Ovarian stimulation with follitropin delta for in vitro fertilization: a multicentre, randomized, assessor-blind comparison with follitropin alfa using conventional dosing regimens (ADAPT-1 trial)

Objective: To present a rare case of late-onset ovarian hyperstimulation syndrome (OHSS) with isolated right-sided pleural effusion occurring after spontaneous conception during a luteal phase ovarian stimulation cycle without exogenous human chorionic gonadotropin (hCG) administration. Design: Case report. Materials and Methods: A 36-year-old woman with primary infertility underwent luteal phase ovarian stimulation with menotropins, follitropin alfa, letrozole, and somatropin. By day 11 of stimulation, 17 follicles were noted and estradiol was 279 pg/mL. The cycle was canceled following a positive urine pregnancy test (serum β-hCG 53 mIU/mL). The patient discontinued stimulation medications and started progesterone injections. Subsequently, she presented multiple times to the emergency department due to recurrent dyspnea and right-sided pleural effusions requiring thoracenteses. Results: Initial thoracentesis drained 1,500 cc of straw-colored fluid. The patient had recurrent effusions requiring additional drainage procedures of 1,800 cc and 1,400 cc. Laboratory findings included mild hyponatremia, hypocalcemia, and hypoalbuminemia. After final hospitalization, a pigtail catheter drained 1,600 cc. The patient stabilized with conservative management. Ultrasound confirmed a viable singleton pregnancy carried to 32 weeks and 4 days, resulting in a successful delivery. Conclusions: This case highlights late-onset OHSS triggered by endogenous hCG following spontaneous conception during luteal phase ovarian stimulation. Clinicians should be vigilant of OHSS risks even in the absence of exogenous hCG administration. Routine pregnancy checks and close monitoring during luteal phase stimulation cycles are critical to early detection and effective management of severe OHSS complications, such as pleural effusions.

EE195 Cost-Effectiveness of Follitropin Delta versus Follitropin Alfa in Controlled Ovarian Stimulation for IVF/ICSI Cycles in China

Objectives: This research aimed to study the effect of 15mcg/day of follitropin delta on normo-responding women. Methods: A single-center, open-label, matched case–control pilot trial was carried out from September 2021 to June 2022. In this trial, normo-responding oocyte donors were given 15 mcg/day of follitropin delta or 225 IU/day of follitropin alfa, as well as medroxyprogesterone acetate for pituitary suppression during the cycle. The main outcome measured was the number of oocytes retrieved. Results: A fixed dose of 15 mcg/day of follitropin delta for ovarian stimulation in normo-responders achieved an average of 17 oocytes retrieved. No differences were observed vs. 225 IU/day of follitropin alfa in the number of oocytes [17.8 ± 7.8 vs. 18.5 ± 7.7, respectively, p = 0.156], the number of metaphase II oocytes [13.5 ± 6.9 vs. 15 ± 6.3, p = 0.105], the fertilization rates (71.1% vs. 72.9%, p = 0.523), the number of usable blastocysts (4.9 ± 2.4 vs. 4.5 ± 2.5, p = 0.466), and the implantation rate (64% vs. 57%, p = 0.575). In the follitropin delta group, the duration of the stimulation was significantly shorter (9.4 ± 1.2 vs. 10.9 ± 1.2, p < 0.01), and the overall gonadotropin intake was lower. There were no clinically relevant differences between treatment groups regarding the safety profile. Global patient satisfaction with the follitropin delta ovarian stimulation was very high (7.7 ± 2.2). Conclusions: A daily dose of 15 mcg of follitropin delta may provide a similar ovarian response to 225 IU/day of follitropin alfa; aiming to retrieve 17 oocytes in normo-responders undergoing progestin-primed ovarian stimulation, it could reduce gonadotropin intake by reducing the duration of the stimulation cycle, with a possible high patient satisfaction level.

Objective: This crossover study compared the effects of two recombinant follicle-stimulating hormone (rFSH) preparations, follitropin alfa and follitropin delta, on assisted reproductive technology (ART) outcomes.Methods: Patients aged 25-42 years (body mass index: 18-30, anti-Müllerian hormone level ≤2.03 ng/mL) underwent two oocyte retrieval cycles, one with follitropin alfa and the other with follitropin delta, and were divided into four groups based on the crossover use of these preparations. Eighty-one patients received follitropin alfa during both cycles. Fifty-one patients received follitropin delta during both cycles. Forty-four patients received follitropin delta during the first cycle and follitropin alfa during the second cycle. Thirty patients received follitropin alfa during the first cycle and follitropin delta during the second cycle.Results: There was no significant difference in the rate of increase in the number of oocytes retrieved between the first and second cycles, regardless of whether follitropin alpha or follitropin delta was used initially. No significant difference in the blastocyst formation rate was observed. However, cycles in which follitropin alfa was used for the first stimulation and follitropin delta for the second showed a significantly smaller decline in oocyte yield compared to cycles that began with follitropin delta followed by follitropin alfa.Conclusion: The present study concluded that in non-polycystic ovary syndrome (PCOS) patients with an anti-Müllerian hormone (AMH) level of ≤2.03 ng/mL - classified as intermediate responders - the use of follitropin delta (12 μg) in the second in vitro fertilization (IVF) cycle resulted in a significantly smaller change in the number of retrieved oocytes compared to the first cycle. This suggests that the use of follitropin delta in the second cycle may be a viable and proactive option in such cases.

Abstract Study question How do ovarian responses with follitropin delta 15 µg/day compare with follitropin alfa 225 IU/day in women undergoing ovarian stimulation using conventional dosing regimens? Summary answer The ADAPT-1 trial demonstrates similar ovarian responses with follitropin delta 15 µg/day and follitropin alfa 225 IU/day as starting doses in a conventional dosing regimen. What is known already Follitropin delta, a recombinant follicle-stimulating hormone (rFSH), is currently approved for ovarian stimulation using an individualised 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. Ovarian stimulation with follitropin delta 10 µg/day provides a similar ovarian response to follitropin alfa 150 IU/day for serum oestradiol concentration and number of follicles ≥12 mm. Study design, size, duration This randomised, assessor-blinded, multicentre trial compared the efficacy and safety 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 pregnancy rates from first fresh/frozen transfers within 3 months and ovarian hyperstimulation syndrome (OHSS) rates were assessed. Participants/materials, setting, methods Participants, 18–40 years, undergoing IVF/ICSI were enrolled at specialist reproductive clinics in Austria, France, Italy, Spain, and United Kingdom for ovarian stimulation if they had no contraindications for treatment with 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 &amp;gt;37 years, and regular menstrual cycles (21–35 days). All cycles used a gonadotropin-releasing hormone (GnRH) antagonist protocol. Main results and the role of chance Between August 1, 2022, and April 16, 2024, 300 of 337 screened patients were randomised 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 (2,105±315 IU) for follitropin alfa. A total of 75% (226/300) used a human choriogonadotropin trigger for final follicular maturation. A mean of 9.9 oocytes was retrieved for both groups (estimated difference: 0.0 oocytes; 95% confidence interval [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). The proportion of participants who experienced adverse events was 36.5% and 40.0%. 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 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 dosed in micrograms can be planned and adjusted, leveraging the established IU dose equivalence to follitropin alfa. Trial registration number Yes

Abstract Study question Is follitropin delta cost-effective compared with follitropin alfa for controlled ovarian stimulation (COS) for IVF/ICSI in China? Summary answer Follotropin delta leads to higher live birth rates at lower costs compared with follitropin alfa, making it a dominant treatment option (higher effect, lower cost). What is known already Follitropin delta for injection (REKOVELLE) was approved by Chinese authorities in April 2024. Follitropin delta is associated with higher serum levels of FSH and ovarian response compared to other follitropins. Follitropin delta is based on personalised dosing regimens dependent on the patient’s ovarian reserve (measured through anti-Müllerian hormone [AMH] level) and body weight, allowing the administration of personalised and fixed daily doses. The clinical safety and efficacy of follitropin delta was demonstrated compared with follitropins alfa and beta in three non-inferiority clinical studies (GRAPE, ESTHER &amp; STORK). An economic analysis for France has demonstrated cost-effectiveness of follitropin delta. Study design, size, duration An economic model was developed in Microsoft excel® to estimate the relative costs and effect of follitropin delta versus follitropin alfa for COS for women undergoing an IVF or ICSI cycle in China. The decision-tree model reflects one COS cycle with one fresh and up to three frozen transfers. The time horizon of the model is up to live birth (LB). The rate and costs of OHSS and miscarriages are also captured in the model. Participants/materials, setting, methods Input data was based on an individual patient level analysis of the pan-Asian GRAPE study. Data was stratified by treatment allocation, age and ovarian response profile. Each step in the model were associated with healthcare consumption and medical costs, including treatment acquisition and administration, pregnancy follow-up, adverse events management, procedures and hospitalisations. Resource use and costs were estimated from the GRAPE study, literature review, local guidelines and the PHARMCUBE study. Probabilistic sensitivity analyses were performed. Main results and the role of chance The mean total dose was 78 μg for follitropin delta versus 110 μg for follitropin alfa. The LB rate for fresh transfers was 31.3% in the follitropin delta arm and 24.7% in the follitropin alfa arm (p = 0.02). Costs until LB was ¥25,689 in the follitropin delta arm and ¥27,189 in the follitropin alfa arm (diff -¥1,500). Extending the analysis to include one frozen transfer, the LB rates were 53.5% vs 45.7% for follitropin delta vs alfa and the costs were ¥29,725 vs 31,582(diff -¥1,857) respectively. Including up to three frozen cycles, the LB rates become 77% vs 71% and the cost ¥33,940 vs 36,907(diff -¥2,967) respectively. Follitropin delta provided a higher LB rate at a lower cost and were considered a dominant treatment strategy (higher efficacy, lower cost). As the number of frozen transfers (up to 3) increases, the greater the cost savings. The cost per live birth of follitropin delta and alfa were ¥44,262 and ¥51,806 (diff -¥7,544) with up to three frozen transfers. Probabilistic sensitivity analyses demonstrated &amp;gt;82% probability of follitropin delta being a dominant treatment strategy for fresh cycles and 95% probability of follitropin delta being dominant when including up to three frozen transfers. Limitations, reasons for caution The analysis was based on the characteristics of patients and treatment practices in the GRAPE trial. Up to three frozen embryo transfers were analysed, assuming a similar LB rate as in the fresh cycle for both treatment arms in line with the approach used in previous economic evaluations. Wider implications of the findings Results of the analysis demonstrates that follitropin delta has a high probability of being a more effective and less costly treatment option for COS for IVF/ICSI in Chinese treatment practices, providing a more efficient use of limited health care resources. Trial registration number No

Abstract Study question To assess dispensing pharmacists' knowledge of ovarian stimulation treatments, to study their perceptions about biosimilar interchangeability and the difficulties encountered when dispensing these specific treatments. Summary answer As substitution by the follitropin alfa biosimilars is justified in case of stock shortage, it would be necessary to have in-depth knowledge of MAR treatments. What is known already In France, MAR is fully covered by Health Insurance unlike other countries in Europe. In 2022, follitropin alfa is the most used treatment among other types of gonadotropins and it costs more than 60 million euros for Social Security. There is no demonstrated superiority between the different types of recombinant FSH, even if follitropin alfa remains the main one prescribed today. The missions of the pharmacist have evolved in recent years with leading role as a public health actor. The substitution of biosimilars by the pharmacist may emerge in the coming years in close collaboration with prescribers. Study design, size, duration An online survey was performed using Lime Survey platform in partnership with the University of Rennes and Equasens Group (expert in business software solutions for professionals and healthcare establishments). The inquiry has 11 questions in total including 8 multiple choice questions and 3 open questions divided into two parts: the first part on pharmacists' knowledge about these treatments and the second part on the notion of interchangeability of gonadotropins. Participants/materials, setting, methods The distribution was scheduled in the 8,500 French pharmacies equipped with id software. We obtained 530 responses in total thanks to the distribution on all French territory. Main results and the role of chance 344 participants felt they did not have enough knowledge to answer the questionnaire. 186 participants actively responding. Of the participants, 60% were assistant pharmacists, 23% full pharmacists and 17% students in their 6th year of pharmacy. 16 respondents (8%) stated that they had never dispensed gonadotropins in the context of MAR. The majority (n = 71) responded that gonadotropin biosimilars are not interchangeable and substitutable by the retail pharmacist. However, 37 believe that these biosimilars are interchangeable and substitutable by the pharmacist given that clinical trials have demonstrated the clinical efficacy of biosimilars to be ‘non-inferior’, which led to their approval by the EMA.Pharmacists say they have experienced a supply shortage or stockout of gonadotropins. Indeed in recent years, stock-outs of medicines have become a frequent occurrence, and pharmacists are finding it increasingly difficult to supply pharmacies. Limitations, reasons for caution Feedback from pharmacists on the content of the questionnaire was considered very academic and quite difficult to answer, particularly on the part concerning pharmacists' knowledge. Most pharmacists would like to be more involved in ovarian stimulation protocols. Wider implications of the findings Laboratories have a growing global market with an increasing demand for MAR throughout the world. There is a need to update and deepen pharmacists' knowledge regarding gonadotropins and MAR treatments. Coordination protocols between the hospital and the city will enable pharmacists to provide better care for patients. Trial registration number No

Available evidence indicate that Intrauterine Insemination (IUI) cycles with controlled ovarian stimulation (COS) yield better oocyte quality and higher pregnancy rates compared to those without COS in infertile women. As follitropin delta is an improved version of recombinant FSH, its ability to stimulate the development of multiple ovarian follicles is supposedly superior to follitropin alfa. The objective of this study was to evaluate the efficacy and safety of follitropin delta with a simplified dosage equivalent method in Indonesian women undergoing IUI. The design of this study was a retrospective observational study conducted from February 2022 to December 2023 involving 248 IUI cycles at Halim Fertility Center (HFC) IVF Center, Indonesia. Controlled Ovarian Stimulation was performed with follitropin delta with a simplified dosage equivalent method in IUI. From this study, we found that the clinical pregnancy rate (CPR) for IUI was 27.8%. The Ovarian Hyperstimulation Syndrome (OHSS) rates was 0.4%, with 2,9% multiple pregnancies in the follitropin delta with a simplified dosage equivalent method. This study showed no statistically significant differences in pregnancy rates based on age groups and BMI (p=0.288 vs p=0.934). WE conclude that follitropin delta may improve the outcome of intrauterine insemination in women undergoing IUI.

Polycystic Ovarian Syndrome (PCOS) is a prevalent endocrine condition that affects roughly 10% of women of childbearing age and is marked by polycystic ovarian anatomy, oligo-anovulation and/or hyperandrogenism. While endometrial carcinoma most commonly occurs in the sixth decade of life, younger women with PCOS can have a higher risk of endometrial carcinoma. The association of PCOS and the risk of developing endometrial carcinoma stems from the effects of unopposed estrogen exposure resulting from chronic anovulation. There are no clear, current guidelines specifying routine screening recommendations or indications for endometrial biopsies in women with PCOS; however, a 2022 cross-sectional, retrospective study recommended routine endometrial biopsies following results demonstrating a 30% prevalence of endometrial hyperplasia and/or carcinoma in women aged 18-40 with PCOS. This age disparity combined with pre-existing menstrual abnormalities and the absence of well-studied, clear recommendations for the evaluation of abnormal uterine bleeding in patients with PCOS decreases the likelihood of timely detection of endometrial cancer in young women with PCOS, which can result in metastasis, loss of fertility and diminished quality of life. A 31-year-old G0 female with a history of PCOS and obesity was referred to the University of South Alabama Gynecologic Oncology department in June 2020 following a D&amp;C and polypectomy with dye study that revealed FIGO Grade 1 endometrial carcinoma. She initially presented to her reproductive endocrinologist in March 2020 with complaints of heavy bleeding at which time a pelvic ultrasound showed a thickened endometrial lining. She had been taking oral contraceptive pills from March 2018 to January 2020. A previous endometrial biopsy in 2018 revealed atypical cells. An MRI was obtained at the beginning of her workup in June 2020, which confirmed no myometrial invasion. Therefore, due to the patient’s desire for future fertility, a Mirena IUD was placed three weeks later. In September 2020, an endometrial biopsy revealed minimal residual hyperplasia without evidence of carcinoma. A repeat endometrial biopsy in December 2020 revealed persistent focal complex atypical hyperplasia which prompted continuation of the IUD and added supplementation with megestrol eighty milligrams twice daily for three months. Of note, the patient’s family history was significant for colonic polyps in her mother and sister and a maternal grandmother with colorectal cancer at the age of 58. The patient was tested for mutations associated with Lynch syndrome and was found to be negative. In April 2021, a repeat endometrial biopsy was negative, and the IUD was removed through consultation with reproductive endocrinology. Pregnancy was achieved in August 2021 through follitropin alfa stimulation and hCG trigger shot with timed intercourse. In December 2021, the patient was referred to the high-risk obstetrics clinic for follow-up of a prenatal ultrasound that revealed choroid plexus cysts and a single umbilical artery. Two weeks later, the patient experienced premature preterm rupture of membranes at 21+6 weeks gestation and delivered in early January of 2022 via spontaneous vaginal delivery at 23+2 weeks gestation. Her pregnancy was complicated by retained products of conception, which required only medical intervention with misoprostol. The infant was discharged from the NICU in October 2022. In June of 2022, the patient underwent a colonoscopy following a five-month history of painless hematochezia that resulted in a polypectomy for a sessile serrated adenomatous polyp of the ascending colon less than one centimeter in size. In February 2023, the patient desired fertility but continued to experience irregular menses. She was placed on metformin three times daily and cyclic progesterone with planned monthly pregnancy tests to minimize teratogenicity. She did not follow up again until March 2024, when a repeat endometrial biopsy was performed that revealed FIGO Grade 2 carcinoma. In May 2024, the patient underwent a curative robot-assisted total laparoscopic hysterectomy, bilateral salpingectomy with right oophorectomy, bilateral pelvic sentinel node and right paraaortic lymphadenectomy. Pathology revealed all lymph nodes to be negative for malignancy and Stage 1A FIGO grade 2 endometrioid adenocarcinoma focally invading the superficial myometrium with formation of squamous morule and without evidence of angiolymphatic invasion. Endometrial cancer occurs in only 4% of women under the age of 40 while PCOS is among the most common endocrine disorders affecting women of childbearing age. While the standard treatment for endometrial cancer is a hysterectomy with bilateral salpingo-oophorectomy, this plan is not ideal for women of reproductive age who desire fertility. Similarly, several hormonal therapies used in the process of assisted reproductive technology (ART) are not ideal for women with a history of endometrial cancer as these therapies often promote estrogen. Our case highlights a unique therapeutic dilemma that considers the delicate balance of hormonal therapy required for fertility in the background of PCOS and the necessity of prompt treatment in young patients with endometrial carcinoma.

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. 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). 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) andFollitropin Deltademonstrated 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). 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.

Is the probability of pregnancy different between women using biosimilars versus the originator of follitropin alfa for ovarian stimulation in ART? Meta-analysis of eight randomized clinical trials (RCTs) suggests that live birth, clinical, and ongoing pregnancy rates are significantly lower with biosimilars of follitropin alfa compared to the originator. All biosimilars of follitropin alfa have received regulatory approval by demonstrating non-inferiority in the number of retrieved oocytes compared to the originator. Nevertheless, the most clinically relevant outcome in ART for both clinicians and patients is live birth. A meta-analysis published in 2021 suggested that biosimilars of follitropin alfa are associated with lower live birth rates compared to the originator. Since then, more relevant RCTs have been published, and thus an updated critical synthesis of the available evidence is urgently warranted. A systematic review and meta-analysis were performed to compare biosimilars versus the originator of follitropin alfa in women undergoing ovarian stimulation for ART. A literature search was conducted until January 2024 in MEDLINE, Embase, Cochrane CENTRAL, Scopus, Web of Science, WHO, Clinicaltrials.gov, and others to identify eligible RCTs. The primary outcome was live birth. Secondary outcomes included clinical and ongoing pregnancy, duration of gonadotrophin administration and total FSH dose, number of oocytes retrieved, and ovarian hyperstimulation syndrome (OHSS). Data were extracted independently by two reviewers. Quality was assessed using the RoB-2 Tool by Cochrane, and a sensitivity analysis was performed by excluding studies having high risk of bias. Meta-analysis was performed using the random or fixed effects model depending on the presence or not of significant (>50%) statistical heterogeneity (I2). Results were combined using the intention-to-treat principle and are reported as risk ratio (RR) or weighted-mean-difference (WMD) with 95% CIs. Eight RCTs (n = 2987) (published between 2015 and 2023) were identified, assessing seven biosimilar products of follitropin alfa. The number of patients included in the eligible studies ranged from 100 to 1100. Three of the RCTs were deemed to be at high risk of bias. The duration of gonadotrophin administration was shorter in the biosimilars group (WMD: -0.19 days, 95% CI: -0.34 to -0.05; I2 = 0%, 5 studies, n = 2081), while no difference was observed in the total dose of FSH (WMD: -34.69 IUs, 95% CI: -74.54 to 5.16; I2 = 15.53%, 5 studies, n = 2081). No difference was observed in the number of oocytes retrieved (WMD: 0.27, 95% CI: -0.43 to 0.96; I2 = 10.7%, 6 studies, n = 1527) and OHSS rates (RR: 1.17, 95% CI: 0.90-1.52; I2 = 0%, 8 studies, n = 2986) between the two groups. A significantly lower live birth rate was observed using the biosimilars of follitropin alfa compared to the originator in women undergoing ovarian stimulation for ART (RR: 0.83, 95% CI: 0.72-0.96; I2 = 0%, 6 studies, n = 2335; moderate certainty of evidence). Similarly, clinical pregnancy (RR: 0.82, 95% CI: 0.73-0.92; I2 = 0%, 7 studies, n = 2876; low certainty of evidence) and ongoing pregnancy rates (RR: 0.81, 95% CI: 0.70-0.94; I2 = 0%, 7 studies, n = 1886; low certainty of evidence) were lower in the biosimilars group. These results were not materially altered in the sensitivity analyses performed where studies deemed at high risk of bias were excluded. This meta-analysis included RCTs evaluating seven different biosimilars of follitropin alfa; however, pooled data appeared to be homogeneous. No data were available comparing biosimilars of follitropin alfa with the originator regarding cumulative live birth rate per aspiration or the probability of live birth in frozen thawed cycles. The population examined in the eligible RCTs includes mainly normal responders and no RCTs were identified focusing on poor or high responders. Clinicians should be informed that although biosimilars of follitropin alfa produce similar number of oocytes with the originator, pregnancy rates after a fresh transfer are likely to be lower. Future research should focus on optimizing the production and use of biosimilars of follitropin alfa, so that they lead to pregnancy rates comparable to the originator. No external funding was used for this study. K.I.K. and A.S. have no competing interest to disclose. E.M.K. reports personal fees and non-financial support from Merck, Ferring, IBSA, and Vianex. B.W.M. has been supported by an investigator grant from NHMRC, has received consulting fees from Organon, Merck, and Norgine, research support and non-financial support from Merck KGaA, Darmstadt, Germany. B.W.M. also reports having stocks from OBsEva. C.A.V. reports grants, personal fees, and non-financial support from Merck KGaA, Darmstadt, Germany, personal fees, and non-financial support from Merck, Sharpe and Dohme, personal fees and non-financial support from Organon, grants and non-financial support from Ferring, personal fees from IBSA, and personal fees and non-financial support from Gedeon Richter and Vianex. Protocol for the systematic review registered in The International Prospective Register of Systematic Reviews (PROSPERO; CRD42024498237).

This large multicenter study aimed to evaluate clinical outcomes using three follitropin alfa preparations within a progestin-primed ovarian stimulation (PPOS) protocol, while identifying contributing factors to cycle success. A retrospective, anonymized cohort analysis was conducted on donor-recipient cycles from 12 clinics during 2019 to 2021. 7389 oocyte donors underwent ovarian stimulation (OS) with three follitropin alfa preparations (Ovaleap® [n=3231], Bemfola® [n=3542], Gonal-F® [n=616]) were included. Stimulation began on cycle days 2 or 3 with daily administration of 150-225 IU follitropin alfa. 10 mg medroxyprogesterone acetate (MPA) was administered daily until GnRH agonist trigger using a single dose of 0.2mg GnRH agonist for final follicular maturation. Statistical analysis included ANOVA, Chi-squared, and logistic regression. Whilst there were some differences in patient and stimulation characteristics, including donor age and number of retrieved oocytes, clinical variables did not significantly differ among the three study groups. Linear regression revealed donor age [0.986 (0.974-0.999)] and number of mature oocytes [1.027 (1.007-1.047)] significantly impacted ongoing pregnancy rates, while the type of follitropin alfa [1.048 (0.956-1.149)] used did not. No significant differences were observed in the cumulative live birth rate (CLBR) among oocytes obtained from stimulation with Bemfola (64.9%), Gonal-F (64.1%) and Ovaleap (66.1%), p= 0.385. This study demonstrated comparable clinical outcomes and CLBR between biosimilars and the reference product of follitropin alfa within PPOS protocols, hence they are interchangeable in a real-world patient setting.

Abstract Study question What is the effectiveness of individualised follitropin delta dosing compared to conventional follitropin alfa dosing in patients with potential poor response undergoing ovarian stimulation? Summary answer Individualised follitropin delta dosing provides a favourable efficacy and safety balance and is as good as follitropin alfa in patients with potential poor ovarian response. What is known already Poor ovarian response to controlled ovarian stimulation constitutes a challenge in in-vitro fertilisation/intracytoplasmic sperm injection (IVF/ICSI) treatment. The dosing algorithm of follitropin delta incorporates the prediction of ovarian response based on anti-Müllerian hormone (AMH), an accurate marker of ovarian reserve, and body weight, for an individualised dosing. In the general IVF/ICSI population and potential high responders, individualised follitropin delta reduces the risk of ovarian hyperstimulation syndrome (OHSS) and/or preventive interventions for OHSS, with sustained efficacy compared to conventional follitropin alfa. However, the performance of follitropin delta in the subpopulation of patients with potential poor response has not been evaluated. Study design, size, duration Post hoc analysis of 332 patients with potential poor response from the ESTHER-1 trial (determined by AMH level at screening &amp;lt;9 pmol/L). Patients received the maximum daily dose of 12 µg follitropin delta (fixed dosing throughout stimulation) as stipulated by the dosing algorithm for patients with AMH &amp;lt;15 pmol/l, or follitropin alfa at a starting dose of 150 IU, with potential dose adjustments from stimulation day 6 and onwards (maximum daily dose of 450 IU). Participants/materials, setting, methods Participants were women, 18–40 years, undergoing their first IVF/ICSI cycle in a GnRH antagonist protocol, including triggering with human chorionic gonadotrophin, IVF/ICSI insemination, and single or double blastocyst transfer on Day 5. Ultrasound was performed 10–11 weeks after transfer to confirm ongoing pregnancy. All pregnancies were followed until birth. Study outcomes include number of oocytes retrieved and number of good quality blastocysts, ongoing pregnancy and live birth rates, cycle cancellation and OHSS rates. Main results and the role of chance A total of 332 patients (25.0% of the overall ESTHER-1 population) had serum AMH at screening of &amp;lt; 9 pmol/l and were included in the analysis: 168 were treated with follitropin delta and 164 were treated with follitropin alfa. Baseline characteristics were similar between the treatment groups, with a mean age of 34.8 years, a median AMH of 5.7 pmol/l and a mean weight of 64.5 kg. With follitropin delta, the mean daily dose was 12.0 µg and with follitropin alfa 12.4 µg, resulting in mean total doses of 104.6 µg and 112.3 µg, respectively. The mean number of oocytes retrieved was 5.8 ± 3.5 with follitropin delta and 5.5 ± 3.6 with follitropin alfa and the mean number of good-quality blastocysts was 1.2 ± 1.4 with both treatments. The ongoing pregnancy rate was 29.8% with follitropin delta and 29.3% with follitropin alfa and the live birth rates were 29.2% and 28.7%, respectively. Thirteen patients (7.7%) treated with follitropin delta and 14 (8.5%) treated with follitropin alfa had their cycles cancelled due to poor response. One case of OHSS (0.6%) was observed in the follitropin delta group, and 3 cases (1.8%) were observed in the follitropin alfa group. Limitations, reasons for caution The main limitation of the study is its post hoc nature. Furthermore, the study is based on a relatively small number of patients. Wider implications of the findings This subgroup analysis, alongside the normoresponder and the potential hyperresponder subgroup of the ESTHER-1 trial, adds evidence for the effectiveness of follitropin delta across all ovarian reserve subgroups of the infertile population. Trial registration number NCT01956110

Abstract Study question Could the individualized fixed-dose algorithm with follitropin delta show a similar pregnancy rate to conventional dosing with follitropin alfa in PPOS protocol? Summary answer Individualized fixed-dose algorithm with follitropin delta showed a similar pregnancy rate to follitropin alfa In PPOS protocol. What is known already Follitropin delta (REKOVELLE, Ferring Pharmaceuticals, Switzerland) is the first human cell line driven recombinant follicle-stimulating hormone (FSH) with an individualized fixed-dose algorithm based on serum AMH level and body weight. Follitropin alfa is a Chinese hamster ovarian cell driven recombinant FSH and its dosing is adjusted according to follicular response during the stimulation period. There was no significant difference between follitropin delta and follitropin alfa in terms of pregnancy rate under GnRH antagonist protocol. Study design, size, duration A retrospective analysis of 355 patients aged under 40 years who underwent ovarian stimulation in PPOS protocol using follitropin delta or follitropin alfa and on whom frozen-thawed single blastocyst transfer was conducted between August 2021 and November 2023 was performed. Participants/materials, setting, methods 193 cycles of women who used follitropin delta were compared to 162 cycles of women who used follitropin alfa. The following clinical outcomes on each treatment group were analyzed: chemical pregnancy rate (serum β hCG), clinical pregnancy rate (gestational sac), ongoing pregnancy rate(gestational sac and fetal heartbeat), serum E2 level at trigger day, cycle proportion of ≥ 10 oocytes retrieval, blastocyst formation rate, cycle proportion of ≥ 5 blastocysts and cycle proportion of ≥ 2 good quality blastocysts. Main results and the role of chance Baseline demographics in the follitropin delta group and the follitropin alfa group were not significantly different: age, 33.9 ± 3.5 years vs 34.5 ± 3.2 years; body weight, 53.5 ± 8.3 kg vs 53.8 ± 5.9 kg; number of previous IVF cycles, 0.2 ± 0.6 vs 0.3 ± 0.7; serum AMH level, 5.5 ± 2.9 ng/mL vs 5.3 ± 3.8 ng/mL, respectively. The chemical pregnancy rate (69.9% vs. 64.8%, P = 0.308), clinical pregnancy rate (58.0% vs. 56.2%, P = 0.748) and ongoing pregnancy rate (51.8% vs. 46.3%, P = 0.338) were comparable between the follitropin delta group and the follitropin alfa group. The individualized follitropin delta treatment resulted in a smaller cycle proportion of ≥ 10 oocytes retrieval (77.7% vs. 90.8%, P &amp;lt; 0.001) with lower serum E2 level at trigger day (3273 ± 1577 pg/mL vs. 3927 ± 1732 pg/mL, p &amp;lt; 0.001). However, the blastocyst formation rate was significantly higher in the follitropin delta group (75.5% vs. 68.7%, p &amp;lt; 0.001). Moreover, the cycle proportion of ≥ 5 blastocysts (71.0% vs. 76.4%, P = 0.286) and the cycle proportion of ≥ 2 good quality blastocysts (51.8% vs. 60.3%, P = 0.115) were comparable between the groups. Limitations, reasons for caution This is a non-controlled, retrospective study. Wider implications of the findings Follitropin delta in its individualized fixed-dose regimen could have the potential to decrease the risk of OHSS by minimizing excessive ovarian response, whereas a similar pregnancy rate to conventional dosing regimen could be expected due to the number of good quality blastocysts secured. Trial registration number not applicable

Abstract Study question Is ovarian stimulation with follitropin delta (FD) in its individualized regimen as efficacious as follitropin alfa and human menopausal gonadotropin (FAHMG)? Summary answer Ovarian stimulation with individualized FD dosing resulted in a significantly higher fertilization rate and number of blastocysts with good quality compared to conventional FAHMG dosing. What is known already Previous randomized controlled trials conducted in Japan, China, Europe, and both North and South America have demonstrated that ovarian stimulation using the individualized FD dosing regimen, which is based on serum anti-Müllerian hormone (AMH) levels and body weight, effectively modulated the ovarian response without compromising pregnancy and live birth rates. Study design, size, duration A retrospective study was conducted by reviewing the medical records of 1,720 IVF/ICSI cycles in 1,272 Japanese patients. The primary endpoint of the study was the ongoing pregnancy rate, assessed at 8 weeks of gestation, in the frozen-thawed embryo transfer. Participants/materials, setting, methods The FD treatment consisted of a fixed daily dose individualized according to each patient’s initial AMH level and body weight (AMH &amp;lt;2.04 ng/ml: 12 μg; AMH ≥2.04 ng/ml: 0.19 to 0.10 μg/kg; min-max 6–12 μg). The FAHMG dose was determined by the antral follicle count (AFC), with the following protocol: for AFC &amp;lt;25, 300 IU/day; for 40&amp;gt; AFC ≥25, 225 IU/day; and for AFC ≥40: 150 IU/day). A progestin-primed ovarian stimulation (PPOS) protocol was applied. Main results and the role of chance Multiple regression analyses (MRA) showed that the use of FD was negatively correlated with the number of oocytes retrieved (NOR) (P = 0.001), and positively correlated with the fertilization rate (FR) (P = 0.02). NOR was comparable between FD and FAHMG (10.9 ± 6.4 versus 11.8 ± 7.8) when the Mann-Whitney test (MW) was applied (P = 0.111), but significantly higher in FAHMG when the patient is younger than 40 years old with AMH ≥2 ng/ml (P &amp;lt; 0.01). The total gonadotropin use was significantly (P &amp;lt; 0.001) reduced from an average of 167.1 ± 46.9 μg (2789.9 ± 782.9 IU) FAHMG to 102.6 ± 31.6 μg FD. FR was significantly higher in FD compared with FAHMG (78.7% versus 74.1%, P &amp;lt; 0.05) on MW. Additionally, MW indicated a significantly higher number of good-quality blastocysts in FD (2.9±2.6) versus with FAHMG (2.4±2.5) (P &amp;lt; 0.05). The blastocysts obtained from FD also showed a significantly higher implantation rate (50.1% versus 39.7%, P &amp;lt; 0.01) and a comparable ongoing pregnancy rate (28.7% versus 25.7%, P = 0.292) compared to those from FAHMG as determined by chi-square test. The higher implantation rate in FD may be attributed to the greater number of good-quality blastocysts obtained compared with FAHMG. Limitations, reasons for caution This study only covered the clinical outcome of women undergoing PPOS protocol with frozen-thawed blastocyst transfers. Wider implications of the findings The present study shows that FD in its individualized fixed-dose regimen has the potential to improve the success rate in frozen-thawed embryo transfer across all ages and with a lower gonadotropin consumption compared to conventional FAHMG dosing. Trial registration number not applicable

Abstract Study question To compare OHSS rates with conventional dosage of follitropin delta in the RITA-1 and RITA-2 trials (hereafter ‘RITA’) to personalized dosing in the ESTHER-1 trial. Summary answer RITA and ESTHER-1 had similar efficacy and OHSS rates despite differences in dosing regimens, possibly due to differences in fresh transfer cancellation rates. What is known already Follitropin delta is a human cell-line derived follicle stimulating hormone whose fixed dosage in ovarian stimulation, personalized based upon body weight and serum anti-Müllerian hormone (AMH) and body weight, has been shown to be safe and effective in Gonadotrophin Releasing Hormone (GnRH) antagonist ovarian stimulation protocols. In the present trial, conventional dosing of follitropin delta allowing for dose revisions has been evaluated in GnRH antagonist ovarian stimulation protocols to demonstrate the broad utility of this gonadotrophin therapeutic and to address United States (US) regulatory considerations. Study design, size, duration RITA were randomized, double-blind, controlled, US multicentre trials of follitropin delta. The primary endpoint was cumulative ongoing pregnancy rate after fresh/frozen transfers within 12 months of cycle start. 1058 women 18-42 years randomized 10:1 to follitropin delta or placebo. ESTHER-1 was a randomized, European multicentre, assessor-blind, noninferiority trial of follitropin delta. The primary endpoints were fresh transfer ongoing pregnancy and implantation rates. 1329 women 18-40 years randomized 1:1 to follitropin delta or follitropin alfa. Participants/materials, setting, methods In RITA, 12 µg/day, 15 µg/day dosages were used for 4 days: 18-34 or 35-42 years, respectively, with 3 µg dose adjustments thereafter depending on response. Human chorionic gonadotropin (hCG) was used if &amp;lt; 20 follicles of ≥ 12 mm and estradiol level &amp;lt;3,000 pg/mL. Else, agonist trigger and fresh transfer cancellation; ≥20 oocytes retrieved also cancelled fresh transfer. In ESTHER-1, hCG was used if &amp;lt; 25 follicles of ≥ 12 mm. Else, agonist trigger, and fresh transfer cancellation. Main results and the role of chance The ongoing pregnancy rate per fresh transfer with follitropin delta was 41.9% in RITA and 36.3% in ESTHER-1. The primary efficacy endpoint was met for all 3 trials. Rates and severity defined by Golan criteria of OHSS observed in RITA and ESTHER-1 were similar, respectively for: all OHSS, any grade (3.1% versus 3.5%), Grade 1 (0.3% versus 0.5%), Grade 2 (0.8% versus 0.9%), Grade 3 (1.8% versus 1.1%), Grade 4 (0.2% versus 0.6%), and Grade 5 (0.1% versus 0.5%). The rate of early OHSS, defined as onset ≤9 days after trigger of final follicular maturation, was also similar, respectively for any grade (2.2% versus 2.6%), Grade 1 (0.3% versus 0.3%), Grade 2 (0.6% versus 0.9%), Grade 3 (1.1% versus 0.8%), Grade 4 (0.1% versus 0.3%) and Grade 5 (0.1 % versus 0.3%). However, the fresh transfer cancellation rate was &amp;gt;3x higher in RITA (35.2%) than in ESTHER-1 (11.1%). Limitations, reasons for caution Other reasons for transfer cancellation in all trials included adverse events or no blastocyst available for transfer; however, no significant differences were observed. A placebo comparator was selected for RITA to meet regulatory requirements for double-blinding; women with ≤3 oocytes retrieved were offered support for treatment outside of the trials. Wider implications of the findings Stimulation with follitropin delta is effective and associated with low rates of OHSS when used with either conventional or personalized dosing. However, stricter criteria for the use of hCG as trigger and allowance of fresh transfer may be required with conventional dosing to maintain this safety profile. Trial registration number NCT01956110, NCT03740737, NCT03738618

Reproductive medicine is actively developing, and new methods, drugs, and protocols are being developed and introduced for the treatment of infertility. Assisted reproductive technologies (ART) are the most effective methods. In ART protocols, ovarian stimulation (OS) is based on gonadotropin use. The choice of the starting dose of gonadotropin is a critical factor in the successful OS and the effectiveness of ART programs. The article describes the development history of gonadotropins and provides current data on their use in ART programs. The use of biosimilars of follitropin alfa in OS is discussed, and the effectiveness of its Russian biosimilar is also addressed. TRANSLATE with x English Arabic Hebrew Polish Bulgarian Hindi Portuguese Catalan Hmong Daw Romanian Chinese Simplified Hungarian Russian Chinese Traditional Indonesian Slovak Czech Italian Slovenian Danish Japanese Spanish Dutch Klingon Swedish English Korean Thai Estonian Latvian Turkish Finnish Lithuanian Ukrainian French Malay Urdu German Maltese Vietnamese Greek Norwegian Welsh Haitian Creole Persian TRANSLATE with COPY THE URL BELOW Back EMBED THE SNIPPET BELOW IN YOUR SITE Enable collaborative features and customize widget: Bing Webmaster Portal Back

Determining the cost-effectiveness of follitropin alfa biosimilar compared to follitropin alfa originator in women undergoing fertility treatment in France

To compare the cost-effectiveness of originator (reference) recombinant human follicle stimulating hormone alfa (rhFSH-α) (follitropin alfa, GONAL-f) and its biosimilar (rhFSH, JinSaiHeng) in assisted reproductive technology (ART) from a Chinese patient perspective. A decision tree model was developed to simulate the treatment pathway of infertile women undergoing ART using GONAL-f or JinSaiHeng. Published clinical and cost data were used to evaluate the cost-effectiveness of the rhFSH-α. The cumulative live birth rate (CLBR), direct medical costs and costs per cumulative live birth were estimated via an analytic decision-tree model. CLBR of GONAL-f was higher than JinSaiHeng preparation (88.3% vs 84.4%), while the cost per cumulative live birth was lower (51,475 vs 52,095 CNY). The originator rhFSH-α was associated with higher CLBR and lower cost per cumulative live birth, with incremental cost per additional live birth of 38,096 CNY (Chinese Yuan).