ObsEva is currently advancing nolasiban (OBE001), an oral oxytocin receptor antagonist with the potential to decrease contractions, improve uterine blood flow and enhance the receptivity of the endometrium to embryo implantation. This increases the chance of successful pregnancy and live-birth among patients undergoing embryo transfer following ART.
The Phase 2 dose-ranging IMPLANT 1 clinical trial (n=247) showed that a single oral 900 mg dose of nolasiban about 4 h before fresh, day 3, single or double embryo transfer had the highest increase in on-going pregnancy and live birth rates compared to lower doses of 100 and 300 mg and placebo.
The EU pivotal Phase trial IMPLANT 2 was a multinational, double-blind, randomized, parallel group, placebo-controlled trial assessing a single oral dose (900 mg) of nolasiban administered before SET following IVF. A single good-quality embryo was transferred on either day 3 (D3) or day 5 (D5) after oocyte pick-up. The decision to transfer on D3 or D5 was made clinically for each patient before randomization to study treatments. An equal number of patients undergoing ET on D3 or D5 were recruited. The trial was conducted at 41 fertility centers in 9 European countries.
The Phase 3 IMPLANT 2 met its primary endpoint. Ongoing pregnancy rates in the pooled D3/D5 ET population were 28.5% with placebo and 35.6% with nolasiban (p=0.031). The greatest impact was observed in the D5 ET group; 34.7% with placebo compared to 45.9% with nolasiban (p=0.034). Live birth rates were 27.7% and 34.8% in the pooled D3/D5 (p=0.025), and 33.2% and 44.8% after D5 ET (p=0.025), respectively with placebo and nolasiban. Nolasiban was well tolerated with a safety profile similar to placebo. A single oral dose of nolasiban given prior to fresh SET resulted in a significant increase in ongoing pregnancy and live birth rates compared to the placebo. Use of nolasiban has the potential to increase pregnancy and live birth rates following embryo transfer in IVF. Maternal and obstetric outcomes were very similar between the treatment groups. The neonatal (at birth and 28 days after birth) and infant developmental outcomes (assessed using the Ages and Stages Questionnaire-3® (ASQ-3) completed at 6 months after birth) were similar between the nolasiban and placebo groups Neonatal outcomes at birth and 28 days after birth were also comparable, with a similar incidence of congenital anomalies.
This ability of nolasiban to improve ongoing pregnancy and live birth rates, especially in the D5 ET group, indicates that nolasiban has the potential to increase IVF efficacy after ET, and hence reduce the number of IVF cycles required to have a baby. Furthermore, favorable outcomes with a single embryo could help encourage increased use of SET, thereby decreasing the incidence of multiple births.
On November 7, 2019, we announced that the IMPLANT 4 trial did not meet the primary endpoint of an increase in ongoing pregnancy rate at 10 weeks, (39.1 % placebo vs 40.5 % nolasiban) (p = 0.745). As these results did not confirm the prior positive Phase 3 IMPLANT 2 trial findings, we have discontinued the current development of nolasiban for IVF, and are exploring potential repositioning of the compound e.g. higher dose, earlier and longer exposure, and potentially “enriched” IVF population (i.e. subject with high uterus contraction rate at the time of ET). For that purpose, on January 13, 2020, ObsEva and Yuyuan BioScience Technology (PRC) (“Yuyuan”) have entered into a sublicense agreement to develop and commercialize nolasiban for improving clinical pregnancy and live birth rates in women undergoing embryo transfer as part of an in-vitro fertilization or IVF cycle in the People’s Republic of China (PRC). Under the terms of the agreement, Yuyuan has the exclusive rights to develop and commercialize nolasiban in the PRC. They will fund all development and registration activities in PRC starting with the obligation to fund and conduct a Phase 1 study and a Phase 2 Proof-of -Concept study in China. After which time, both companies will collaborate on the global development of nolasiban, but ObsEva will retain all rights to the product outside of PRC.