Safety and Tolerability of Delayed-Release Dimethyl Fumarate Administered as Add-On Therapy to Beta Interferons or Glatiramer Acetate in Relapsing-Remitting Multiple Sclerosis (RRMS) Patients (I7-2.003)

OBJECTIVE: Describe the safety and tolerability of delayed-release dimethyl fumarate (DMF) as add-on therapy to beta-interferons (IFNβ) or glatiramer acetate (GA) in RRMS patients in the Phase 2, open-label EXPLORE study. BACKGROUND: EXPLORE evaluated the safety of delayed-release DMF as add-on therapy in patients with disease activity on IFNβ or GA monotherapy. DESIGN/METHODS: Eligibility criteria included age 18-55 years, RRMS diagnosis (McDonald criteria), EDSS score 0-5.0, established therapy with the same dose of IFNβ or GA for 蠅12 months at enrollment, and 蠅1 relapse within 12 months prior to enrollment or gadolinium-enhancing lesion(s) on MRI within 6 weeks prior to enrollment. Patients continued on their prescribed MS therapy for 2 months (monotherapy period), then received delayed-release DMF 240mg three times daily (TID) in addition to their prescribed MS therapy for 6 months (add-on therapy period). RESULTS: 104 patients completed the monotherapy period and were dosed with delayed-release DMF/IFNβ (n=57) or delayed-release DMF/GA (n=47). During the add-on therapy period, in the delayed-release DMF/IFNβ and delayed-release DMF/GA groups, respectively, the overall incidence of AEs was 95% and 100%; the most common AEs were flushing (42% and 53%), diarrhea (32% and 15%), and abdominal pain (21% and 6%). Most AEs were mild or moderate in severity. There was no overall increased risk of infection. No malignancies were reported. At Week 24, mean percentage decrease of lymphocyte counts from baseline was 22% (delayed-release DMF/IFNβ) and 7% (delayed-release DMF/GA), compared with an 18% decrease at Week 24 in patients receiving delayed-release DMF TID in the Phase 3 studies. There was a transient increase in liver transaminases, but no case fulfilled Hy’s law for drug-induced liver injury. There were no deaths. CONCLUSIONS: The overall safety profile of delayed-release DMF in combination with IFNβ or GA was similar to the known safety profile of delayed-release DMF monotherapy. Study supported by: Biogen Idec, Inc. Disclosure: Dr. Viglietta has received personal compensation for activities with Biogen Idec as an employee. Dr. Vollmer has received personal compensation for activities with Cleveland Clinic, Novartis, Mandell Center for Multiple Sclerosis, Teva Neuroscience, Questcor Pharmaceuticals, Biogen Idec, Xenoport, University of Florida PeerView, and Krog & Partners. Dr. Vollmer has received research support from Biogen Idec, Teva Neuroscience, Genzyme Corp., Ono Pharmaceuticals, Elan Pharmaceuticals, Novartis, Avanir Pharmaceuticals, and Janssen Pharmaceutica. Dr. Zhang has received personal compensation for activities with Biogen Idec. Dr. Novas has received personal compensation for activities with Biogen Idec as am employee. Dr. Novas holds stock and/or stock options in Medtronic Inc. Dr. Sheikh has received personal compensation for activities with Biogen Idec as an employee. Dr. Sheikh holds stock and/or stock options in Biogen Idec which sponsored research in which Dr. Sheikh was involved as an investigator. Dr. Fox has received personal compensation for activities with Allozine, Avanir Pharmaceuticals, Biogen Idec, Novartis, Questcor, Teva Neuroscience, and Xenoport. Dr. Fox has received research support from Novartis.