Pregnancy Outcomes in Partners of Male Study Participants Treated with Teriflunomide

Background: Teriflunomide is a once-daily oral immunomodulator approved for treatment of relapsing–remitting multiple sclerosis. Embryo-fetal toxicity and teratogenicity occur when teriflunomide is administered to pregnant rats and rabbits, but not when treated male rats are bred to untreated females. Teriflunomide is present in seminal fluid, although the estimated plasma exposure in females from semen transfer from a male patient is expected to be ≥100 times lower than exposure following oral dosing of teriflunomide 14 mg. To date, there is no signal for teratogenicity in humans for teriflunomide or its parent compound, leflunomide (in patients with rheumatoid arthritis [RA]).

Objectives: To report pregnancy outcomes in partners of male study participants in the teriflunomide clinical program, with reference to preclinical genotoxicity studies.

Methods: Participants in teriflunomide studies were required to use effective contraception; despite this, pregnancies occurred in teriflunomide-exposed women and partners of male study participants. Pregnancy outcomes through October 2013 will be reported. Preclinical genotoxicity tests and tissue distribution studies were performed in support of the clinical program.

Results: Across teriflunomide clinical trials, 22 pregnancies were reported in partners of male study patients (teriflunomide, n=19; placebo, n=3). There were 18 live births; 16 to partners of patients who had been exposed to teriflunomide. Newborns were healthy and free from structural and functional abnormalities. Two induced abortions and one spontaneous abortion were reported in the teriflunomide group; one induced abortion was reported in the placebo group. No induced abortions were performed for defects or malformations. Additionally, there is no preclinical evidence that teriflunomide would directly damage DNA in vivo, as indicated by negative in vitro mutagenicity and in vivo clastogenicity assays. The drug was undetectable in rat sperm within 14 days following a single oral dose, suggesting it does not bind irreversibly to sperm.

Conclusions: Data from the clinical program have shown no teratogenic signal for teriflunomide. These outcomes are supported by preclinical data and are consistent with findings of over 2.5 million patient-years of post-marketing exposure to leflunomide in patients with RA. Additional information will be provided by prospective data from teriflunomide pregnancy registries.