Delayed-release dimethyl fumarate and pregnancy: preclinical studies and pregnancy outcomes from clinical trials and postmarketing experience
Author(s): ,
J. Li
Affiliations:
Biogen, Inc., Cambridge, MA
,
R.J. Fox
Affiliations:
Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic, Cleveland, OH
,
J.T. Phillips
Affiliations:
Multiple Sclerosis Program, Baylor Institute for Immunology Research, Dallas, TX, United States
,
E. Havrdova
Affiliations:
First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic
,
A. Bar-Or
Affiliations:
Montreal Neurological Institute, McGill University, Montreal, QC, Canada
,
L. Kappos
Affiliations:
University Hospital Basel, Basel, Switzerland
,
N. Kim
Affiliations:
Biogen, Inc., Cambridge, MA
,
P. Valencia
Affiliations:
Biogen, Inc., Cambridge, MA
,
L. Oliva
Affiliations:
Biogen, Inc., Cambridge, MA
,
M. Novas
Affiliations:
Biogen, Inc., Cambridge, MA
,
R. Gold
Affiliations:
St. Josef Hospital, Ruhr University, Bochum, Germany
J. Rana
Affiliations:
Biogen, Inc., Cambridge, MA
ECTRIMS Online Library. Li J. 10/08/15; 115441; 367
Jie Li
Jie Li
Contributions
Abstract
Abstract: P608

Type: Poster

Abstract Category: Risk management for disease modifying treatments

Background: Delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) demonstrated efficacy and an acceptable safety profile in relapsing-remitting multiple sclerosis (RRMS) in clinical studies. As women of childbearing age comprise a large proportion of the MS population, it is important to evaluate effects of DMF exposure on pregnancy.

Objectives: We report preclinical data from animal reproductive toxicology studies and the outcomes of pregnancies occurring during the DMF clinical development program, as well as postmarketing experience.

Methods: Reproductive and developmental toxicology was evaluated in rats and rabbits. As of 26 March 2014, clinical studies included 2,898 MS patients, 320 psoriasis patients, 101 rheumatoid arthritis patients, and 813 healthy volunteers; subjects were required to use reliable contraception and immediately discontinue drug in the event of pregnancy. Outcomes as of June 30, 2014 are reported for pregnancies in clinical trials and postmarketing experience.

Results: There was no evidence of impaired fertility in rats or teratogenicity in rats and rabbits given DMF. As of 30 June 2014, a total of 63 pregnancies were reported in clinical studies, including 45 in subjects exposed to DMF, 13 in subjects exposed to placebo, and four in subjects exposed to glatiramer acetate. Pregnancy outcomes are known for 40 of 45 pregnancies in subjects receiving DMF: 27 live births (60%), 3 spontaneous abortions (7%), and 10 elective terminations (22%). Information is pending for 4 subjects and 1 was lost to follow-up. The incidence of spontaneous abortion was consistent with the expected rate of early pregnancy loss in the general population (12-22%). A total of 135 pregnancies were reported in the postmarketing setting (104 spontaneous reports and 31 solicited reports); pregnancy is ongoing in 103 cases. There were 10 live births, 13 spontaneous abortions, and 5 elective terminations; 2 patients were lost to follow-up. There was one reported foetal abnormality (not considered associated with DMF). Outcomes continue to be monitored through spontaneous reports in the postmarketing setting and a pregnancy registry; updated data will be presented.

Conclusions: Based on available evidence with known gestational exposure limited to the first trimester, DMF was not associated with increased risk of foetal abnormalities or adverse pregnancy outcomes. The overall benefit-risk of DMF remains favourable.

Disclosure: This study was funded by Biogen, Inc.

Jie Li: Employee of and holds stock/stock options in Biogen.

Robert J. Fox: Consultant fees from Actelion, Biogen, MedDay, Novartis, Questcor, Teva, and Xenoport; served on advisory committees for Actelion, Biogen, and Novartis; research grant funding from Novartis.

J. Theodore Phillips: Consulting fees from Acorda, Biogen, Genzyme, Merck Serono, and Sanofi; research support from Roche.

Eva Havrdova: Honoraria from Bayer, Biogen, Genzyme, GlaxoSmithKline, Merck Serono, Novartis, Sanofi, and Teva; research support from Biogen; supported by PRVOUK-P26/LF1/4, program of Ministry of Education, Czech Republic.

Amit Bar-Or: Honoraria and/or research support from Amplimmune, Aventis, Bayhill Therapeutics, Berlex, Biogen, Diogenix, Eli-Lilly, EMD Serono, Genentech, GlaxoSmithKline, Medimmune, Novartis, Ono Pharma, Receptos, Roche, Sanofi Genzyme, and Teva Neuroscience.

Ludwig Kappos: Institution (University Hospital Basel) received and used exclusively for research support: steering committee, advisory board and consultancy fees from Actelion, Addex, Bayer Health Care, Biogen, Biotica, Genzyme, Lilly, Merck, Mitsubishi, Novartis, Ono Pharma, Pfizer, Receptos, Sanofi-Aventis, Santhera, Siemens, Teva, UCB, Xenoport; speaker fees from Bayer Health Care, Biogen, Merck, Novartis, Sanofi-Aventis, Teva; support of educational activities from Bayer Health Care, Biogen, CSL Behring, Genzyme, Merck, Novartis, Sanofi, Teva; royalties from Neurostatus Systems GmbH; grants from Bayer Health Care, Biogen, Merck, Novartis, Roche, Swiss MS Society, the Swiss National Research Foundation, the European Union, and Roche Research Foundations.

Norman Kim: Employee of and holds stock/stock options in Biogen.

Patricia Valencia: Employee of and holds stock/stock options in Biogen.

Lauren Oliva: Employee of and holds stock/stock options in Biogen.

Mark Novas: Employee of and holds stock/stock options in Biogen.

Ralf Gold: Honoraria from Bayer HealthCare, Biogen, Merck Serono, Novartis, and Teva Neuroscience; research support from Bayer HealthCare, Biogen, Merck Serono, Novartis, and Teva Neuroscience; compensation from Sage for serving as editor of Therapeutic Advances in Neurological Disorders.

Jitesh Rana: Employee of and holds stock/stock options in Biogen.

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