Improving the Gastrointestinal Tolerability of Fumaric Acid Esters: Early Findings on Gastrointestinal Events with Diroximel Fumarate in Patients with Relapsing-Remitting Multiple Sclerosis from the Phase 3, Open-Label EVOLVE-MS-1 Study

Abstract

Introduction: Diroximel fumarate (DRF) is a novel oral fumarate in development for patients with relapsing forms of multiple sclerosis (MS). Clinical findings from the DRF development program suggest that rates of gastrointestinal (GI) treatment-emergent adverse events (TEAEs) and discontinuation due to GI TEAEs are low, based on clinical and real-world observations of other fumaric acid esters, including dimethyl fumarate (DMF). The incidence of GI TEAEs varies from 40 to 88% in clinical and real-world studies of DMF. The objective of this study is to present GI tolerability findings from the EVOLVE-MS-1 study and present biologic hypotheses for the improved GI properties of DRF.

Methods: GI TEAEs and treatment discontinuation because of GI TEAEs were assessed in DRF-treated patients with relapsing-remitting MS who were participating in the ongoing, 96-week, open-label, phase 3 EVOLVE-MS-1 study.

Results: As of March 30, 2018, a total of 696 patients were enrolled in EVOLVE-MS-1. GI TEAEs were reported in 30.9% (215/696) of patients; the vast majority (96%; 207/215) experienced events that were mild or moderate in severity. When GI AEs did occur, they occurred early in treatment, resolved (88.8%; 191/215), and were of short duration [median 7.5 (range 1-87) days] in most patients. GI TEAEs led to < 1% of patients discontinuing treatment.

Conclusions: We suggest that the distinct chemical structure of DRF contributes to the observed low rates of GI TEAEs and GI-associated treatment discontinuations, possibly due to a combination of several factors. We hypothesize that these factors may include less reactivity with off-target proteins and/or lower production of a methanol leaving group that may contribute to GI irritation. A direct comparison of GI tolerability with DRF versus DMF is being evaluated in the EVOLVE-MS-2 study.

Trial registration: ClinicalTrials.gov number NCT02634307.

Funding: Alkermes Inc. (Waltham, MA, USA) and Biogen (Cambridge, MA, USA).

Keywords: Dimethyl fumarate; Diroximel fumarate; Fumaric acid ester; Gastrointestinal; Multiple sclerosis; Neurology; Relapsing-remitting multiple sclerosis; Tolerability.

Fig. 1

Fumaric acid ester metabolism. a Upon oral administration, DMF undergoes esterase cleavage before systemic circulation to produce the major metabolites MMF and methanol. b DRF undergoes esterase cleavage to produce the major metabolites MMF and HES and the minor metabolites RDC-8439 and methanol. DMF dimethyl fumarate, DRF diroximel fumarate, HES 2-hydroxyethyl succinimide, MMF monomethyl fumarate

Fig. 2

GI TEAEs occurred early in treatment. Incidence of all GI TEAEs, diarrhea, nausea, and vomiting were reported by time interval. Patients with multiple events in a time interval were counted only once for that interval. Patients who experienced events in multiple time intervals were counted with each interval. DRF diroximel fumarate, GI gastrointestinal, TEAE treatment-emergent adverse event

Fig. 3

Median duration of overall and individual GI TEAEs that resolved in the overall population. Events occurring in ≥ 5 patients were included. GI gastrointestinal, TEAE treatment-emergent adverse event

Fig. 4

Hypotheses for enhanced GI tolerability of DRF. Diester fumarates, such as DMF and DRF, are small-molecular-weight drugs capable of modifying the function of several proteins. These interactions can be considered on target when contributing to the efficacy of the drug and off target when contributing to the unwanted side effects, such as GI events. a DMF hydrolyzes to MMF and methanol (a known GI irritant). This localized methanol production within the GI tract may contribute to DMF GI tolerability issues. In contrast, DRF mainly hydrolyzes to HES (a biologically inert metabolite) and MMF. b DRF is a larger molecule than DMF; therefore, DRF may not fit into as many protein-binding pockets as DMF because of steric clashes between DRF and off-target proteins. c DRF could be less electrophilic; therefore, DRF may not react with certain off-target proteins compared with DMF. d The rate of hydrolysis to MMF may be slightly faster for DRF compared with DMF, thereby lowering the amount of DRF exposure to the GI tract and causing less covalent binding to off-target proteins compared with DMF. DMF dimethyl fumarate, DRF diroximel fumarate, GI gastrointestinal, HES 2-hydroxyethyl succinimide, MMF monomethyl fumarate