Fetal Exposure with Ponesimod Treatment across Clinical Development Studies

Background: Multiple sclerosis (MS) is 3 times more common in women and typically diagnosed between the ages of 20-50, a time of childbearing potential, with limited data for the class of S1P receptor modulators in pregnant women. Outcomes of pregnancies that occurred in the ponesimod (PON) clinical development program, despite clinical study protocols requiring a negative pregnancy test at enrollment and use of reliable contraception by women of childbearing potential in all studies are reported.

Objectives: The primary objective was to assess the risk of reproductive and embryofetal toxicity in women exposed to PON during pregnancy in the PON clinical development program.

Methods: Pregnancy outcomes were evaluated in women exposed to PON during pregnancy across all phase 2 and 3 studies including long-term safety extensions.

Results: Across all studies, including 1062 women, 20 pregnancies with fetal exposure to PON, all during the first trimester, were reported as of September 2021. Nineteen pregnancies were reported in patients with MS [n=990] receiving PON 20 mg (17) or other doses (2). Of the 20 pregnancies, outcomes were reported in 18 pregnancies: 6 normal newborns, 8 induced abortions (no indication of fetal toxicity in 5 cases, benign hydatidiform mole in 1 case and unknown in 2 cases), and 4 spontaneous abortions; outcomes were not reported in 2 pregnancies (pregnancy ongoing [1], lost to follow up [1]). Among the 12 cases of abortion, the presence of fetal abnormalities was reported as unknown in 11 cases (the 1 remaining case was a benign hydatidiform mole). All pregnancy cases were assessed by the investigator as not related to study treatment, except for 1 case of benign hydatidiform mole and 1 case of spontaneous abortion.

Conclusions: The proportion of spontaneous abortions in patients with MS (3/19, 15.8%) was within range of that reported for the general population (14.2%-20.9%) and within the range reported for the unexposed MS population (4.3%-21.1%). Based on the limited clinical data, there is no evidence of teratogenicity with PON treatment. Recognizing the importance of collecting more information on pregnancy exposure, a multinational Pregnancy Outcomes Enhanced Monitoring program (POEM) has been established in order to record prospective data on pregnancy outcomes in women exposed to PON. Women of childbearing potential should use effective contraception to avoid pregnancy during PON treatment and for 1 week after discontinuation.