Commentary: The Development of Gonadotropins for Clinical Use in the Treatment of Infertility

Abstract

Almost a century has passed since the development of the first commercially available gonadotropin. With their recent article, entitled "The Development of Gonadotropins for Clinical Use in the Treatment of Infertility, " Lunenfeld et al. provide an overview of the major milestones in the development of gonadotropin products. The authors also describe the issues that affected the decision making during the development processes, and summarize the available evidence supporting the use of recombinant gonadotropin products for the treatment of infertility. While this review provides an insightful overview of the proposed topics, we feel that some of the content would benefit from additional clarification to ensure that the article provides a fair and balanced review of available data.The review begins by highlighting what Lunenfeld et al. believe to be the major events in the development of gonadotropins, which are then depicted in Figure 1. While the authors rightly dedicate a full sub-section of the article to data on follitropin delta, which was approved by European Medicines Agency (EMA) in 2016, we noticed that this milestone has been omitted from Figure 1. We feel that its inclusion in the figure would grant a more complete and accurate representation of the milestones in gonadotropin development.Following an overview of available recombinant gonadotropins such as follicle-stimulating hormone, follitropin alfa, and follitropin beta, the authors delineate existing data on follitropin delta. The ESTHER-1 trial is fittingly included and described, as it remains one of the primary randomized clinical trials demonstrating the non-inferiority of follitropin delta to follitropin alfa for the co-primary endpoints of ongoing pregnancy rate and implantation rate. However, a typographical error was made in the description of the dosing regimen tested in the ESTHER-1 trial: it should state that the starting dose was individualized based on body weight and anti-Müllerian hormone, and not body mass index. We feel that this should be corrected to avoid any potential confusion with healthcare physicians who may prescribe this gonadotropin (1).Furthermore, in the section that discusses the European public assessment reports (EPAR) for follitropin delta, published by the EMA, we noticed that Lunenfeld et al. cite comments posted on an online discussion board for the Fertility and Sterility journal (references 75 and 76). These citations were used to support the premise that non-inferiority was not demonstrated for women aged ≤37, and that the dose in the follitropin delta arm was individualized according to clinical markers while the dose of follitropin alfa was at the lower end of the recommended range, therefore reducing the comparability of the outcomes.

Human Recombinant FSH and Its Biosimilars: Clinical Efficacy, Safety, and Cost-Effectiveness in Controlled Ovarian Stimulation for In Vitro Fertilization

“…Follitropin δ was introduced on the market much more recently; its efficacy was compared to follitropin α in the phase III study ESTHER-1, including 1326 women submitted to COS using either a starting dose of follitropin δ based on body weight and anti-Müllerian hormone (AMH) or a daily dose of 150–450 IU of follitropin α [ 41 , 42 ]. The non-inferiority of follitropin δ to follitropin α for the primary endpoints (ongoing pregnancy rate: 30.7% and 31.6%, respectively, and ongoing implantation rate: 35.2% and 35.8%, respectively) was demonstrated.…”