Background

Diroximel fumarate (DRF) is a novel oral fumarate for relapsing forms of multiple sclerosis (MS). DRF is converted to monomethyl fumarate (MMF), the same pharmacologically active metabolite as dimethyl fumarate (DMF). Oral administration of DRF 462mg and DMF 240mg produce bioequivalent MMF exposure and are therefore expected to exhibit comparable efficacy and safety profiles. DRF has an improved gastrointestinal (GI) tolerability profile compared to DMF.

Objectives

To report interim safety, tolerability, and efficacy outcomes in DRF-treated patients from EVOLVE-MS-1 and to assess GI tolerability in a subgroup of patients who received DMF prior to DRF.

Methods

EVOLVE-MS-1 (NCT02634307) is an ongoing, open-label, 96-week study assessing DRF safety, tolerability, and efficacy in adults with relapsing-remitting MS. Patients entered the study either as newly enrolled in the DRF clinical development program or after completing EVOLVE-MS-2 (NCT03093324), a randomized, blinded, phase 3 study in which patients received DRF or DMF over 5 weeks.

Results

As of 2 July 2019, 1051 patients were enrolled, 458 of whom had completed EVOLVE-MS-2. Median DRF exposure was 1.5 (range 0.0-1.9) years. Overall, 44.2% of patients completed the study and 17.3% discontinued treatment; 6.3% discontinued due to AEs and 0.7% due to GI AEs. AEs occurred in 82.1% (863/1051) of patients; 90% (779/863) were mild or moderate in severity. Incidence of GI AEs was 28.4% (299/1051) in the overall population, 21.7% (51/235) in patients with prior DRF treatment, and 21.5% (48/223) in patients with prior DMF treatment. Patients who had experienced GI AEs in EVOLVE-MS-2 (DRF to DRF, 33.6% [79/235]; DMF to DRF, 44.8% [100/223]) had low rates of recurrence (3.4% [8/235] and 3.6% [8/223] for those previously treated with DRF and DMF, respectively) and/or onset of new GI AEs (19.6% [46/235] and 20.6% [46/223], respectively) in EVOLVE-MS-1, regardless of prior treatment group. In the overall population (n=1051), annualized relapse rate was 0.14, and 86.1% of patients were relapse-free. Outcomes in patients who were newly diagnosed or most recently switched from interferon or glatiramer acetate will be presented.

Conclusions

Safety and efficacy results from the ongoing EVOLVE-MS-1 study were consistent with previous findings of DRF and the known benefit-risk profile for DMF. In patients who switched from DMF to DRF, no worsening of tolerability was observed.

Supported by: Biogen

Background

FLUENT investigated immune cell subset changes in the innate and adaptive immune systems during fingolimod therapy, and their associations with efficacy and safety outcomes.

Objectives

To report changes in immune cell profile, efficacy and safety of fingolimod 0.5 mg/day in adults with relapsing multiple sclerosis (RMS).

Methods

In FLUENT (NCT03257358), a prospective, 12 month, phase 4, multicenter, nonrandomized, open-label study, patients were stratified as fingolimod naive (Cohort 1) or previously treated with fingolimod 0.5 mg/day continuously for ≥2 years (Cohort 2). Primary outcome was change from Baseline to Month 12 in immune cell subsets. Secondary outcomes included Patient Determined Disease Steps (PDDS), anti-John Cunningham virus (anti-JCV) antibody status, serum neurofilament light chain (NfL) concentration, and adverse events (AEs) incidence. Data were analyzed from all patients completing Month 12 follow-up.

Results

165 patients enrolled in Cohort 1; 217 in Cohort 2. Proportionally more patients in Cohort 1 than Cohort 2 relapsed in the year before baseline. At Baseline, patients in Cohort 1 had proportionally more naive and central memory CD4+ and CD8+ T cells and memory B cells, and proportionally fewer effector memory CD4+ and CD8+ T cells and regulatory B cells, than those in Cohort 2. At Month 12, between-cohort differences in the proportions of these lymphocyte types/subtypes were much reduced or negligible. Levels were essentially unchanged in Cohort 2, indicating reductions in naive T cells and increases in effector memory T cells and regulatory B cells in Cohort 1. Mean baseline PDDS scores were low (Cohort 1, 1.7; Cohort 2, 1.8), and changed little by Month 12. Median change from Baseline in anti-JCV antibody index was small in both cohorts. Proportions of patients with positive JCV serology remained stable at Month 12 (61% and 67% in Cohorts 1 and 2 vs 57% and 65% at Baseline). Mean serum NfL level was higher in Cohort 1 than Cohort 2 at Baseline (12.2 vs 9.6 pg/mL); levels were similar at Month 12 (8.7 vs 9.8 pg/mL), having reduced substantially in Cohort 1. Proportionally more patients in Cohort 1 than in Cohort 2 had treatment-emergent AEs (54.6% vs 44.2%), and discontinued study treatment (12.3% vs 5.5%); 5.5% of patients in each cohort reported serious AEs.

Conclusions

These data expand our knowledge of changes in immune cell profiles over time in patients with RMS treated with fingolimod in the short or long term.