O-259 Oral gonadotropin-releasing hormone (GnRH) antagonist SHR7280 versus ganirelix injection in controlled ovarian hyperstimulation (COH) for assisted reproductive technologies (ART): a non-inferiority phase 3 trial
Y Song, H Chi, L Jin, J Tan, Y Cao, L Li, X Song, D Xu, L Hu, Q Ma, X Li, G Cheng, Z Li, H Chen, J QiaoAbstract
Study question
Is SHR7280, an oral GnRH antagonist, non-inferior to ganirelix injection in premature luteinizing hormone (LH) surge inhibition and oocyte number retrieved during COH for ART?
Summary answer
Oral SHR7280 desmontrated non-inferiority to ganirelix injection in suppressing premature LH surges and in number of oocytes retrieved per cycle. SHR7280 was well-tolerated and safe.
What is known already
All GnRH antagonists currently approved for preventing premature LH surges are injectable, peptide-based formulations, which can cause inconvenience and injection site reactions. This highlights a significant unmet need for an orally available GnRH antagonist. In a previous phase 2 trial, SHR7280 at a dose of 200 mg Q12h showed effective LH suppression and a favorable safety profile in women undergoing COH for ART.
Study design, size, duration
This multi-center, randomized, double-blind, double-dummy, active-controlled, non-inferiority phase 3 trial was conducted in 22 hospitals in China. Between Sep. 25, 2023 and Jun. 28, 2024, 315 infertile women aged 20-39 years, for whom in vitro fertilization or intracytoplasmic sperm injection with embryo transfer was indicated, were enrolled and treated (SHR7280, n = 154; ganirelix, n = 161).
Participants/materials, setting, methods
Patients were randomized 1:1 to receive oral SHR7280 at 200 mg Q12h or ganirelix acetate injection at 0.25 mg Q24h. GnRH antagonists were started on day 5 of Gonal-F stimulation until human chorionic gonadotropin administration. The dual primary endpoints were rate of premature LH surge (LH ≥ 10 IU/L and progesterone ≥1.0 ng/mL) suppression during treatment period of study drugs (noninferiority margin, -10%) and number of oocytes retrieved after 1 stimulation cycle (noninferiority margin, -3).
Main results and the role of chance
The mean (±SD) treatment duration was 5.5±1.1 days for SHR7280 and 5.4±1.1 days for ganirelix. The rate of premature LH surge suppression was 99.4% (153/154; 95% CI 96.4–100.0) with SHR7280 and 99.4% (160/161; 95% CI 96.6–100.0) with ganirelix (difference, 0.0% [95% CI -1.8 to 1.8]; p < 0.0001 for non-inferiority). The LS mean number of oocytes retrieved was 9.9 (95% CI 8.9–10.9) with SHR7280 and 9.9 (95% CI 9.0–10.9) with ganirelix (LS mean difference, -0.0 [95% CI -1.0 to 1.0]; p < 0.0001 for non-inferiority). The mean (±SD) number of two-pronuclei zygotes was 6.6±3.6 in the SHR7280 group and 6.9±3.7 in the ganirelix group; the mean (±SD) number of high-quality embryos was 4.1±3.1 and 4.3±3.2, respectively. Per transfer, the blood pregnancy test positive rate was 63.1% (77/122; 95% CI 53.9–71.7) in the SHR7280 group vs 53.0% (61/115; 95% CI 43.5–62.4) in the ganirelix group; clinical pregnancy rates was 54.9% (67/122; 95% CI 45.7–63.9) vs 52.2% (60/115; 95% CI 42.7–61.6), and ongoing pregnancy rate was 49.2% (60/122; 95% CI 40.0–58.4) vs 47.8% (55/115; 95% CI 38.4–57.3). Treatment-related adverse events (TRAEs) occurred in 2 (1.3%) patients with SHR7280 and 10 (6.2%) with ganirelix. No serious TRAEs occurred.
Limitations, reasons for caution
This study involved a general ART population, excluding specific groups like those with diminished ovarian reserve or polycystic ovary syndrome. Additionally, the utility of SHR7280 in COH for diverse racial/ethnic populations remains underexplored, requiring further investigation to establish broader efficacy and safety.
Wider implications of the findings
This is the first head-to-head phase 3 trial comparing an oral GnRH antagonist to a standard, peptide-based formulation. The findings suggest that oral GnRH antagonists could be a convenient, non-invasive alternative to injectable formulations, improving overall treatment experience in women undergoing COH for ART.
Trial registration number
Yes