Efficacy and Safety Outcomes with Diroximel Fumarate After Switching from Prior Therapies or Continuing on DRF: Results from the Phase 3 EVOLVE-MS-1 Study

Abstract

Introduction: Diroximel fumarate (DRF) is an oral fumarate for relapsing multiple sclerosis (MS) with the same active metabolite as dimethyl fumarate (DMF). DRF has a safety/efficacy profile similar to DMF but with improved gastrointestinal (GI) tolerability and low (< 1%) treatment discontinuation due to GI adverse events (AEs). Efficacy and safety outcomes in patients who switched to DRF from other disease-modifying therapies (DMTs) have not been evaluated.

Methods: EVOLVE-MS-1 is an ongoing, 2-year, open-label, phase 3 study of DRF in adults with relapsing-remitting MS. Patients either entered as newly enrolled to DRF trials, or from the 5-week, randomized, head-to-head, phase 3 EVOLVE-MS-2 study of DRF and DMF. This analysis evaluated safety and GI tolerability in patients continuing on DRF (DRF-rollover) or switching from DMF (DMF-rollover) following EVOLVE-MS-2. Safety and efficacy were evaluated in a subset of newly enrolled patients who had received prior glatiramer acetate (GA; GA/DRF) or interferons (IFN; IFN/DRF) as their most recent DMT, prior to switching to DRF in EVOLVE-MS-1.

Results: As of September 1, 2020, 1057 patients were enrolled in EVOLVE-MS-1, including 166, 182, 239, and 225 patients in the GA/DRF, IFN/DRF, DRF-rollover, and DMF-rollover groups, respectively. Treatment discontinuation due to GI AEs was < 1% in all groups. GA/DRF and IFN/DRF patients experienced improvements from baseline in clinical and radiological efficacy outcomes, including significantly reduced annualized relapse rates. Rollover patients had low rates of new or recurrent GI AEs (DRF-rollover, 26.8%/4.2%; DMF-rollover, 27.1%/4.9%).

Conclusion: After 2 years of DRF exposure, patients with prior GA, IFN, or fumarate treatment had safety outcomes consistent with previous fumarate studies. Efficacy in patients with prior GA or IFN treatment was consistent with previous fumarate studies. The data suggest that transition to DRF from GA, IFN, or DMF is a reasonable treatment strategy, with low rates of discontinuation due to GI AEs.

Trial registration: ClinicalTrials.gov (NCT02634307). INFOGRAPHIC.

Keywords: Dimethyl fumarate; Diroximel fumarate; Efficacy; Glatiramer acetate; Interferon; Multiple sclerosis; Relapsing–remitting multiple sclerosis; Safety; Tolerability.

Fig. 1

Patient disposition. ^aIncludes pregnancy, physician decision, lack of efficacy, noncompliance with study drug, or other reason. Of the patients enrolled in EVOLVE-MS-1, only those who were previously treated with IFN or GA, or who rolled over from the completed EVOLVE-MS-2 study were included in this analysis. AE adverse event, DMF dimethyl fumarate, DRF diroximel fumarate, GA glatiramer acetate, IFN interferon

Fig. 2

Change in ALC over time. ^aPatients in the DRF-rollover and DMF-rollover groups received 5 weeks of DRF or DMF treatment before EVOLVE-MS-1 enrollment. ALC absolute lymphocyte count, DMF dimethyl fumarate, DRF diroximel fumarate, LLN lower limit of normal

Fig. 3

Adjusted ARR on DRF treatment compared with the 12 months before DRF or DMF initiation in GA/DRF and IFN/DRF treatment groups: adjusted ARR for protocol-defined relapses during the EVOLVE-MS-1 treatment period (up to 2 years of DRF treatment) compared with patient-reported relapses in the 12 months before DRF initiation in EVOLVE-MS-1. ARR annualized relapse rate, DRF diroximel fumarate, GA glatiramer acetate, IFN interferon

Fig. 4

Estimated proportion of patients with NEDA-3 after 1 or 2 years of DRF treatment in EVOLVE-MS-1. DRF diroximel fumarate, GA glatiramer acetate, IFN interferon, NEDA-3 no evidence of disease activity-3

Fig. 5

a Mean (SE) number of Gd⁺ lesions and b percentage of patients free from Gd⁺ lesions. DRF diroximel fumarate, GA glatiramer acetate, Gd⁺ gadolinium-enhancing, IFN interferon

Fig. 6

Mean (SE) PBVC from year 1 to year 2^a in EVOLVE-MS-1. ^aPBVC from baseline to year 1 is not reported to avoid confounding by pseudo-atrophy. ^bEstimated yearly brain volume loss in healthy adults [35]. DRF diroximel fumarate, GA glatiramer acetate, IFN interferon, PBVC percentage brain volume change