Diroximel fumarate (DRF)(ALKS8700, BIIB098; Alkermes, Waltham, MA and Biogen, Cambridge, MA) is an oral fumarate in development for treatment of multiple sclerosis (MS). Like dimethyl fumarate (DMF) (Tecfidera; Biogen, Cambridge, MA), DRF is a prodrug that is converted to monomethyl fumarate. The unique chemical structure of DRF, however, creates potential for similar efficacy with better gastrointestinal tolerability; this is supported by interim data from week 48 of a 96-week open-label safety study (NCT02634307) presented at the American Academy of Neurology May 4-10 in Philadelphia, PA.
Although the overall profile of adverse events (AEs) from DRF treatment (462 mg twice daily) was similar to that seen with DMF, the discontinuation rate due to gastrointestinal AEs was less than 1% (5/696), suggesting improved gastrointestinal tolerability for DRF. In comparison, the discontinuation rate for DMF due to gastrointestinal AEs in the registrational trials for this compound was close to 4%.
Aaron Deykin, MD, vice president of late-stage clinical development at Biogen, noted, “A fumarate with fewer gastrointestinal side effects can positively impact adherence to treatment and quality of life. We consider the lower rate of discontinuation for GI AEs in this trial as a sentinel marker. We are currently recruiting for a clinical trial that will compare DRF and DMF head to head with an emphasis on gastrointestinal tolerability to aid clinicians and patients further in making treatment decisions.”
Interim data for DRF also support efficacy, with the adjusted annualized relapse rate (ARR) dropping by 79.5% (P < .0001) from 0.78 (95% CI: 0.72-0.84) in the year before enrollment to 0.16 (95% CI: 0.13-0.20) at week 48 of treatment. Only 13.1% of participants had a relapse during 48 weeks of treatment and 31.8% achieved no evidence of disease activity-3 (NEDA-3, ie, no relapses, no new lesions, no increased disability). The mean number of GD+ lesions was reduced by 77% (P < .0001). Mean EDSS scores remained stable. Of note, newly diagnosed participants also experienced reductions in lesion number and relapse rate.
Serious AEs occurred in 7.5% (52/696) of participants and 0.3% (2/696) had serious infections. The mean absolute lymphocyte count (ALC) declined by 28.4% and then stabilized remaining about the lower limit of normal for the majority of patients (64.8%). Moderate prolonged lymphopenia for more than 6 months occurred in 7.3% of participants and 4 participants discontinued treatment due to lymphopenia. No serious opportunistic infections, including progressive multifocal leukoencephalopathy (PML), occurred.
A new drug application for DRF was filed in December 2018 with the Food and Drug Administration under the 505b2 regulatory pathway based on pharmacokinetic studies. The FDA has tentatively approved a brand name of Vumerity.