Follitropin beta 150units/0.5ml solution for injection vials

Abstract Background Follitropin delta is a novel recombinant follicle stimulating hormone preparation uniquely expressed in a human fetal retinal cell line by recombinant DNA technology. To date, no systematic review was available about the safety and the efficacy of the follitropin delta. The objective of this study was systematically reviewing the available literature and to provide updated evidence regarding the efficacy-safety profile of follitropin delta when compared to other gonadotropin formulations for ovarian stimulation in in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) cycles. Methods An extensive search was performed to identify phase 1, phase 2 and phase 3 RCTs in humans focused on follitropin delta use for ovarian stimulation in IVF/ICSI cycles. The risk of bias and the overall quality of the evidence was analyzed. All data were extracted and analyzed using the intention-to-treat principle and expressed per woman randomized. Results A total of 7 RCTs (1 phase 1 RCT, 2 phase 2 RCTs and 4 phase 3 RCTs) were included in the qualitative analysis, whereas data of three phase 3 RCTs were meta-analyzed. All trials compared personalized recombinant follitropin delta treatment versus conventional recombinant follitropin alfa/beta administration in potentially normo-responder patients who receive ovarian stimulation in GnRH antagonist IVF/ICSI cycles. No difference between two regimens was detected for clinical pregnancy rate [odds ratio (OR) 1.06; 95% confidence intervals (CI): 0.90, 1.24; P = 0.49; I 2 = 26%], ongoing pregnancy rate (OR 1.15; 95%CI: 0.90, 1.46; P = 0.27; I 2 = 40%), and live birth rate (OR 1.18; 95%CI: 0.89, 1.55; P = 0.25; I 2 = 55%). No data were available regarding cumulative success rates. The rate of adoption of strategies to prevent ovarian hyperstimulation syndrome (OHSS) development (OR 0.45; 95%CI: 0.30, 0.66; P < 0.0001; I 2 = 0%), and the rate of both early OHSS (OR 0.62; 95%CI: 0.43, 0.88; P = 0.008; I 2 = 0%) and all forms of OHSS (OR 0.61; 95%CI: 0.44, 0.84; P = 0.003; I 2 = 0%) were significantly lower in the group of patients treated with personalized follitropin delta treatment compared to those treated with conventional follitropin alfa/beta administration. Conclusion Personalized follitropin delta treatment is associated with a lower risk of OHSS compared to conventional follitropin alfa/beta administration in potentially normo-responder patients who receive ovarian stimulation in GnRH antagonist IVF/ICSI cycles. The absence of cumulative data does not allow definitive conclusions to be drawn regarding the comparison of the effectiveness of the two treatments. Protocol study registration CRD42023470352 (available at http://www.crd.york.ac.uk/PROSPERO ).

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Background: Follitropin δ may be an alternative to conventional follitropin α/β for controlled ovarian stimulation (COS) within assisted reproductive treatment (ART), but its efficacy and safety remain unknown. We performed a random-effects meta-analysis to compare the efficacy and safety of follitropin δ and follitropin α/β. Methods: We searched randomized controlled trials comparing follitropin δ and follitropin α/β using MEDLINE, Embase, CENTRAL, ClinicalTrials.gov, and WHO-ITCRP on December 14, 2022. The primary outcomes were the live birth rate and the incidence of moderate or severe ovarian hyperstimulation syndrome (OHSS). The certainty of the evidence was assessed using the grading of recommendations assessment, development, and evaluation approach. The protocol was registered on the Open Science Framework. Results: Three studies involving 2682 participants were included in our meta-analysis. The results indicated that follitropin δ may result in little to no difference in live birth rates (risk ratio [RR], 1.12; 95% confidence interval [CI], 0.91-1.38; low certainty) and the incidence of moderate or severe OHSS (RR, 0.78; 95% CI, 0.48-1.26; low certainty) compared with follitropin α/β. Conclusion: Follitropin δ may result in little to no difference in COS compared with follitropin α/β, especially in terms of live births and safety.

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PURPOSE: To investigate whether the ovarian stimulation with follitropin delta in an individualized algorithm-based manner is inferior to recombinant human-follicle stimulating's follitropin alfa or follitropin beta conventional dosing regarding a series of established primary endpoints. METHODS: We conducted a registered systematic review (CRD42024512792) on PubMed-MEDLINE, Web of Science™, Cochrane Database of Systematic Reviews, and Scopus. Our search was designed to cover all relevant literature, particularly randomized controlled trials. We critically and comparatively analyzed the outcomes for each primary endpoint based on the intervention, reflected by the positive βhCG test, clinical pregnancy, vital pregnancy, ongoing pregnancy, live birth, live birth at 4 weeks, and multiple pregnancies. RESULTS: Six randomized controlled trials were included in the quality assessment as priority manuscripts, revealing an 83.3% low risk of bias. Follitropin delta led to non-significant differences in each parameter of interest from positive βhCG test (691; 53.44% vs. 602; 46.55%), ongoing pregnancies (603; 53.79% vs. 518; 46.20%), clinical and vital pregnancies (1,073; 52.80% vs. 959; 47.19%), to live birth and at 4 weeks (595; 54.14% vs. 504; 45.85%) with only 2 losses, and even multiple pregnancies (8; 66.66% vs. 4; 33.33%). However, follitropin delta was well-tolerated among hypo- and hyper-responders without significant risk of ovarian hyperstimulation syndrome and/or preventive interventions in contrast with follitropin alfa or follitropin beta. CONCLUSION: The personalized individualized-based algorithm dosing with follitropin delta is non-inferior to conventional follitropin alfa or follitropin beta. It is as effective in promoting a similar response in women without significant comparable adverse effects.

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Understanding the variability in ovarian response following administration of follicle-stimulating hormone medications in women undergoing in vitro fertilization may help inform prescribing decisions. A systematic review was conducted to compare the number of retrieved oocytes and fertility outcomes following the administration of different follicle-stimulating hormone medications. Databases were searched from inception to November 2024, including studies that compared two follicle-stimulating hormone medications, including follitropin alfa, follitropin beta, follitropin delta, and urofollitropin. Meta-analyses were performed in random effects models with the restricted maximum likelihood method. From 3867 identified articles, 26 (12613 participants) were included. More oocytes were retrieved with follitropin alfa compared to beta (mean difference 0.64, 95% CI 0.09-1.19). Compared to follitropin delta, more oocytes were retrieved with follitropin alfa and beta (1.38, 95% CI 0.09-2.67, and 1.40, 95% CI 0.41-2.39, respectively); however, higher total doses of follitropin alfa and beta were administered (199.29 IU, 95% CI 43.15-355.43 and 181.08 IU, 95% CI 55.67-306.49, respectively), and the risk of hyperstimulation increased (risk ratios 1.42, 95% CI 1.04-1.96 and 1.75, 95% CI 1.15-2.70, respectively). More oocytes were retrieved with urofollitropin compared to follitropin beta (1.12, 95% CI -1.63 to -0.62), with higher total doses of urofollitropin administered (782.32 IU, 95% CI -1493.79 to -70.85). Variability in ovarian response and hyperstimulation rates across the medications decreased when similar total doses were administered. Fertilization, pregnancy, and live birth rates were similar across the medications, despite differences in the number of retrieved oocytes. Additional research is required to evaluate oocyte quality across follicle-stimulating hormone medications.

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Importance For women undertaking assisted conception, the dose of gonadotropin has historically been driven by clinical experience. A different and individualised strategy was developed for follitropin delta, a human cell line derived recombinant follicle stimulating hormone, with dose based on anti-Müllerian hormone (AMH) stratification; for women with a high ovarian reserve (AMH ≥15pmol/l; approx. 2.1ng/ml) the dose is based on the combination of AMH and body weight in a continuous manner. The clinical effectiveness of this approach to dosing for ovarian stimulation on live birth and safety is unknown. Objective Undertake a one-stage meta-analysis of individual patient data from randomised trials comparing individualised dosing of follitropin delta versus other forms of follitropin (alpha, beta) for live birth rates and safety parameters in women undergoing ovarian stimulation for IVF. Evidence Review We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science to identify eligible phase 3 trials between Jan 1 2000 and Feb 1 2023. All analyses were based on individual participant data. We used a general linear mixed effects logistic regression model using fixed effects for treatment drug interacting with log(AMH), age, and random effects for country and trial to compare the primary efficacy and safety outcomes of live birth and early ovarian hyperstimulation syndrome (OHSS) and/or the need for OHSS preventative measures, with ovarian stimulation parameters and neonatal outcomes also assessed. PROSPERO registration CRD42023399711. Findings Three trials met inclusion criteria and included 2685 women undertaking 2,682 cycles between October 2013, and May 2020, with live birth follow-up through to February 1, 2023. For women with an elevated AMH (≥15 pmol/L), there was high quality evidence that the use of individualised dosing of follitropin delta was associated with an increased live birth rate (adjusted OR 1.64, 95%CI 1.14, 2.36). Safety outcomes were also improved with a reduced risk of both early OHSS and/or the need for preventative interventions (adj OR 0.27, 95% CI 0.15, 0.49) and early moderate or severe OHSS (adj OR 0.30, 95% CI 0.16, 0.58). These improvements in outcomes were obtained with a lower total dose of gonadotropin (-48.7μg, 95%CI -53.7, -43.8) and no adjustments in the daily dose. In contrast, similar live birth rates (adj OR 0.86, 95%CI 0.63, 1.17) and safety outcomes (adj OR 1.92 95%CI 0.76, 4.87) were observed for women with an AMH <15pmol/l. There were no clinical meaningful differences in neonatal outcomes. Conclusion and relevance Using follitropin delta in an AMH and weight-based algorithm rather than conventional licenced dosing of follitropin alpha or beta for ovarian stimulation women is associated with improved live birth rates and safety outcomes for women with elevated AMH levels.

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Follitropin alfa biosimilars: unfounded doubts on the road to reproductive careDear Editors,We have read with interest Kiose et al. (2025) comparing the clinical outcome of different follitropin preparations.In essence, the authors conclude that biosimilar medicines'-induced pregnancy rates are likely to be lower than original follitropin alfa.Such a statement challenges the science of biosimilarity behind the European Medicines Agency (EMA)'s regulation proven successful for over 110 biosimilar medicines (covering 25 active substances).Who is driving the wrong way?Kiose et al. make conceptual mistakes captured in the sentence ' two biosimilars have been approved in the EU, Ovaleap and Bemfola , based on Phase III clinical studies and by demonstrating non-inferiority '.Beyond the fact that the trials were powered for equivalence rather than non-inferiority, asserting that biosimilar medicines approval is 'based on Phase III trials' is misleading.The least sensitive approach to pick-up differences is a comparative clinical trial; hence, EMA's principle that structural and functional comparability is the foundation of biosimilar medicines approval (Wolff-Holz et al., 2019) Interestingly, Merck supports that same notion (Magnenat et al., 2017) which also explains that Gonal-f 's intrinsic heterogeneity, and differences between original follitropin alfa and beta, are not substantiated clinically.Accordingly, the British Medicines & Healthcare products Regulatory Agency asserted that efficacy trials are not an effective discriminating tool in biosimilar development (Bielsky et al., 2020), in alignment with a recently issued EMA reflection paper (EMA, 2025).However, if conducted, EMA regulators remind us that a tailored clinical program partly aiming at a reduction of the amount of clinical data required for the development of biosimilar medicines is scientifically meaningful (Guillen et al., 2023).While, for instance, the overall response rate is not the efficacy measure in advanced follicular lymphoma, it is the preferred endpoint for comparability.Similarly, EMA recommends follitropin-mediated 'number of oocytes retrieved' as the best endpoint to prove similarity.In an analysis of complex biosimilar medicines, EMA experts (Kirsch-Stefan et al., 2023) called ' into question the usefulness of comparative efficacy studies', to the extent that in some cases where the efficacy trials failed, biosimilarity was ultimately accepted.Evidence argues against homogeneity in the meta-analysis from Kiose et al. (2025).The authors wrongly identify Follitrope as a biosimilar medicine.Follitrope 's development was not meant to demonstrate biosimilarity to Gonal-f (LG Chem, 2024; Ministry of Food and Drug Safety of South Korea (MFDS), 2024).Furthermore, neither biosimilarity of Afolia with the USA Gonal-f RFF Redi-Ject TM , has been accredited, nor data from trial NCT01687712 were used for approval of Afolia in Australia.

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STUDY QUESTION: How do ovarian responses using conventional dosing for follitropin delta 15 µg/day compare with follitropin alfa 225 IU/day in women undergoing ovarian stimulation? SUMMARY ANSWER: The ADAPT-1 trial demonstrates similar ovarian responses with follitropin delta 15 µg/day and follitropin alfa 225 IU/day starting doses in a conventional dosing regimen. WHAT IS KNOWN ALREADY: Follitropin delta, a recombinant FSH (rFSH), is currently approved for ovarian stimulation using an individualized fixed daily dose based on serum anti-Müllerian hormone (AMH) and bodyweight (maximum 12 µg/day for first cycle and 24 µg/day in subsequent cycles). Other rFSHs, such as follitropin alfa, conventionally apply a starting dose of 150-225 IU, fixed for the initial days of stimulation, after which dose adjustments can be made (maximum 450 IU/day). Ovarian stimulation with follitropin delta 10 µg/day provides a similar ovarian response to follitropin alfa 150 IU/day for serum concentration and number of follicles ≥12 mm. STUDY DESIGN, SIZE, DURATION: ADAPT-1 was a randomized, accessor-blinded, multicentre trial comparing efficacy and safety of a starting dose of follitropin delta 15 µg/day with follitropin alfa 225 IU/day in conventional dosing regimens. The primary endpoint was the number of oocytes retrieved; mean difference between treatment groups was estimated using a negative binomial regression model (treatment and serum AMH level as factors). During the follow-up period, clinical pregnancies resulting from the first fresh/frozen transfers within 3 months of the start of stimulation, and ovarian hyperstimulation syndrome (OHSS) rates were assessed. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants, 18-40 years, undergoing IVF/ICSI could enrol at specialist reproductive clinics in Austria, France, Italy, Spain, and the United Kingdom for ovarian stimulation if they had no contraindications for treatment with a starting gonadotropin dose of 225 IU/day. Patients could enrol if they reported infertility for at least 1 year if ≤37 years and at least 6 months for those >37 years, and regular menstrual cycles (21-35 days). All cycles used a GnRH antagonist protocol. MAIN RESULTS AND THE ROLE OF CHANCE: Between 1 August 2022 and 16 April 2024, 300 of 337 screened patients were randomized to, and received, follitropin delta (n = 200) or follitropin alfa (n = 100). The two treatment groups were comparable in terms of demographics, baseline characteristics, and duration of infertility. The mean duration of treatment was ∼9 days in both groups. The mean total dose of follitropin delta was 143.7 ± 33.6 µg and 154.3 ± 23.1 µg (2105 ± 315 IU) for follitropin alfa. Three-quarters (226/300) used an human Chorionic Gonadotropin trigger for final follicular maturation. A mean of 9.9 oocytes was retrieved for both groups (estimated difference: 0.0 oocytes; 95% CI -1.3, 1.2). The category of 8-14 oocytes retrieved was the most common ovarian response (follitropin delta: 45.5%; follitropin alfa: 50.0%). Clinical pregnancy rates were comparable (31.6% and 31.0%; estimated difference 0.6 (95% CI -10.6, 11.8)). Early OHSS (≤9 days after triggering) occurred in 2.5% and 3.0%, and all cases were Grade 3 (moderate) or lower. No participant had the stimulation cycle cancelled due to excessive ovarian response. LIMITATIONS, REASONS FOR CAUTION: Only pregnancies from the first fresh or cryopreserved transfer within 3 months of oocyte retrieval were recorded. Cumulative pregnancy rates after the first transfer were not followed up. All analyses are of descriptive nature and no formal hypothesis testing or multiplicity adjustment was applied. WIDER IMPLICATIONS OF THE FINDINGS: Treatment groups had similar ovarian responses, supporting equivalence for starting doses follitropin delta 15 µg and follitropin alfa 225 IU, with low rates of early OHSS. Ovarian stimulation cycles with follitropin delta in µg can be planned and adjusted, leveraging the established IU dose equivalence to follitropin alfa. STUDY FUNDING/COMPETING INTEREST(S): This trial was funded by Ferring Pharmaceuticals A/S, Kastrup, Denmark. Medical writing support for manuscript development was provided by Celia J. Parkyn, PhD, and was funded by Ferring Pharmaceuticals A/S, Kastrup, Denmark. P.Z. and R.A. have none. A.B. has received grants from Gedeon Richter, IBSA, GP Pharm & Seid, Miguel Hernandez University, Centre for Technological Development and Innovation, Valencian Innovation Agency, Regional Secretary for Industry, Trade and Consumption, and the Government Ministry of Industry and Tourism; payments from University Complutense of Madrid, Ferring Pharmaceuticals, Fentypharm, Miguel Hernandez University, Gedeon Richter, & Vall d'Hebron Hospital; travel support from Ferring Pharmaceuticals, Fentypharm, Gedeon Richter, International ESHRE Congress Organising Committee, Spanish Society of Gynaecology and Obstetrics, CROG Congress Organising Committee, & Vall d'Hebron Hospital; has a patent pending for Sperm plate (U202431456); and is Chair of the Organising Committee of the Infertility and Sterility Section of the Spanish Society of Gynaecologist (non-paid role) and equipment from Obstetrics; & equipment from Cook Medical. J.S. has received consulting fees from Ferring Pharmaceuticals. E.P. has received grants from Merck, Ferring, Theramex, Gedeon Richter, IBSA, and Organon; payments from Merck, Ferring, IBSA, and Organon; travel support from Merck, IBSA, Organon, Theramex, and Ferring; and participated in a Safety Monitoring Board or Advisory Board for Merck. M.G.S. has received patient medication from Ferring; payments from Ferring, Merck for educational events; and travel support from Ferring, Merck, Theramex, and IBSA. R.L. and S.M. are employees of Ferring Pharmaceuticals. I.E.J. was an employee of Ferring Pharmaceuticals at the time of the trial conduct. TRIAL REGISTRATION NUMBER: clinicaltrials.gov NCT05263388; Eudract 2021-001785-38. TRIAL REGISTRATION DATE: 16 November 2021 (clinicaltrials.gov); 5 August 2021 (Eudract). DATE OF FIRST PATIENT’S ENROLMENT: 1 August 2022.

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Background: Follitropin delta is the third recombinant human follicle-stimulating hormone (r-hFSH) expressed in a host cell line of human fetal retinal origin that currently emphasizes that the actual tendency of administration is a personalized dosing algorithm based on the anti-Müllerian hormone (AMH) and body mass index (BMI) for ovarian stimulation. Methods: In this context, we aimed, in the present manuscript, to gather all available data published between 2018–2022 regarding the co-administration and administration of follitropin delta and the clinical outcomes reported following an in vitro fertilization (IVF). Results: Follitropin delta is non-inferior in contrast to its previously launched agents for ovarian stimulation, enhancing a similar-to-superior response reflected by both the reproductive and pregnancy outcomes in parallel with a low risk of ovarian hyperstimulation syndrome (OHSS), being well tolerated. The body weight and AMH level are factors that may influence the outcome in a patient. Despite controversy and results that refute these arguments on several occasions, follitropin delta exceeds the benefits of conventional dosing with either follitropin alfa or follitropin beta. Thus, all post hoc, derived analyses and subsets of patients that participated in subsequent studies support this statement. Conclusions: Despite the relatively limited spectrum of data in the current literature, most authors brought potent proof, supporting the subsequent use of this drug depending on the patient’s profile and overcoming ethnic-related limitations. Although others contradict these observations, this topic and drug possess substantial potential, which is why additional studies are mandatory to fill the existing gaps in our knowledge and expand these experiences at a larger scale supported by the obtained reproductive and clinical outcomes that clearly indicate an overcoming of all limitations.

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Aim: This study compared the cost-effectiveness of two recombinant follicle-stimulating hormones (rFSH) formulations, Follitropin Delta and Follitropin Alfa, in controlled ovarian stimulation using cumulative live birth rates as an efficacy indicator. Methodology: This retrospective study was conducted across five clinics in Japan from April 2022 to December 2023, involving 446 first assisted reproductive technology (ART) cycles (200 with Follitropin Delta and 246 with Follitropin Alfa) were treated with rFSH monotherapy using either Follitropin Delta or Follitropin Alfa. We compared clinical outcomes such as cumulative pregnancy and live birth rates and analyzed cost-effectiveness using the cumulative live birth rates as the efficacy indicator and the incremental cost-effectiveness ratio (ICER). Results: The Follitropin Delta group had a significantly lower incidence of ovarian hyperstimulation syndrome (15.90% vs. 27.00%, P = 0.045) and higher cumulative pregnancy rates than the Follitropin Alfa group (87.30% vs. 76.20 %; P = 0.03) after propensity score matching (PSM). Although cumulative live birth rates showed no significant differences (85.70% vs. 76.20%, P = 0.08) and Follitropin Delta demonstrated higher cost than Follitropin AlfaFollitropin Alfa (832,036 yen and 826,936 yen), ICER indicated low costs per percentage of live births (538.58 yen/%: 95% confidence interval [CI]: 275.34-12,568.69 yen). Conclusions: Using Follitropin Delta for controlled ovarian stimulation in ART may be more cost-effective than Follitropin Alfa under Japan’s Health Care Insurance System, offering higher cumulative live birth rates and minimal additional costs.

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