Diroximel Fumarate in Patients with Relapsing-Remitting Multiple Sclerosis: NEDA-3 after Re-baselining in the Phase 3 EVOLVE-MS-1 Study
James Bowen1, Jessica Stulc2, Samuel Hunter3, Ariel Antezana4, Hailu Chen5, James Lewin5, Matthew Scaramozza5, Ivan Bozin5, Florian Then Bergh6
1Swedish Neuroscience Institute, 2Minneapolis Clinic of Neurology, 3Advanced Neurosciences Institute, 4Neuromedical Clinic of Central Louisiana, 5Biogen Inc., 6University of Leipzig, Klinik u. Poliklinik fuer Neurologie
Objective:
To assess No Evidence of Disease Activity (NEDA) in patients on diroximel fumarate (DRF).
Background:
NEDA, a composite endpoint of clinical and MRI outcomes, is increasingly evaluated in multiple sclerosis (MS) studies. However, carry-over disease activity, before achieving the full effect of a disease-modifying therapy, may confound NEDA outcomes. Previous analyses with DRF and dimethyl fumarate (DMF), oral fumarates for relapsing MS, showed significant reductions in MRI activity as early as 7 weeks after initiation.
Design/Methods:
Patients with relapsing-remitting MS (aged 18-65 years) completing EVOLVE-MS-2 (NCT03093324), a randomized, blinded, 5-week, phase 3 study of DRF or DMF could continue into EVOLVE-MS-1 (NCT02634307), an open-label, 96-week study assessing DRF safety, tolerability, and efficacy. Relapses, Expanded Disability Status Scale scores, and MRI parameters were assessed during screening or on Day 1 of each study (~7 weeks apart). In this analysis, patients who had received DRF in both studies were re-baselined after ~7 weeks’ DRF treatment, and NEDA-3 was assessed over 96 weeks.
Results:
Overall, 239 patients received DRF in EVOLVE-MS-2 and entered EVOLVE-MS-1. Mean (standard deviation) age was 44.0 (11.0) years; 69.0% (n=165) were female. Over 96 weeks, the estimated proportion of patients who achieved NEDA-3 was 50.2%. Most patients (84.1%) were relapse-free on DRF over 96 weeks. An estimated 92.4% of patients were free of 24-week confirmed disability progression; 90.2% had no gadolinium-enhancing lesions; and 79.2% were free of new/newly-enlarging T2 lesions during the full study. Treatment-emergent adverse events occurred in 212 (88.7%) patients; 23 (9.6%) patients discontinued DRF due to adverse events.
Conclusions:
At Week 96, 50.2% of patients on DRF achieved NEDA-3 after re-baselining. Safety outcomes were consistent with those previously reported for EVOLVE-MS-1; discontinuations due to adverse events were low. Re-baselining may be useful for assessing DRF efficacy by mitigating the influence of disease activity prior to the onset of efficacy.