Background

Diroximel fumarate (DRF) is a novel oral fumarate for relapsing forms of multiple sclerosis (MS). DRF is converted to monomethyl fumarate (MMF), the same pharmacologically active metabolite as dimethyl fumarate (DMF). Oral administration of DRF 462mg and DMF 240mg produce bioequivalent MMF exposure and are therefore expected to exhibit comparable efficacy and safety profiles. DRF has an improved gastrointestinal (GI) tolerability profile compared to DMF.

Objectives

To report interim safety, tolerability, and efficacy outcomes in DRF-treated patients from EVOLVE-MS-1 and to assess GI tolerability in a subgroup of patients who received DMF prior to DRF.

Methods

EVOLVE-MS-1 (NCT02634307) is an ongoing, open-label, 96-week study assessing DRF safety, tolerability, and efficacy in adults with relapsing-remitting MS. Patients entered the study either as newly enrolled in the DRF clinical development program or after completing EVOLVE-MS-2 (NCT03093324), a randomized, blinded, phase 3 study in which patients received DRF or DMF over 5 weeks.

Results

As of 2 July 2019, 1051 patients were enrolled, 458 of whom had completed EVOLVE-MS-2. Median DRF exposure was 1.5 (range 0.0-1.9) years. Overall, 44.2% of patients completed the study and 17.3% discontinued treatment; 6.3% discontinued due to AEs and 0.7% due to GI AEs. AEs occurred in 82.1% (863/1051) of patients; 90% (779/863) were mild or moderate in severity. Incidence of GI AEs was 28.4% (299/1051) in the overall population, 21.7% (51/235) in patients with prior DRF treatment, and 21.5% (48/223) in patients with prior DMF treatment. Patients who had experienced GI AEs in EVOLVE-MS-2 (DRF to DRF, 33.6% [79/235]; DMF to DRF, 44.8% [100/223]) had low rates of recurrence (3.4% [8/235] and 3.6% [8/223] for those previously treated with DRF and DMF, respectively) and/or onset of new GI AEs (19.6% [46/235] and 20.6% [46/223], respectively) in EVOLVE-MS-1, regardless of prior treatment group. In the overall population (n=1051), annualized relapse rate was 0.14, and 86.1% of patients were relapse-free. Outcomes in patients who were newly diagnosed or most recently switched from interferon or glatiramer acetate will be presented.

Conclusions

Safety and efficacy results from the ongoing EVOLVE-MS-1 study were consistent with previous findings of DRF and the known benefit-risk profile for DMF. In patients who switched from DMF to DRF, no worsening of tolerability was observed.

Supported by: Biogen

Background

Diroximel fumarate (DRF) is a novel oral fumarate approved for relapsing forms of multiple sclerosis (MS) with the same active metabolite as dimethyl fumarate (DMF). DRF demonstrated improved gastrointestinal (GI) tolerability vs DMF, with significantly fewer days with a score of ≥2 on the patient-assessed Individual Gastrointestinal Symptom and Impact Scale (IGISIS).

Objectives

To determine whether an IGISIS score ≥2 is an appropriate threshold for comparing GI tolerability and detecting clinically meaningful quality of life (QoL) improvements in EVOLVE-MS-2.

Methods

EVOLVE-MS-2 (NCT03093324) was a 5-week, randomized study comparing GI tolerability of DRF vs DMF in patients with relapsing-remitting MS. Patients self-assessed severity of 5 key GI symptoms by completing IGISIS and Global GISIS (GGISIS) questionnaires. GGISIS assessed interference of GI symptoms on daily activities and missed work. The association between worst IGISIS score ≥2 and measures of treatment burden (worst interference with daily activities, missed work due to GI symptoms, and use of concomitant symptomatic medication to treat GI AEs) by treatment group was assessed using risk ratios (RR; DRF/DMF).

Results

Overall, 253 patients received DRF and 251 received DMF. Fewer DRF-treated patients reported any IGISIS score ≥2 (DRF, 43.1% [109/253]; DMF, 51.4% [128/249]). IGISIS score ≥2 detected moderate/severe GI AEs of IGISIS with 90% sensitivity and 59% specificity. Among patients reporting GI symptoms as “Quite a Bit” or “Extremely” interfering with daily activities (n=47) or missing ≥ 1 hour work due to GI symptoms (n=46) using GGISIS, 89.4% and 91.3% reported a worst IGISIS score ≥2, respectively. In patients with worst IGISIS score ≥2, DRF was associated with lower likelihood of GI symptoms interfering with daily activities “Quite a bit” or “Extremely” (RR 0.88; 95% CI 0.51–1.53), leading to missed work (RR 0.88; 95% CI 0.51–1.53), and resulting in concomitant symptomatic medication use for GI AEs (RR 0.57; 95% CI 0.32–1.00).

Conclusions

Fewer patients reported IGISIS score ≥2 with DRF vs DMF, and an IGISIS score ≥2 was sensitive for identifying moderate/severe GI AEs and clinically meaningful GI symptoms that could impact QoL from a patient perspective.

Supported by: Biogen