Long-term treatment with dimethyl fumarate (DMF) demonstrated a favorable benefit-risk profile in patients with relapsing remitting multiple sclerosis (RRMS) up to 13 years in the ENDORDSE trial, according to study results published in Multiple Sclerosis Journal.
Prior studies aimed at determining the safety and efficacy of DMF, including the phase III DEFINE and CONFIRM trials, and ENDORSE extension, have supported the safety and efficacy of DMF in patients with RRMS. The objective of the current study was to determine the benefit-risk profile of DMF up to 13 years in ENDORSE.
ENDORSE was an extension of DEFINE and CONFIRM trials, as patients randomized to DMF in one to the earlier studies continued the same treatment regimen, while those in the placebo or glatiramer aceteate group were re-randomized to DMF twice or thrice daily. All participants receiving DMF thrice daily switched to treatment given twice daily following the 2013 market authorization of DMF.
Of 2079 patients who completed DEFINE or CONFIRM trials, 1736 were enrolled in ENDORSE and the median total follow-up time from randomization in DEFINE/CONFIRM and ENDORSE was 8.76 years (2.04-12.98 years). Of these participants, 501 were continuously treated with DMF and 249 were initially treated with placebo followed by DMF.
Of the 501 patients continuously treated with DMF, 264 (53%) discontinued treatment, including 15 patients who discontinued treatment within 3 months of the study, and 249 who discontinued DMF after 3 months of the study. Of 249 patients who received placebo initially, followed by DMF, 148 patients discontinued treatment, including 33 patients who discontinued DMF within 3 months and 115 patients who discontinued treatment after 3 months of the study. Overall, 236 patients continuously treated with DMF and 100 patients who switched from placebo to DMF completed the study.
Most common adverse events (incidence ≥ 10% in any treatment group) included RRMS relapse (39%), nasopharyngitis (26%), urinary tract infection (21%), flushing (19%), upper respiratory tract infection (16%), and headache (16%). MS relapse was reported in 41% of patients continuously treated with DMF and in 37% of those who switched from placebo to DMF. Nasopharyngitis (29% vs. 22%, respectively), urinary tract infection (25% vs. 19%, respectively), upper respiratory tract infection (18% vs. 16%, respectively), headache (19% vs. 14%, respectively) were more common among patients continuously treated with DMF, compared to patients who switched from placebo to DMF.
Serious adverse events were reported in 551 patients (32%), with RRMS relapse reported in 238 patients (14%) and fall in 31 patients (2%).
When stratified by lymphocyte category, incidence of infection and malignancy was low, as incidence of opportunistic infection was <0.01 per patient-year among those with prolonged severe lymphopenia or mild lymphopenia, and incidence of serious infection was 0.01 in those with prolonged severe, moderate or mild lymphopenia and among those without lymphopenia. Incidence of malignancy was 0.01 per patient-year among those with prolonged severe or moderate lymphopenia and <0.01 among those with mild lymphopenia or without lymphopenia.
Overall annualized relapse rate was low among patients continuously treated with DMF (0.143, 95% CI, 0.120-0.169), while for with patients who switched from placebo to DMF, annualized relapse rate decreased from 0.330 (95% CI, 0.266-0.408) to 0.151 (95% CI, 0.118-0.194) after initiating DMF and remained low throughout.
At 10 years, 72% of patients continuously treated with DMF and 73% of those who switched from placebo to DMF had no 24-week confirmed disability worsening.
The study had several limitations, including the lack of a control group, selective dropout, and discontinuation secondary to adverse events. These findings are relevant for the population who remained on the study.
“Sustained DMF safety/efficacy was observed in patients followed up to 13 years, supporting DMF’s positive benefit/risk profile for long-term RRMS treatment,” concluded the researchers.
Disclosure: This research was supported by Biogen, Cambridge, MA, United States. Please see the original reference for a full list of disclosures
Gold R, Arnold DL, Bar-Or A, et al. Long-term safety and efficacy of dimethyl fumarate for up to 13 years in patients with relapsing-remitting multiple sclerosis: final ENDORSE study results. Mult Scler. Published online September 1, 2021. doi: 10.1177/13524585211037909