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

IntroductionDiroximel 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.MethodsGI 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.ResultsAs 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.ConclusionsWe 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 RegistrationClinicalTrials.gov number NCT02634307.FundingAlkermes Inc. (Waltham, MA, USA) and Biogen (Cambridge, MA, USA).Electronic supplementary materialThe online version of this article (10.1007/s12325-019-01085-3) contains supplementary material, which is available to authorized users.

Diroximel Fumarate Demonstrates an Improved Gastrointestinal Tolerability Profile Compared with Dimethyl Fumarate in Patients with Relapsing–Remitting Multiple Sclerosis: Results from the Randomized, Double-Blind, Phase III EVOLVE-MS-2 Study

“…AEs leading to DMF treatment discontinuation were GI AEs (n = 12, listed in table), depression (n = 1), and urticaria (n = 1) c One patient in the DMF arm reported an AE after the last study-dose date (post-treatment period, during the follow-up period) that led to discontinuation from the study. This patient is captured as having an AE leading to discontinuation from the study ( compared with DMF, owing to its distinct chemical structure [13]. The potential impact would likely be most evident in the upper GI tract, given that both DRF and DMF are formulated to be released from their capsules and microspheres upon traversing from the stomach into the small intestine; this region of the GI tract would be exposed to the highest concentrations of DRF and DMF, allowing for greater differentiation of their tolerability effects.…”

“…The distinct chemical structure of DRF is hypothesized to elicit less irritation in the GI tract than DMF through lower production of methanol (a GI-irritating promoiety), and less reactivity with pre-systemic off-target proteins or receptors [13]. Interim findings from the ongoing, multicenter, 2-year, prospective, single-arm, open-label DRF phase III EVOLVE-MS-1 study have demonstrated a low rate (~ 31%) of GI AEs when considered within the context of those reported in separate clinical trials and real-world effectiveness studies of DMF [9,10,14].…”

Dimethyl Fumarate and Its Esters: A Drug with Broad Clinical Utility?

“…Thereafter, the number of side effects reported by patients reduced significantly [ 62 ]. While flushing is associated with increased prostaglandin production through key MOA agonism of HCAR2, GI symptoms are the primary reason for treatment discontinuation [ 63 , 64 ] and attributable to the action of major metabolite methanol on small intestine mucosa [ 63 ]. Progress toward improved formulations/molecules to minimise GI-related side effects, whilst maintaining the efficacy of DMF have recently been made.…”

Diroximel fumarate (DRF) in patients with relapsing–remitting multiple sclerosis: Interim safety and efficacy results from the phase 3 EVOLVE-MS-1 study

“…DRF is hypothesized to Diroximel fumarate (DRF) in patients with relapsing-remitting multiple sclerosis: Interim safety and efficacy results from the phase 3 EVOLVE-MS-1 study produce less irritation and reactivity toward off-target receptors within the gastrointestinal (GI) tract than DMF, potentially leading to improved GI tolerability. 8 A secondary major metabolite of DRF hydrolysis is 2-hydroxyethyl succinimide (HES). HES has been studied extensively in preclinical, in vitro, and healthy volunteer studies.…”