72-Week Safety and Tolerability of Dimethyl Fumarate in Japanese Patients with Relapsing-remitting Multiple Sclerosis: Analysis of the Randomised, Double Blind, Placebo-Controlled, Phase III APEX Study and its Open-Label Extension

Abstract

IntroductionThe long-term safety of dimethyl fumarate (DMF) in patients with relapsing-remitting multiple sclerosis (RRMS) has been studied in mainly Caucasian patients. The present interim analysis aimed to evaluate the 72-week safety of DMF in Japanese patients with RRMS.MethodsSafety data of Japanese subjects enrolled in the 24-week randomised, double-blind, placebo-controlled APEX study (Part I) and its following open-label extension (Part II) were analysed at 72 weeks from the beginning of Part I. In Part I, subjects were randomised to DMF treatment or matching placebo while all subjects received DMF treatment during Part II. Adverse events (AEs) reported throughout the study period were recorded.ResultsOverall, 109 Japanese subjects completed 72 weeks of treatment. The incidence of AEs and serious AEs was 95% and 19%, respectively, in the DMF group compared with 84% and 18%, respectively, in the placebo group at 24 weeks. Common AEs (at least 5%) reported with treatment included nasopharyngitis, flushing, hot flush, gastrointestinal events, pruritus, rash, headache, increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST). AEs led to discontinuation of DMF in 5% of patients and included MS relapse, flushing, abdominal pain, liver disorder and increased ALT/AST. After an initial decrease from baseline of 17% in the DMF group at week 24, the mean lymphocyte counts stabilised and were maintained until week 72. No opportunistic/serious infections nor malignancies were reported with DMF treatment. The incidences of AEs, serious AEs, and discontinuation due to AEs were similar between the DMF and the placebo groups.ConclusionThe 72-week safety profile of DMF in Japanese patients with RRMS was consistent with previous studies that enrolled mostly Caucasian patients, with a lower incidence of flushing and related symptoms and a lower reduction in the lymphocyte count compared with previous reports.Trial RegistrationClinicalTrials.gov identifier NCT01838668.FundingBiogen Japan Ltd.Electronic supplementary materialThe online version of this article (10.1007/s12325-018-0788-8) contains supplementary material, which is available to authorized users.

Antioxidant and Anti-inflammatory Effect of Nrf2 Inducer Dimethyl Fumarate in Neurodegenerative Diseases

“…Moreover, DMF is considered a molecule with a secure profile as demonstrated by many studies performed by Gold et al [ 135 ] and Ochi et al [ 136 ]. Considering all of its properties, we are convinced that DMF offer enormous growth potential as a future therapeutic agent for the treatment of NDs (or in association with the general treatment of NDs), which could assist in alleviating symptoms and improving the quality of life of patients.…”

Efficacy of dimethyl fumarate in Japanese multiple sclerosis patients: interim analysis of randomized, double-blind APEX study and its open-label extension

“…The results on the safety and tolerability of DMF in Japanese patients with RRMS from the 72-week APEX study have already been published. 18 Overall, treatment was well tolerated, with a lower incidence of flushing and related symptoms and lower decrease in lymphocyte counts compared with previous studies of DMF that mainly enrolled Caucasian patients. 18 This sub-analysis aimed to evaluate the efficacy of DMF in Japanese patients with RRMS enrolled in the APEX study.…”

Current Landscape of NRF2 Biomarkers in Clinical Trials

“…Such action likely precludes the use of DMF in any disease prevention settings. A summary of clinical trials utilizing fumaric acid esters, all of which include DMF, is listed in Table S1 [ 15 , 16 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 ].…”