EBOPIPRANT (OBE022)

To date, preterm labor (PTL) is a condition for which only treatments with limited efficacy or restrictive safety issues are available. This includes the off-label use of tocolytics, which have a limited efficacy in suppressing uterine contractions and delaying birth.

Ebopiprant (OBE022) is a potential first-in-class, novel, orally-active prostaglandin F_2α (PGF_2α) receptor antagonist designed to control preterm labour by reducing inflammation and uterine contractions as well as  preventing cervical changes and fetal membrane rupture without causing the potentially serious vasoconstriction in the foetus (e.g. premature closure of the ductus arteriosus and/or renal impairment) seen with non-specific prostaglandin synthesis inhibitors such as indomethacin.

The PROLONG study is the first clinical Phase 2 proof-of-concept trial of ebopiprant in pregnant women with threatened spontaneous PTL. The study was conducted in two parts.

PROLONG Part A was an open-label single arm trial of ebopiprant administered orally for 7 days to pregnant women with nine subjects enrolled. Ebopiprant was well tolerated by the mothers and their fetuses and the pharmacokinetics of ebopiprant were similar to those previously observed in non-pregnant women.

PROLONG Part B was a randomized, double-blind, placebo-controlled, parallel-group trial to assess the efficacy, safety and pharmacokinetics of ebopiprant. Subjects were pregnant women presenting with spontaneous threatened preterm labor between gestational ages of 24 to 34 weeks. Furthermore, they had to have been prescribed the standard-of-care therapy for preterm labor, atosiban infusion for 48 hours.

Ebopiprant or placebo was administered orally, with 1000 mg as a starting dose (within 24 hours after starting the atosiban infusion), then 500 mg twice a day for 7 days. The women were assessed up to 14 days (unless delivery occurred sooner) and then again at delivery and up to 28 days after delivery. Follow-up of infants at 6, 12 and 24 months after birth is continuing and results will be available in 2021 and 2022.

In this study, 113 women with spontaneous preterm labor (gestational age between 24 and 34 weeks) were randomized and treated with atosiban plus ebopiprant or atosiban plus placebo for 7 days. There were 83 (73%) women with singleton pregnancies and 30 (27%) with twin pregnancies. One hundred and forty-one neonates were born.

In the PROLONG study, ebopiprant reduced delivery in singleton pregnancies at 48 hours after the start of dosing by 55% compared to atosiban alone. Overall, 7/56 (12.5%) of women receiving ebopiprant delivered within 48 hours of starting treatment compared to 12/55 (21.8%) receiving placebo (OR 90% CI: 0.52 (0.22, 1.23)). In singleton pregnancies, 5/40 (12.5%) of women receiving ebopiprant delivered within 48 hours compared to 11/41 (26.8%) receiving placebo (OR 90% CI: 0.39 (0.15, 1.04)).  A modest effect on delivery at 7 days was seen in the singletons.

The incidence of maternal, fetal and neonatal adverse events were comparable between subjects in the ebopiprant group and the placebo group.

Preterm labour is a critical situation that requires urgent medical intervention. One of the key objectives in reducing the mortality and morbidity associated with preterm birth is delaying delivery for at least 48 hours thereby allowing for the administration and the full effect of critical drugs that induce lung maturation and neural protection for the neonate. The encouraging PROLONG results offer new hope for women presenting with spontaneous threatened preterm labor and their babies.

Building on the strong effect seen with ebopiprant at 48 hours, a Phase 2b dose range finding, including testing of higher doses, will be initiated during the course of 2021 to more fully define this product’s potential and the longer-term benefits for babies.