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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.

Authors
  • Palte, Michael J1
  • Wehr, Angela2
  • Tawa, Mark2
  • Perkin, Kristopher3
  • Leigh-Pemberton, Richard2
  • Hanna, Jerome4
  • Miller, Catherine5
  • Penner, Natasha5
  • 1 Biogen, 225 Binney St, Cambridge, MA, USA. [email protected]
  • 2 Alkermes Inc., Waltham, MA, USA.
  • 3 Alkermes Pharma Ireland Limited, Dublin, Ireland. , (Ireland)
  • 4 Biogen, Maidenhead, UK.
  • 5 Biogen, 225 Binney St, Cambridge, MA, USA.
Type
Published Article
Journal
Advances in therapy
Publication Date
Nov 01, 2019
Volume
36
Issue
11
Pages
3154–3165
Identifiers
DOI: 10.1007/s12325-019-01085-3
PMID: 31538304
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

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. 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. 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. 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. ClinicalTrials.gov number NCT02634307. Alkermes Inc. (Waltham, MA, USA) and Biogen (Cambridge, MA, USA).

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