SHR7280, an oral gonadotropin-releasing hormone antagonist, for the prevention of premature luteinizing hormone surge in controlled ovarian hyperstimulation: a dose-finding, phase 2 trial

STUDY QUESTION: What is the minimum effective dose of SHR7280, a novel oral GnRH antagonist, to prevent a premature LH surge in women undergoing controlled ovarian hyperstimulation for ART? SUMMARY ANSWER: SHR7280 at 200 mg once every 12 h (Q12h) was the minimal effective dose to suppress an LH surge and was associated with high-quality embryos, and a high clinical pregnancy rate. SHR7280 was well-tolerated and safe. WHAT IS KNOWN ALREADY: Currently, all approved GnRH antagonists for preventing a premature LH surge are injectable, peptide-based formulations, which can cause inconvenience and injection site reactions. There is a significant unmet need for an orally available GnRH antagonist to address this issue. SHR7280 has previously demonstrated effective suppression of LH levels in healthy volunteers in phase 1 trials. STUDY DESIGN, SIZE, DURATION: This multi-center, open-label, dosing-finding phase 2 trial was conducted between 26 January 2022 and 3 August 2023 in 85 infertile women. PARTICIPANTS/MATERIALS, SETTING, METHODS: The starting dose of SHR7280 was 300 mg Q12h, followed by dose exploration in two lower dose groups (200 mg Q12h and 200 mg Q24h) sequentially. Dose exploration was terminated if an LH surge occurred. SHR7280 was administrated orally starting on Day 5 of recombinant human FSH stimulation until hCG administration. The primary endpoint was the rate of premature LH surge inhibition during SHR7280 treatment. MAIN RESULTS AND THE ROLE OF CHANCE: Eighty-five patients received SHR7280: 300 mg Q12h, n = 40; 200 mg Q12h, n = 42; 200 mg Q24h, n = 3. The mean ( ± SD) duration of SHR7280 treatment was 5.7 ± 1.2, 5.7 ± 1.3, and 3.7 ± 0.6 days, respectively. The rate of LH surge inhibition was 99% (95% CI 94-100) in all patients, 100% (95% CI 91-100) in the 300 mg Q12h group, 100% (95% CI 92-100) in the 200 mg Q12h group, and 67% (95% CI 9-99) in the 200 mg Q24h group. Two hundred milligrams Q12h was established as the minimal effective dose. Embryological and pregnancy outcomes were comparable in the 300 and 200 mg Q12h groups. In the 200 mg Q12h group, the mean ( ± SD) number of oocytes retrieved per patient, two-pronucleate zygotes, and high-quality embryos was 10.7 ± 4.6, 6.9 ± 3.2, and 3.9 ± 2.6, respectively; among patients receiving fresh embryo transfer, 62% (95% CI 44-78) were tested positive for serum β-hCG and 53% (95% CI 35-70) were confirmed to be clinically pregnant per transfer. No spontaneous ovulation occurred on the day of oocyte retrieval. In all 85 patients, treatment-related adverse events were reported in 1 (1%; mild in severity) patient. LIMITATIONS, REASONS FOR CAUTION: The sample size was moderate and there was no standard peptide-based GnRH antagonist as a control group. Additionally, the performance of SHR7280 in specific populations, such as patients with diminished ovarian reserve and at high risk of OHSS, remains to be established. Further research is also needed to determine the recommended dose in patients with high BMI, intending for frozen embryo transfer, and using a GnRH agonist as trigger. Moreover, the study included only Chinese patients and allowed up to 2 embryos per transfer. The efficacy and safety of SHR7280 in other racial groups and regions require further investigation. WIDER IMPLICATIONS OF THE FINDINGS: Findings from this phase 2 trial suggest that an oral GnRH antagonist could be an effective alternative for preventing a premature LH surge in ART. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by Jiangsu Hengrui Pharmaceuticals. Z.L., Yu.S., C.S., Hong.C., and K.S. were employees of Jiangsu Hengrui Pharmaceuticals at the time of study. All other authors have no conflicts of interests to declare. TRIAL REGISTRATION NUMBER: NCT05082233.