Comparing a biosimilar follitropin alfa (Cinnal-f®) with Gonal-f® in women undergoing ovarian stimulation: An RCT

Background: Advances in recombinant DNA technology led to the development of recombinant follitropin alfa. Recombinant human follicle-stimulating hormone products are used to stimulate follicular maturation. Objective: To compare the efficacy and safety of a biosimilar-candidate recombinant human follicle-stimulating hormone (Cinnal-f® ; CinnaGen, Iran) with the reference product (Gonal-f® ; Merck Serono, Germany) in women undergoing ovarian stimulation for intracytoplasmic sperm injection (ICSI). Materials and Methods: In this randomized controlled trial, a total sample size of 200 women (age < 35 yr, candidate for ICSI) was calculated. Participants began a pituitary downregulation protocol with buserelin. They received 150 IU daily of either Cinnal-f® or Gonal-f® from the second day of their cycle. The primary outcome of the study was the percentage of metaphase II (MII) oocytes. The secondary outcomes included the number and quality of oocytes retrieved, duration of stimulation, fertilization rate, embryo quality, the number of clinical and ongoing pregnancies, and the incidence of ovarian hyperstimulation syndrome (as an important safety marker). Results: A total of 208 women were enrolled, of whom, 200 completed the study period. Ovarian stimulation with Cinnal-f® resulted in a comparable percentage of MII oocytes as with Gonal-f® (78.64% vs 80.02%, respectively; p = 0.81). No statistically significant difference was seen in the secondary outcomes between the groups. Conclusion: Cinnal-f® proved non-inferior to Gonal-f® , based on the percentage of MII oocytes in women aged < 35 yr undergoing ICSI. Our findings confirm that the efficacy and safety profiles of Cinnal-f® and Gonal-f® are similar. Key words: Follitropin alfa, Biosimilar, Efficacy, Safety, Intracytoplasmic sperm injection.

Advisory Board on potential import substitution of follitropin alfa preparations in IVF cycles

On July 17, 2021, Advisory Board with the participation of more than 60 leading reproductive specialists and healthcare executives was held. The primary task was to discuss the real world data on the first Russian biosimilar follitropin alfa and the possibilities of import substitution of follitropin alfa drugs. The information about drug development stages, experience of usage in ovarian stimulation for artificial insemination and assisted reproductive technologies (ART), the results of the largest Russian study in reproduction "FОLLITROPIN" (2020), where biosimilar recombinant human follicle stimulating hormone (FSH) was studied in 5484 IVF cycles in real clinical practice, experience of drug use in leading ART medical centers have been provided in research reports. After discussion the Advisory Board Resolution has been developed.

Pregnancy and neonatal outcomes in fresh and frozen cycles using blastocysts derived from ovarian stimulation with follitropin delta

Purpose To describe the pregnancy and neonatal outcomes using fresh and vitrified/warmed blastocysts obtained from ovarian stimulation with follitropin delta in controlled trials versus follitropin alfa. Methods This investigation evaluated the outcome from 2719 fresh and frozen cycles performed in 1326 IVF/ICSI patients who could start up to three ovarian stimulations in the ESTHER-1 (NCT01956110) and ESTHER-2 (NCT01956123) trials, covering 1012 fresh cycles and 341 frozen cycles with follitropin delta and 1015 fresh cycles and 351 frozen cycles with follitropin alfa. Of the 1326 first cycle patients, 513 continued to cycle 2 and 188 to cycle 3, and 441 patients started frozen cycles after the fresh cycles. Pregnancy follow-up was continued until 4 weeks after birth. Results The overall cumulative take-home baby rate after up to three stimulation cycles was 60.3% with follitropin delta and 60.7% with follitropin alfa (−0.2% [95% CI: −5.4%; 5.0%]), of which the relative contribution was 72.8% from fresh cycles and 27.2% from frozen cycles in each treatment group. Across the fresh cycles, the ongoing implantation rate was 32.1% for follitropin delta and 32.1% for follitropin alfa, while it was 27.6% and 27.8%, respectively, for the frozen cycles. Major congenital anomalies among the live-born neonates up until 4 weeks were reported at an incidence of 1.6% with follitropin delta and 1.8% with follitropin alfa (−0.2% [95% CI: −1.9%; 1.5%]). Conclusions Based on comparative trials, the pregnancy and neonatal outcomes from fresh and frozen cycles provide reassuring data on the efficacy and safety of follitropin delta. Trial registration ClinicalTrials.gov Identifier: NCT01956110 registered on 8 October 2013; NCT01956123 registered on 8 October 2013.

O-113 Effectiveness and treatment cost of assisted reproduction technology for women stimulated by gonadotropin in France: A cohort study using the National Health Database

Study question How effective is Assisted Reproduction Technology (ART) in terms of cumulative live birth rate (CLBR) in France, depending on the gonadotropin used? Summary answer Among 214,539 stimulations, originator follitropin-alfa was associated with significantly higher CLBR when compared to Highly Purified-Human Menopausal Gonadotropin (HP-HMG) and biosimilars. What is known already Deciding which type of gonadotropin to prescribe for a woman undergoing controlled ovarian stimulation (COS) remains difficult. The effectiveness of different gonadotropins is one factor to consider. However, studies comparing r-hFSH-alfa, its biosimilars and HP-HMG are scarce and are mostly based on a single ART treatment cycle and fresh embryo transfers. Some clinical trials have shown similar pregnancy, pregnancy loss, and live birth rates after fresh embryo transfer (ET) between HP-HMG and r-hFSH. However, because more oocytes are retrieved with r-hFSH when compared to HP-HMG, it is logical to hypothesize that the CLBR is higher with r-hFSH. Study design, size, duration A non-interventional study based on the French National Health System (SNDS) database was designed to assess the CLBR and treatment costs from the national payer perspective of four gonadotropin groups (originator follitropin-alfa (r-hFSH-alfa), its biosimilars, HP-HMG and r-hFSH-beta) used for COS cycles leading to oocyte pick-up (OPU) between 01/01/2013 and 31/12/2017 with a follow-up period up to 31/12/2018. The study compared CLBR, with originator r-hFSH-alfa as the reference. Participants/materials, setting, methods Women with COS cycles resulting in OPU with one of the specified gonadotropins were included. Data were extracted from billing and reimbursement records of outpatient healthcare consumption and national hospital discharge databases using a unique, anonymized patient number. CLBR was estimated using an Andersen–Gill model, adjusted for clinical baseline, stimulation and ET variables. Costs were reported as secondary outcomes. Main results and the role of chance 135,752 women (mean age 34.1), underwent 214,539 stimulations leading to OPU and contributed one (61.5%), two (24.8%), three (9.4%) or four (3.2%) COS cycles. COS cycles were stimulated with either Originator r-hFSH-alfa (46%), HP-HMG (29%), r-hFSH-beta (21%) or r-hFSH-alfa biosimilars (4%). Over the study period, CLBR reached 20.5%; 21.9% with originator r-hFSH-alfa, 17.9% with HP-HMG, 21.3% with r-hFSH-beta and 18.4% with r-hFSH-alfa biosimilars. After adjusting for age, pre-treatment, GnRH analog, ovulation triggering, luteal phase support, previous COS, fresh or frozen ET and type of center, as possible cofounding variables, the adjusted hazard ratio (HR) for CLBR (delivery [originator r-hFSH-alfa as reference]) was 0.88 (95% CI 0.86 to 0.95, p &lt; 0.0001) with HP-HMG; 0.98 (95% CI 0.95 to 1.00, p = 0.1020) with r-hFSH-beta, and 0.84 (95% CI 0.79 to 0.90, p &lt; 0.0001) with r-hFSH-alfa biosimilars. Although the mean acquisition cost of r-hFSH-alfa during the study was 33% higher than HP-HMG and 20% higher than r-hFSH-alfa biosimilars, the global ART management costs were only 4% higher than HP-HMG, 3% higher than r-hFSH-beta, and similar to r-hFSH-alfa biosimilars. Limitations, reasons for caution Patients were included only from oocyte pick-up, due to missing data in the SNDS database, meaning that it was not possible to estimate the proportion of cancelled cycles. Furthermore, as r-hFSH-alfa biosimilars were only available since 2015, results for biosimilars should be interpreted with caution. Wider implications of the findings This population-wide French study confirms other Real-World and meta-analysis evidence that CLBR is higher with originator r-hFSH-alfa than with HP-HMG or r-hFSH-alfa biosimilars, respectively, and are relevant for healthcare professionals to support gonadotropin treatment decision making. To further support this, the cost analysis should be completed by a cost-effectiveness analysis. Trial registration number Not applicable

P–592 Safety and effectiveness of follitropin alfa biosimilar to originator follitropin alfa in real-world clinical practice: A Multinational Comparative, Prospective Cohort Study

Study question Are safety and effectiveness of Ovaleap® (follitropin alfa), and Gonal-f®, comparable in one treatment cycle of ART in routine clinical practice? Summary answer Safety in terms of incidence proportions of OHSS and OHSS severity, as well as pregnancy and live birth rates, were similar between Ovaleap® and Gonal-f®. What is known already Ovaleap® (Theramex), a r-hFSH, is a biosimilar medicinal product to Gonal-f® (Merck). As a biosimilar, it went through a rigorous series of physio-chemical, in vitro, in vivo tests and confirmatory Phase I and III studies, to demonstrate similarity/equivalence in quality, safety and efficacy to the reference medicinal product, per the European Medicines Agency (EMA) guidelines. Ovaleap® was approved by the EMA in 2013 for use at the same dose and for the same therapeutic indications as Gonal-f®. Further outcome data from a broader patient population on safety and live birth outcomes provides clinically important insights on newly introduced FSH medicines. Study design, size, duration SOFIA (Safety of Ovaleap® Follitropin alfa in Infertile women undergoing superovulation for Assisted reproductive technologies) was a multi-national, comparative, non-interventional, prospective cohort study. The study was performed at 56 centers specializing in ART from six European countries, (Belgium, France, Germany, Italy, Spain, and the United Kingdom) from January 2017 to September 2019 and comprised of 817 infertile women undergoing controlled ovarian hyperstimulation in one treatment cycle for ART Participants/materials, setting, methods The study population comprised of infertile women undergoing controlled ovarian hyperstimulation for ART, who were administered Ovaleap® or Gonal-f® and were naïve to any FSH containing products. Eligible patients were enrolled at a ratio of approximately 1:1, both within and between countries. They were followed up to 30 days after the last FSH dose administration. Women who had a confirmed clinical pregnancy were followed until the end of the pregnancy or until delivery. Main results and the role of chance A total of 408 and 409 women who were administered Ovaleap® or Gonal-f®, respectively, were eligible for analysis. A total of 382 patients (94%) in the Ovaleap® and 390 patients (95%) in the Gonal-f® cohort completed FSH treatment (up to oocyte maturation triggering), respectively. The two cohorts were generally similar with regard to demographic and baseline characteristics. The incidence proportion of OHSS was 5.1% (95% CI: 3.4, 7.7) in the Ovaleap® and 3.2% (95% CI: 1.9, 5.4) in the Gonal-f® cohort. This difference in OHSS incidence proportion between the two cohorts was not statistically significant neither before (p = 0.159) nor after univariate adjustment for each potential confounder (p &gt; 0.05). The incidence proportion of OHSS severity grades was similar in the two treatment groups (3.4% versus 2.0% for Grade I, 1.2% versus 1.0% Grade II, and 0.5% versus 0.2% Grade III, in the Ovaleap® and Gonal-f® cohorts, respectively) and without a significant statistical difference (p = 0.865, for each grade). Among patients who had embryo transfer, clinical pregnancy rates were 33% and 31%, live birth rates 27% and 26% in the Ovaleap® and Gonal-f® cohorts, respectively. Limitations, reasons for caution Since treatment was non-randomised, the study may have been susceptible to selection bias. This was addressed at both the design stage, by balancing recruitment to a 1:1 ratio for Ovaleap® and Gonal-f® treatments, and also at the analysis stage in which, a univariate analysis was performed. Wider implications of the findings: Findings from this first large European prospective comparative real-world SOFIA study demonstrated that effectiveness (pregnancy and delivery rates) and safety (risk and severity of OHSS), were similar between Ovaleap®and Gonal-f® treatments. Ovaleap, a biosimilar r-hFSH is therefore a suitable option for follicular stimulation in routine clinical practice. Trial registration number EUPAS17328