occurred in 78.3% of patients receiving Vumerity and 83.7% taking Tecfidera, but most of those adverse effects were mild or moderate in severity. Overall, 1.6% of patients receiving Vumerity and 5.6% of those taking Tecfidera experienced adverse effects that caused them to stop participating in the study. Among those patients who discontinued due to any adverse effect, 0.8% in the Vumerity group stopped due to GI effects, as compared to 4.8% in the Tecfidera group.²⁴

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