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

Introduction: The 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.

Methods: Safety 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.

Results: Overall, 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.

Conclusion: The 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 registration: ClinicalTrials.gov identifier NCT01838668.

Funding: Biogen Japan Ltd.

Keywords: APEX; Dimethyl fumarate; Japanese; Phase 3; Relapsing-remitting multiple sclerosis; Safety.

Figures

Fig. 1

a Incidence of gastrointestinal events that occurred in patients receiving dimethyl fumarate during Part I. b Incidence of flushing and related events that occurred in subjects receiving dimethyl fumarate during Part I. Data labels indicate the number of patients

Fig. 2

a Mean lymphocyte count during Part I and Part II. b Mean eosinophil count during Part I and Part II. c Mean alanine aminotransferase during Part I and Part II. d Mean aspartate aminotransferase during Part I and Part II. ALT alanine aminotransferase, AST aspartate aminotransferase, DMF dimethyl fumarate, PBO placebo, SD standard deviation

Fig. 2

a Mean lymphocyte count during Part I and Part II. b Mean eosinophil count during Part I and Part II. c Mean alanine aminotransferase during Part I and Part II. d Mean aspartate aminotransferase during Part I and Part II. ALT alanine aminotransferase, AST aspartate aminotransferase, DMF dimethyl fumarate, PBO placebo, SD standard deviation

Fig. 3

a Baseline lymphocyte count by CTCAE grade. Data labels indicate the number of subjects. b Worst post-baseline lymphocyte count by CTCAE grade. Data labels indicate the number of subjects. CTCAE common terminology criteria for adverse events, DMF dimethyl fumarate, PBO placebo, LLN lower limit of normal. Categories by lymphocyte counts (×109 cells/L): 0: LLN (0.91); 1: < LLN to 0.8; 2: < 0.8 to 0.5; 3: < 0.5 to 0.2; 4: < 0.2