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.
Adv Ther
; 36(11): 3154-3165, 2019 11.
Article
in En
| MEDLINE
| ID: mdl-31538304
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).Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Multiple Sclerosis, Relapsing-Remitting
/
Drug-Related Side Effects and Adverse Reactions
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Dimethyl Fumarate
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Fumarates
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Gastrointestinal Diseases
/
Immunosuppressive Agents
Type of study:
Diagnostic_studies
Limits:
Adult
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Female
/
Humans
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Male
/
Middle aged
Language:
En
Journal:
Adv Ther
Journal subject:
TERAPEUTICA
Year:
2019
Document type:
Article
Affiliation country: