Novel pill keeps hopes up in infertile women ≤40 years undergoing IVF/ICSI

In the phase II OXOART2 trial presented at ESHRE 2024, the first-in-class, non-hormonal, oral agent OXO-001 increases implantation and pregnancy rates in infertile women ≤40 years undergoing in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI).

In the exploratory subset, biochemical pregnancy rate (BPR) was higher with OXO-001 as opposed to placebo (75.9 percent vs 52.4 percent; absolute increase, 23.5 percentage points). [ESHRE 2024, abstract O-027]

OXO-001 also trumped placebo in terms of clinical pregnancy rate (CPR; 50 percent vs 35.7 percent), ongoing pregnancy rate (OPR; 46.3 percent vs 35.7 percent), and live birth rate (LBR; 42.6 percent vs 35.7 percent). The differences between arms yielded absolute increases of 14.3, 10.6, and 6.9 percentage points, respectively, in favour of the former vs the latter.

Logistic regression analysis revealed a statistically significant difference between OXO-001 and placebo in BPR (odds ratio, 3.03, 95 percent confidence interval, 1.17–7.85; p=0.022), and clinically meaningful differences for the other outcomes.

Study author Dr Agnès Arbat from Oxolife, Barcelona, Spain, noted that the significant absolute increase in BPR translates to improved early implantation, leading to the improvements in CPR and OPR, and subsequently, the very relevant improvement in deliveries. “From scientific societies, key opinion leaders, clinicians, and patients, we know that an absolute increase of more than 5 percentage points in [OPR] is considered clinically meaningful.”

Session moderator Dr Kilian Vomstein from the Copenhagen University Hospital Hvidovre in Denmark pointed out however that the numbers – from BPR to LBR – were dropping, suggesting greater biochemical pregnancy losses and not live births. Arbat responded, stating that despite the pregnancy losses, the live births are still reflective of OXO-001’s effect throughout the pregnancy.

The frequency of treatment-emergent adverse events (TEAEs) deemed possibly related to the study drug were similar between the investigational and placebo arms (n=14 vs 10). Most TEAEs were mild or moderate in severity. The most common TEAES were headache, nausea and vomiting, gastrointestinal issues, and dizziness.

Infant (n=148) developmental outcomes were also similar between arms during the 6-month follow-up.

New mechanism of action

One in six people of reproductive age worldwide experience infertility during their lifetime. And despite advancing IVF technologies, embryo implantation failure remains a challenge. [https://www.who.int/news-room/fact-sheets/detail/infertility, accessed July 15, 2024; Human Reproduction 2021;36:305-317] “Sixty-five percent of IVF/ICSI are lost during implantation,” Arbat said.

According to Arbat, they developed OXO-001 “to enhance embryo implantation and reduce implantation losses by acting directly on the endometrium.” OXO-001 increases key endometrial adhesion and invasion molecules expression, she said, adding that it is safe for the mum, foetus, and newborn without any detrimental effect on the development, viability, and implantation potential of embryos exposed to OXO-001.

This proof-of-concept study included 173 infertile women (18–45 years) eligible for a fresh single embryo transfer. The exploratory subset comprised women ≤40 years (n=96). Of these, 54 (mean age 36.6 years) received OXO-001 300 mg QD, while the remaining 42 (mean age 37.3 years) were given placebo. Treatment ran for 14 weeks – 9 weeks before embryo transfer (5 weeks cycle 1*, 4 weeks cycle 2*) until 5 weeks post embryo transfer.

“We are thrilled with the results [highlighting] OXO-001’s potential to become the first therapeutic treatment to increase embryo implantation success, with a nonhormonal drug using a new mechanism of action, acting directly on the endometrium,” said Oxolife CSO Dr Ignasi Canals, in the ESHRE press release.

“Despite continuous developments in ovarian stimulation, embryo manipulation, and culture, improving LBR in medically assisted reproduction has been incremental at best. A jump of nearly 7 percent is very good news for our patients, and hopefully this can be confirmed in larger patient groups,” commented ESHRE Chair Professor Dr Karen Sermon.

“We observed an increase higher than 9 [percentage points], giving renewed hope to patients and the scientific community. We look forward to advancing this promising treatment through the next phases of clinical development,” Arbat concluded. Larger, adequately powered phase III trials are warranted to validate the results.