Ferring announces results demonstrating the efficacy and safety of follitropin delta for women undergoing in vitro fertilisation using an agonist protocol

Ferring announces results demonstrating the efficacy and safety of follitropin delta for women undergoing in vitro fertilisation using an agonist protocol

• BEYOND is the first randomised controlled trial comparing efficacy and safety of follitropin delta (Rekovelle^®) in a gonadotrophin-releasing hormone (GnRH) agonist versus antagonist protocol during first ovarian stimulation cycle for in vitro fertilisation (IVF)/ intracytoplasmic sperm injection (ICSI).¹
• An additional estimated 1.3 oocytes were retrieved per woman in the agonist group vs. the antagonist group with similar safety.¹
• These data further support physicians when an agonist protocol is indicated or preferred.
• BEYOND reinforces Ferring’s continuous commitment to science and adds to the robust body of clinical evidence on the efficacy and safety of follitropin delta.

Saint-Prex, Switzerland – 17 May, 2024: Ferring, a global biopharmaceutical company, today announced that Human Reproduction published results from the BEYOND trial. This is the first trial to compare individualised follitropin delta dosing using a GnRH agonist versus a GnRH antagonist protocol in women aged 18-40 years, with anti-Müllerian hormone (AMH) levels below 35 pmol/L who are undergoing their first ovarian stimulation cycle for IVF/ICSI.¹

Results from this randomised, controlled, open-label, multicentre trial showed that a statistically significant mean difference of 1.3 extra oocytes (95% CI: 0.22; 2.40, p=0.0185) were retrieved for women using the GnRH agonist protocol versus women using antagonist protocol.¹ Use of both GnRH agonist and antagonist protocols yielded similar results in safety.¹ The results supported a European Medicines Agency (EMA) SmPC label update to include information on the use of follitropin delta using the GnRH agonist protocol.²

Follitropin delta is the only recombinant follicle-stimulating hormone (rFSH) for ovarian stimulation derived from a human cell line that uses individualised dosing calculated through an approved algorithm based on bodyweight and AMH.² The BEYOND study was set up to address the gap in knowledge when administering a fixed daily dose of follitropin delta in a GnRH agonist protocol.¹ Before BEYOND, there were no comparative randomised clinical trial data examining the efficacy and safety of individualised follitropin delta in a GnRH agonist protocol versus an antagonist protocol.¹

“It’s important to have data that compares the efficacy and safety of both GnRH protocols, when tailoring a fixed-dose of follitropin delta to individual patients,” said Rita Lobo, M.D. ObGyn, Senior Medical Director, Global R&D and Reproductive Medicine, Ferring Pharmaceuticals. “The BEYOND results provide reassurance to physicians that they can safely prescribe either of the GnRH protocols to effectively tailor treatment strategies to the individual circumstances of each person going through IVF.”

Current European Society of Human Reproduction and Embryology (ESHRE)³ international guidelines recommend the general use of GnRH antagonist protocols over GnRH agonist protocols for ovarian stimulation, given comparable efficacy and better safety profile.⁴ However for predicted poor responders, GnRH antagonists and GnRH agonists are equally recommended.⁴ In clinical practice, GnRH agonist protocols can be preferred when there is a need to schedule treatments and during ovulation induction, such as when a patient needs to avoid a weekend oocyte retrieval.⁵

“The BEYOND trial showcases our continued commitment to science, aimed at pioneering advancements and ongoing evidence generation to support individuals on their personal journeys to build families and live better lives,” said Julia Hoover, Global Franchise Head of Reproductive Medicine, Ferring Pharmaceuticals.

The BEYOND¹ study results add to the existing data from the ESTHER⁶, STORK⁷ and GRAPE⁸ randomised clinical trials and the real word evidence PROFILE⁹ study, addressing the efficacy and safety of follitropin delta across a broad range of patients.

About the BEYOND study

BEYOND was a European-based, multi-centre, randomized, controlled, open-label, parallel-group trial comprised of 437 randomised subjects (435 treated) aged 18-40: 220 subjects randomised to the GnRH agonist protocol (n= 220) and 215 subjects randomised to the GnRH antagonist protocol (n=215). The trial covered the first controlled ovarian stimulation cycle and post-trial activities covered pregnancy follow-up to live birth and 4 weeks after birth. Women 18-40 years old with AMH less than or equal to AMH 35 pmol/L and body mass index (BMI) 17.5-32.0 kg/m2 were enrolled at 16 specialist reproductive health clinics in Austria, Denmark, Israel, Italy, the Netherlands, Norway and Switzerland and were undergoing their first IVF/ISCI cycle. Half of participants had unexplained infertility (fertility with no apparent cause).

The primary endpoint was the number of oocytes retrieved. The main secondary and safety endpoints were the total follitropin delta dose and the number of stimulation days; the proportion of subjects with cycle cancellation due to poor ovarian response or excessive ovarian response; blastocyst number and quality on Day 5 after oocyte retrieval; proportion of subjects with blastocyst transfer cancellation due to risk of ovarian hyperstimulation syndrome (OHSS); pregnancy rates; frequency and intensity of adverse events; proportion of participants with either early or late OHSS of moderate/severe grade¹⁰ and the proportion of subjects with late OHSS (including OHSS of moderate/severe grade). The pre-specified post-trial endpoints comprised live birth rate and neonatal health.

Adverse drug reactions

The overall proportions of participants experiencing adverse events and serious adverse events were similar in both the agonist and antagonist treatment groups. A total of 13 participants discontinued from the trial due to an adverse event, comprising 5/202 participants (2.5%) in the GnRH agonist group (COVID-19 infection, n=1; OHSS, n=4) and 8/204 participants (3.9%) in the antagonist group (increased progesterone, n=1; adnexal torsion, n=1; endometrial disorder, n=1; hydrometra, n=1; uterine polyp, n=1). All AEs leading to discontinuation occurred after completion of ovarian stimulation but resulted in fresh blastocyst transfer cancellation.

About GnRH protocols

Gonadotrophin-releasing hormone (GnRH) agonists and antagonists are used as concomitant treatment during ovarian stimulation to prevent premature luteinisation and ovulation for IVF/ICSI.^11,12

About follitropin delta (Rekovelle)

Follitropin delta is a human cell line-derived rFSH with an approved dosing algorithm designed for a predictable ovarian response.² It is the first rFSH derived from a human cell line (PER.C6® cell line). Follitropin delta is structurally and biochemically distinct from other existing rFSH gonadotrophins.^2,13 Follitropin delta is approved in certain markets for use in controlled ovarian stimulation for the development of multiple follicles in women undergoing assisted reproductive technologies (ART), such as IVF or ICSI cycle. The individualised dosing of follitropin delta is determined using an approved algorithm, based on a woman’s AMH level and body weight.^2,6 AMH is a biomarker used to assess ovarian reserve and can help predict ovarian response.^6,14 The follitropin delta dose should be based on AMH level, measured using the ELECSYS AMH Plus immunoassay from Roche, the ACCESS AMH Advanced from Beckman Coulter, or LUMIPULSE G AMH from Fujirebio.² Follitropin delta is approved in certain markets for use.

About Ferring Pharmaceuticals

Ferring Pharmaceuticals is a privately owned, research-driven, specialty biopharmaceutical group committed to building families and helping people live better lives. We are leaders in reproductive medicine and maternal health, and in areas of gastroenterology and urology. We are at the forefront of innovation in microbiome-based therapeutics and uro-oncology intravesical gene therapy. Ferring was founded in 1950 and employs more than 7,000 people worldwide. The company is headquartered in Saint-Prex, Switzerland, and has operating subsidiaries in more than 50 countries which markets its medicines in over 100 countries.

Learn more at www.ferring.com, or connect with us on LinkedIn, Instagram, YouTube, Facebook and X (Twitter).

References

1. Lobo R, Soerdal T, Ekerhovd E et al. “BEYOND: A Randomized Controlled Trial Comparing Efficacy and Safety of Individualized Follitropin Delta Dosing in a GnRH Agonist Versus Antagonist Protocol During the First Ovarian Stimulation Cycle.” Human Reproduction, 2024, deae092. https://doi.org/10.1093/humrep/deae092
2. Follitropin Delta (Rekovelle) Summary of Product Characteristics. Date of publication 2017. Approved on 12 December 2016 and last updated on the EMA website in October 2023. Available from https://www.ema.europa.eu/en/medicines/human/EPAR/rekovelle [Accessed May 2024].
3. European Society of Human Reproduction and Embryology (ESHRE) Reproductive Endocrinology Guideline Group. (October 2019). Ovarian Stimulation for IVF/ICSI. ESHRE Reproductive Endocrinology Guidelines.
4. Ovarian Stimulation, The ESHRE Guideline Group On et al. “ESHRE guideline: ovarian stimulation for IVF/ICSI†.” Human reproduction open vol. 2020,2 hoaa009. 1 May. 2020, doi:10.1093/hropen/hoaa009
5. Feichtinger M, Karlström PO, Olofsson JI, et al. Weekend-free scheduled IVF/ICSI procedures and single embryo transfer do not reduce live-birth rates in a general infertile population. Acta Obstetricia et Gynecologica Scandinavica 2017;96: 1423-1429.
6. Andersen, A. N., Nelson, S. M., Fauser, B. et al. (2017). Individualized versus conventional ovarian stimulation for in vitro fertilization: A multicenter, randomized, controlled, assessor-blinded, phase 3 noninferiority trial. Fertility and Sterility, 107(2), 387-396.
7. Ishihara O, Arce JC, Japanese Follitropin Delta Phase 3 Trial G. Individualized follitropin delta dosing reduces OHSS risk in Japanese IVF/ICSI patients: a randomized controlled trial. Reprod Biomed Online. 2021 May;42(5):909-18. PubMed PMID: 33722477. Epub 2021/03/17.
8. Qiao J, Zhang Y, Liang X, et al. A randomised controlled trial to clinically validate follitropin delta in its individualised dosing regimen for ovarian stimulation in Asian IVF/ICSI patients. Hum Reprod. 2021 Jun 28;36(9):2452-62. PubMed PMID: 34179971. Epub 2021/06/29.
9. Blockeel C, Griesinger G, Rago R, et al. Prospective multicenter non-interventional real-world study to assess the patterns of use, effectiveness and safety of follitropin delta in routine clinical practice (the PROFILE study). Frontiers in Endocrinology. 2022 Dec 22;13:992677. PMID: 36619578.
10. Golan A, Ron-el R, Herman A, et al. Ovarian hyperstimulation syndrome: an update review. Obstet Gynecol Surv 1989;44: 430-440.
11. Lambalk CB, Banga FR, Huirne JA, et al. GnRH antagonist versus long agonist protocols in IVF: a systematic review and meta-analysis accounting for patient type. Hum Reprod Update 2017;23: 560-579.
12. Toftager M, Bogstad J, Lossl K, et al. Cumulative live birth rates after one ART cycle including all subsequent frozen-thaw cycles in 1050 women: secondary outcome of an RCT comparing GnRH-antagonist and GnRH-agonist protocols. Hum Reprod 2017;32: 556-716 567.
13. Olsson H, Sandstrom R, Grundemar L. Different pharmacokinetic and pharmacodynamic properties of recombinant follicle-stimulating hormone (rFSH) derived from a human cell line compared with rFSH from a non-human cell line. J Clin Pharmacol. 2014 Nov;54(11):1299-307. PubMed PMID: 24800998. Epub 20140521.
14. Meczekalski, B et al. “Fertility in women of late reproductive age: the role of serum anti-Müllerian hormone (AMH) levels in its assessment.” Journal of endocrinological investigation vol. 39,11 (2016): 1259-1265. doi:10.1007/s40618-016-0497-6

For more information, please contact

Amy Cheshire
Director, Corporate Communications
Amy.Cheshire@ferring.com

Samara Barr
Senior Account Manager, Syneos Health Communications
Samara.Barr@syneoshealth.com