Long-term follow-up of the safety of delayed-release dimethyl fumarate in RRMS: interim results from the ENDORSE extension study
ECTRIMS Online Library. Pozzilli C. 10/11/14; 63773; P066
Dr. Carlo Pozzilli
Dr. Carlo Pozzilli
Background: The efficacy and safety of oral delayed-release dimethyl fumarate (DMF) was demonstrated in patients with relapsing?remitting multiple sclerosis (RRMS) in the Phase 3 DEFINE and CONFIRM studies. ENDORSE is an ongoing, 5­-year, dose-blind extension study evaluating long-term safety and efficacy.
Objectives: To report safety outcomes from ENDORSE, investigating the longer-term effects of delayed-release DMF.
Methods: Patients randomized to delayed-release DMF 240 mg twice (BID) or three times daily (TID) in DEFINE/CONFIRM continued on the same dosage in ENDORSE. Patients randomized to placebo (PBO; DEFINE/CONFIRM) or glatiramer acetate (GA; CONFIRM) were re­-randomized 1:1 to delayed-release DMF 240 mg BID or TID. Adverse events (AEs) were analyzed according to treatment arm in the parent/extension study: BID/BID, TID/TID, PBO/BID, PBO/TID, GA/BID, and GA/TID.
Results: As of the June 12, 2013 data cut, mean follow-up in each group in the safety population was as follows: BID/BID (n=501), 30.9 mo; TID/TID (n=501), 30.5 mo; PBO/BID (n=249), 27.9 mo; PBO/TID (n=248), 26.7 mo; GA/BID (n=118), 25.5 mo; and GA/TID (n=119), 23.3 mo. A total of 445 patients (435 continuers) had been exposed to delayed-release DMF BID, and 427 patients (416 continuers) had been exposed to delayed-release DMF TID cumulatively for at least 4 years in DEFINE/CONFIRM and ENDORSE. Overall incidence of AEs in each group was as follows: BID/BID, 89%; TID/TID, 90%; PBO/BID, 93%; PBO/TID, 90%; GA/BID, 86%; and GA/TID, 84%. Incidence of serious AEs by group was: BID/BID, 18%; TID/TID, 19%; PBO/BID, 22%; PBO/TID, 15%; GA/BID, 13%; and GA/TID, 18%. The incidence of discontinuations due to AEs was 4%-6% and 14%-23% in patients continuing and new to delayed-release DMF, respectively. The incidence of serious infections was ?3% in all treatment groups, with no confirmed opportunistic infections. There were no new findings in hematologic outcomes compared with DEFINE/CONFIRM. Hepatic AEs occurred in ?3% of patients in any treatment group; there was no evidence of increased risk of renal or urinary events. There were 20 malignancies in 19 patients (11 continuing treatment and eight new to delayed-release DMF). There were four deaths, none of which were considered related to study drug. Updated safety data with longer-term follow-up will be presented.
Conclusions: Sustained treatment with delayed-release DMF continues to demonstrate an acceptable safety profile with no new or worsening safety signals in patients with RRMS.

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