Pregnancy Outcomes in Patients With Ulcerative Colitis, Crohn’s Disease, and Relapsing Multiple Sclerosis: Results From the Ozanimod Clinical Development Program
AIBD 2023
Background:
Ozanimod, an oral sphingosine 1-phosphate (S1P) receptor 1 and 5 modulator, is approved in multiple countries for the treatment of adults with moderately to severely active ulcerative colitis (UC) and relapsing multiple sclerosis (RMS) and is also being studied in Crohn’s disease (CD). S1P receptors are involved in vascular formation during embryogenesis, and prescribing information for S1P receptor modulators, including ozanimod, contain recommendations for effective contraception use and general statements about potential fetal risk based on data from preclinical studies. This analysis reviewed pregnancy outcomes during ozanimod use in the clinical development program in all studies in which patients with UC, CD, or RMS or healthy volunteers received ozanimod and assessed the risk of exposure in female partners of males administered ozanimod.
Methods:
Within studies in the ozanimod clinical development program, female patients of childbearing potential were required to use effective contraception while receiving ozanimod and for up to 3 months after discontinuing the drug; treatment discontinuation was required when pregnancy was confirmed. Pregnancy outcomes were assessed through November 19, 2022. Estimated exposure to ozanimod and its metabolites CC112273 and CC1084037 in female partners of males administered ozanimod was calculated using safety factor assumptions of semen concentrations being 10-fold higher than plasma maximal concentrations after 28 days of ozanimod 1.84 mg and 100% absorption through the vaginal epithelium.
Results:
In ozanimod clinical trials, 78 patient pregnancies occurred: 14 in those with UC, 6 in those with CD, 57 in those with RMS (58 outcomes due to twins), and 1 in a healthy volunteer. All patient pregnancy exposures to ozanimod occurred during the first trimester. Patients discontinued study medication promptly after pregnancy was confirmed, except for those who elected pregnancy termination and remained on study medication. The incidence of spontaneous abortion was 15%. The preterm birth rate was 10% of live births. Outcomes in patients with UC included 7 live births (no congenital abnormalities or premature births), 3 spontaneous early losses, and 4 elective terminations. Outcomes in patients with CD included 2 live births (no congenital abnormalities or premature births), 1 spontaneous early loss, 1 ongoing pregnancy, and 2 with no information. Outcomes in patients with RMS included 33 live births (1 with duplex kidney and 4 premature births), 8 spontaneous early losses (a twin pregnancy led to 1 early loss and 1 live birth), 10 elective terminations, 5 ongoing pregnancies, and 2 with no information. The outcome of the 1 healthy volunteer pregnancy was elective termination. The estimated exposure in female partners relative to male participants was 0.03% for ozanimod and 0.025% each for CC112273 and CC1084037.
Conclusions:
Pregnancy should be avoided in patients receiving ozanimod and for 3 months after discontinuing ozanimod. Clinical experience with ozanimod during pregnancy is limited. In this small cohort of patients, there has been no increased incidence of fetal abnormalities or adverse pregnancy outcomes seen with ozanimod exposure in early pregnancy. Estimated exposure to ozanimod and its metabolites in partners of patients administered ozanimod does not represent a clinically meaningful risk to partners or potential embryos.
