Dr  Bernd Kieseier, MDBernd Kieseier, MD
At the 2019 Annual Meeting of the Consortium of Multiple Sclerosis Centers (CMSC) held in Seattle, Washington, May 28–June 1, Biogen presented new interim data from the ongoing open-label, pivotal phase 3 EVOLVE-MS-1 (NCT02634307) safety study indicating that diroximel fumarate significantly reduced disease activity in patients newly diagnosed with relapsing-remitting multiple sclerosis and those previously treated with interferons or glatiramer acetate, and was well tolerated with low rates of gastrointestinal adverse effects leading to treatment discontinuation.1

The investigational, novel, oral fumarate candidate, which is in development with Alkermes, is currently under review with the FDA and has a Prescription Drug User Fee Act (PDUFA) target action date in the fourth quarter of 2019. The new drug application was accepted February 2019 through the 505(b)(2) pathway and references the dimethyl fumarate data, with the application including findings from the EVOLVE-MS-1 study. If diroximel fumarate is approved by the FDA, Biogen intends to market it under the brand name Vumerity.

"Diroximel fumarate is a novel oral fumarate candidate with a distinct chemical structure that is in development for the treatment of relapsing forms of MS. Diroximel fumarate is designed to rapidly convert to monomethyl fumarate in the body and it is hypothesized that it may offer differentiated gastrointestinal (GI) tolerability compared to dimethyl fumarate. The data we are presenting at CMSC broaden the body of evidence supporting the tolerability of diroximel fumarate," Bernd Kieseier, MD, global head of multiple sclerosis, Biogen, told NeurologyLive. "The data presented at CMSC are consistent with previous results we’ve shared on the potential safety and effectiveness of diroximel fumarate in relapsing MS, particularly in newly diagnosed patients. We look forward to learning more about the GI tolerability profile of diroximel fumarate, which is being evaluated in the ongoing EVOLVE-MS-2, a head-to-head study versus dimethyl fumarate, with results expected later this year."

The single arm, 96-week, phase 3 trial will enroll approximately 1000 patients with relapsing-remitting multiple sclerosis. The interim results, which were presented in a safety and efficacy analyses at the CMSC meeting, includes 696 subjects treated with diroximel fumarate for a median of approximately 1 year.

The efficacy of diroximel fumarate, explored in a sub-group analysis of EVOLVE-MS-1, included participants naïve to prior disease-modifying therapy treatment or those previously treated with interferon or glatiramer acetate.

As of March 2018, the results demonstrated significant improvements in radiologic and clinical endpoints over 1 year compared to baseline. The annualize relapse rate at week 48 versus the previous 12 months was 0.20 vs 1.1 (82% reduction; n=82) in newly diagnosed and 0.19 versus 0.6 (68% reduction; n=361) in those who switched from interferons or glatiramer acetate. A reduction in the mean number of gadolinium-enhancing lesions was observed for both participants newly diagnosed (baseline, 2.2 [6.2]; week 48, 0.1 [0.38]; 96% reduction; P = .0051; n=70) and those who switched from interferons or glatiramer acetate (baseline, 1.1 [3.17]; week 48, 0.4 [2.18]; 64% reduction; P <.0001; n=242). Based on the results of this analysis, investigators concluded that diroximel fumarate may be an effective therapy in both newly diagnosed patients and interferons or glatiramer acetate switchers.3

"Results show that in these interferons/glatiramer acetate switch patients, diroximel fumarate was associated with significant improvements in radiological and clinical endpoints over one year compared to baseline, and annualized relapse rate was reduced by 72% with diroximel fumarate at week 48 compared to baseline," Kieseier explained. "Additionally, the mean number of gadolinium-enhancing (Gd+) lesions was reduced by 64% with diroximel fumarate compared to baseline, and the percentage of patients with no Gd+ lesions at week 48 was 89% compared to 74% at baseline. These data are consistent with additional results we’ve previously shared demonstrating the effectiveness of diroximel fumarate in relapsing MS, including in specific patient populations such as newly diagnosed patients and early switch patients."

The other dataset presented at CMSC demonstrated the tolerability profile of diroximel fumarate in relapsing-remitting multiple sclerosis throughout 1 year. This analysis studied the severity, time to onset, and duration of gastrointestinal and flushing tolerability events in patients with relapsing-remitting multiple sclerosis treated with diroximel fumarate in EVOLVE-MS-1.

As of March 2018, 83.2% of participants were ongoing, 1.9% had completed the study, and 14.9% discontinued treatment. Of those that discontinued treatment, 6.8% discontinued because of adverse effects and <1% due to gastrointestinal adverse effects. The incidence of gastrointestinal adverse effects occurred in 30.9% (215/696) participants and 8/696 (1.1%) experienced severe gastrointestinal adverse effects. The effects were mild or moderate in severity, typically occurred within the first month of treatment, and resolved in 89% (191/215) of patients. Flushing/flushing-related adverse effects occurred in 44.3% (308/696) patients and resolved in 74% (229/308) patients. Overall, with a median of approximately 1 year of treatment, diroximel fumarate appeared to be generally well tolerated.4

"In terms of tolerability, GI adverse events associated with diroximel fumarate occurred at a relatively low rate (30.9%), were mild or moderate in severity, and rarely led to treatment discontinuation (0.7%). In those patients who experienced GI events with diroximel fumarate, effects typically appeared within the first month of treatment and resolved quickly in the vast majority (89%) of patients," Kieseier added.

The gastrointestinal tolerability of diroximel fumarate compared to dimethyl fumarate in subjects with relapsing-remitting multiple sclerosis is currently being evaluated in the EVOLVE-MS-2 (NCT03093324) study, with results expected later this year.
REFERENCE
1.New Phase 3 Interim Results Support Safety and Efficacy of Diroximel Fumarate in Multiple Sclerosis [news release]. Cambridge, Mass.: Biogen Inc; May 30, 2019. www.globenewswire.com/news-release/2019/05/30/1859295/0/en/New-Phase-3-Interim-Results-Support-Safety-and-Efficacy-of-Diroximel-Fumarate-in-Multiple-Sclerosis.html. Accessed May 30, 2019.
3. Gudesblatt M, Wray S, Miller C, et al. Efficacy of Diroximel Fumarate in Relapsing- Remitting Multiple Sclerosis Patients Who Are Newly Diagnosed or Previously Treated with Interferons or Glatiramer Acetate. Presented at: 2019 CMSC Annual Meeting. May 28-June 1, 2019; Seattle, WA. Abstract DXT42.
4. Wray S, Hunter S, Leigh-Pemberton R, et al. Tolerability of Diroximel Fumarate in Patients with Relapsing-Remitting Multiple Sclerosis: Analysis of Gastrointestinal and Flushing Events in the Phase 3 EVOLVE-MS-1 Study. Presented at: 2019 CMSC Annual Meeting. May 28-June 1, 2019; Seattle, WA. Abstract DXT41.