ECTRIMS: EVOLVE-MS-2 Reveals Fewer GI Events with Diroximel Fumarate

Flushing and gastrointestinal (GI) distress are common side effects of oral fumarates used to treat patients with multiple sclerosis, but the frequency of these events was found to be lower with diroximel fumarate (Vumerity) than dimethyl fumarate in new data from the EVOLVE-MS-2 study.

Researchers also found no increase in GI events following titration with the newer drug, but they observed a lower incidence of flushing in patients treated with diroximel fumarate.

The latest analysis of adverse events in the EVOLVE-MS-2 study was presented this week at the virtual 37th Congress of the European Committee for Treatment and Research in Multiple Sclerosis–ECTRIMS 2021.

Diroximel fumarate is a delayed-release, next generation oral fumarate approved by the FDA in the fall of 2019 for the treatment of relapsing forms of multiple sclerosis. It is similar to dimethyl fumarate, with the same active metabolite, but diroximel fumarate has a distinct chemical structure that has been reported to have improved GI tolerability compared with dimethyl fumarate.

Initial findings from the EVOLVE-MS-2 study, which was a 5-week, phase III, head-to-head, randomized, controlled trial involving one week of titration, showed treatment with diroximel fumarate to be associated with a 46% reduction in the number of days with GI symptoms, compared to dimethyl fumarate, as measured by Individual Gastrointestinal Symptom and Impact Scale (IGISIS) intensity score ≥2 relative to exposure (rate ratio: 0.54; 95% CI: 0.39-0.75; P=0.0003). Patients who were treated with diroximel fumarate also had a lower rate of adverse events (34.4% vs. 49.0%, respectively), as well as lower treatment discontinuation rates due to overall (1.6% vs 5.6%) and GI-related adverse events.

Given that GI side effects with dimethyl fumarate tend to peak in weeks 3 and 4 of treatment, some clinicians have taken to the practice of extended titration with the drug in an effort to reduce GI distress.

The newly reported data from EVOLVE-MS-2, presented by Robert T. Naismith, MD, of Barnes-Jewish Hospital, St. Louis, Missouri, evaluated the impact of the 1-week dose titration period on GI tolerability for diroximel fumarate, in an effort to determine if diroximel fumarate tolerability is dose dependent. The latest analysis showed GI event severity to be greatest in treatment weeks 3 and 4 among patients treated with dimethyl fumarate, as expected; however, the same pattern was not seen in patients treated with diroximel fumarate.

Treatment discontinuation due to GI adverse events occurred in two patients treated with diroximel fumarate (0.8%) and in 12 patients treated with dimethyl fumarate (4.8%), and most GI-related discontinuations occurred in week 3 (7/12 patients, 58.3%) of treatment.

Naismith and colleagues concluded that the lack of a GI event peak with diroximel fumarate could simplify initiation of the treatment and eliminate the need for an extended titration schedule.

Although EVOLVE-MS-2 was not designed to assess differences in another common side effect of oral fumarates—flushing—the incidence of flushing was found to be lower in patients treated with diroximel fumarate (46%, 116/253) than in patients treated with dimethyl fumarate (55%, 138/251). The majority of flushing events were mild-to-moderate, occurring in the first week of treatment (diroximel fumarate, 84%; dimethyl fumarate, 86%), though five patients (2%) on dimethyl fumarate experienced severe flushing events. The median duration of flushing events was shorter in the diroximel fumarate-treated patients, and no patients in either treatment group discontinued treatment due to flushing. 

Early real-world use data, also presented at ECTRIMS 2021, showed adherence rates with diroximel fumarate that were similar to or higher than other oral disease modifying therapies during the same observation period.

The retrospective analysis of a large U.S. claims database revealed that 86% of patients on diroximel fumarate remained on the therapy for 90 days or more after initiation, compared to 81% of patients on dimethyl fumarate, 83% of patients on teriflunomide, 79% of patients on fingolimod, and 88% of patients on siponimod.

The researchers concluded that further real-world use research is needed to compare the safety and efficacy of diroximel fumarate to other oral disease modifying therapies.

1. Flushing and gastrointestinal distress are common side effects of oral fumarates used to treat multiple sclerosis, but the frequency of these events was found to be lower with diroximel fumarate than dimethyl fumarate in new data from the EVOLVE-MS-2 study.

2. Diroximel fumarate is a delayed-release, next generation oral fumarate approved by the FDA in the fall of 2019 for the treatment of relapsing forms of multiple sclerosis.

Salynn Boyles, Contributing Writer, BreakingMED™

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Topic ID: 98,708,730,130,36,192,925,708