Delayed−Release Dimethyl Fumarate and Pregnancy: Preclinical Studies and Pregnancy Outcomes Reported During the Clinical Development Program (S24.006)

OBJECTIVE: Present preclinical data from animal reproductive toxicology studies and the outcomes of pregnancies occuring during the delayed-release dimethyl fumarate (DMF) clinical development program. BACKGROUND: No formal studies of delayed-release DMF were conducted in pregnant women, but pregnancies have occurred during the clinical development program. DESIGN/METHODS: Reproductive and developmental toxicology was evaluated in rats and rabbits. Delayed-release DMF clinical studies included 2,665 MS patients, 320 psoriasis patients, 101 rheumatoid arthritis patients, and 338 healthy volunteers. Subjects were required to use reliable contraception and immediately discontinue drug in the event of pregnancy. Pregnancy outcomes as of January 2, 2013 (data cutoff) are reported in this abstract; outcomes as of January, 2014 will be presented. RESULTS: There was no evidence of impaired fertility in rats or teratogenicity in rats and rabbits given dimethyl fumarate at doses that caused reductions in maternal weight gain. As of January 2, 2013, 38 pregnancies in delayed-release DMF recipients (37 MS patients, 1 healthy volunteer) and 14 pregnancies in placebo recipients were reported in clinical studies. Information is pending for three delayed-release DMF recipients and one was lost to follow-up; hence, results for delayed-release DMF are reported for the 34 pregnancies with known outcomes. In patients exposed to delayed-release DMF, 22 live births (64.7%), 3 spontaneous abortions (8.8%), and 9 elective terminations (26.5%) were reported. In placebo recipients, 9 live births (64.3%), 3 spontaneous abortions (21.4%), and 2 elective terminations (14.3%) were reported. No fetal abnormalities were reported. The incidence of spontaneous abortion was consistent with the expected rate of early pregnancy loss in the general population (12-22%). CONCLUSIONS: Based on the available data, no increased risk of fetal abnormalities or adverse pregnancy outcomes associated with gestational exposure to delayed-release DMF during the first trimester has been observed. Further data will be collected through a pregnancy registry. Study supported by: Biogen Idec, Inc. Disclosure: Dr. Gold has received personal compensation in an editorial capacity for Bayer Pharmaceuticals Corp., Biogen Idec, Merck Serono, Novartis, and Teva Neuroscience. Dr. Gold has received personal compensation in an editorial capacity for Therapeutic Advances in Neurological Disorders. Dr. Gold has received research support from Bayer Pharmaceutical Corp., Biogen Idec, Merck Serono, Novartis, and Teva Neuroscience. Dr. Phillips has received personal compensation for activities with Acorda Therapeutics, Biogen Idec, Genzyme Corp., Novartis, Teva Neuroscience, and Xenoport. Dr. Phillips has received research support from Roch Diagnostics Corp. Dr. Havrdova has received personal compensation for activities with Bayer Pharmaceuticals Corp., Biogen Idec, Genzyme Corp., Novartis, Serono Inc., and Teva Neuroscience. Dr. Havrdova has received research support from the Czech Ministries of Education and Health. Dr. Bar-Or has received personal compensation for activities with Amplimmune, Aventis, Bayhill Therapeutics, Berlex/Bayer, Biogen Idec, BioMS, Diogenix, Eli Lilly & Company, EMD Serono, Genentech, Inc., Genzyme, GlaxoSmithKline, Inc., Guthy-Jackson/GGF, Medimmune, Mitsubishi Pharma, Novartis, Ono Pharma, Receptos, Roche, Sanofi-Aventis Pharmaceuticals, Inc., Teva Neuroscience, and Wyeth Pharmaceuticals. Dr. Bar-Or has received research support from Amplimmune, EMD Serono, and Novartis. Dr. Kappos has received personal compensation for activities with the University Hospital Basel. Dr. Kappos has received research support from the Swiss MS Society, Swiss National Research Foundation, the European Union, Gianni Rubatto Foundation, Novartis, and Roche Diagnostics Corp. Dr. Clarke has received personal compensation for activities with Biogen Idec as an employee. Dr. Yuan has received personal compensation for activities with Biogen Idec as an employee. 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. Li has received personal compensation for activities with Biogen Idec. Dr. Sweetser has received personal compensation for activities with Biogen Idec as an employee. Dr. Kurukulasuriya has received personal compensation for activities with Biogen Idec as an employee. Dr. Viglietta has received personal compensation for activities with Biogen Idec as an employee. 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.