July 2, 2018
Ferring Pharmaceuticals announced today a new analysis* of data from the Phase 3 ESTHER-1 trial1 showing that natural variations in anti-Müllerian hormone (AMH) levels during and between a woman’s menstrual cycle have no clinically relevant impact on ovarian response (the number of eggs produced) when using AMH to dose Rekovelle® (follitropin delta) for ovarian stimulation (OS).2 The data were presented today at the 34th Annual Meeting of the European Society of Human Reproduction and Embryology (ESHRE) in Barcelona, Spain.
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AMH Infographic (Photo: Business Wire)
According to the new analysis, for 95% of women treated with Rekovelle, variations in ovarian response were limited to a difference of plus or minus one egg.2 This reinforces that AMH measured on any day of a woman’s menstrual cycle can be used to individualise the dose of Rekovelle. AMH is measured with a companion diagnostic, the Elecsys® AMH Plus immunoassay from F. Hoffmann-La Roche Ltd (Roche).
“We are excited to share the results of this new Rekovelle analysis which add to existing evidence showing AMH is a robust predictor of ovarian response to fertility treatment,” said Professor Klaus Dugi, Chief Medical Officer, Ferring Pharmaceuticals. “I believe these data will further strengthen the growing confidence of doctors in the use of AMH to personalise dosing of fertility treatment for their patients.”
Ovarian response to stimulation varies considerably from woman to woman3 and unexpected extreme responses have implications on efficacy and safety.4,5 Aiming to avoid extremes in ovarian response, the validated Rekovelle dosing algorithm uses AMH and body weight to determine a personalised dose for patients, from the start of treatment.
This analysis of data from the Phase 3 ESTHER-1 trial adds to consistent efficacy results seen with Rekovelle in clinical trials to date. The ESTHER-1 trial showed that women undergoing their first treatment cycle receiving individualised treatment with Rekovelle, compared to conventional dosing regimen with follitropin alfa,Ɨǂ had similar ongoing pregnancy and embryo implantation rates.1
The ESTHER-1 trial also showed that more women receiving individualised treatment with Rekovelleachieved the target response of 8-14 eggs compared to conventional dosing regimen with follitropin alfa.1ǂ§ Evidence shows that beyond 15 eggs there is no additional benefit, in terms of live birth rate, in the number of eggs produced through OS in a fresh cycle.6,7
About Rekovelle (follitropin delta)
Rekovelle is a human recombinant follicle stimulating hormone (rFSH) with an approved dosing algorithm designed for predictable ovarian response.8 It is the first rFSH derived from a human cell line (PER.C6® cell line). Rekovelle is structurally and biochemically distinct from other existing rFSH gonadotrophins.8,9 Rekovelle is approved for use in ovarian stimulation (OS) for induction of the development of multiple follicles in women undergoing assisted reproductive technologies (ART), such as an in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI).8 The individualised dosing of Rekovelle is determined using an approved algorithm, based on a woman’s anti-Müllerian hormone (AMH) level and body weight.1,8,10 AMH is a biomarker used to assess ovarian reserve and can help predict ovarian response.11 AMH will be measured with a companion diagnostic, the Elecsys® AMH Plus immunoassay from F. Hoffmann-La Roche Ltd (Roche).12,13
As of 15 June 2018, Rekovelle was approved in 37 countries and available in 17 countries worldwide.
About the ESTHER trials
The ESTHER trials (Evidence-based Stimulation Trial with Human recombinant FSH in Europe and Rest of World) were randomised, assessor-blind, controlled, multicentre Phase 3 trials involving patients in 11 countries and over 2,000 cycles of OS.1,14
ESTHER-1 was a trial of 1,326 patients in 11 countries undergoing their first ART cycle. Patients were randomised 1:1 to receive treatment with individualised Rekovelle, a fixed daily dose based on serum AMH levels** and body weight, or conventional follitropin alfa dosing.1ǂ The co-primary endpoints of ongoing pregnancy rates and ongoing implantation rates were met, demonstrating comparable efficacy of Rekovelle to conventional treatment.1 Rekovelle’s individualised dosing regimen aims to obtain an ovarian response associated with a favourable safety/efficacy profile, i.e. aims to achieve an adequate number of eggs and reduce interventions to prevent ovarian hyperstimulation syndrome.8
ESTHER-2 evaluated the immunogenicity of Rekovelle in a subset of ESTHER-1 patients undergoing repeated cycles of OS for ART. Data demonstrated no increased immunogenicity risk with Rekovelle after exposure in repeated cycles.8,14
About Ferring Pharmaceuticals
Ferring Pharmaceuticals is a research-driven, specialty biopharmaceutical group committed to helping people around the world build families and live better lives. Headquartered in Saint-Prex, Switzerland, Ferring is a leader in reproductive medicine and women’s health, and in specialty areas within gastroenterology and urology. Ferring has been developing treatments for mothers and babies for over 50 years and has a portfolio covering treatments from conception to birth. Founded in 1950, privately-owned Ferring now employs approximately 6,500 people worldwide, has its own operating subsidiaries in nearly 60 countries and markets its products in 110 countries.
About the Elecsys® AMH Plus immunoassay from Roche
The Elecsys® AMH Plus immunoassay from Roche has been shown to provide a precise, reliable and robust measurement of AMH levels.12,13,15,16,17,18 This fully automated Elecsys® AMH Plus immunoassay, run on the cobas®e and Elecsys® immunoassay analysers, determines AMH levels in 18 minutes, making it appropriate for routine clinical use. The Elecsys® AMH Plus immunoassay is intended to be used for assessment of ovarian reserve, prediction of response to OS and establishment of the individual daily dose of Ferring follitropin delta in combination with body weight in OS for the development of multiple follicles in women undergoing an assisted reproductive technology programme.8,12,15,17,18
1 Nyboe Andersen A, Nelson SM, Fauser BC, et al. Individualised versus conventional ovarian stimulation for an in vitro fertilization: a multicenter, randomized, controlled assessor-blinded, phase 3 noninferiority trial. Fertil Steril. 2017 02 [cited 2018 Jun 14];107(2):387-396.
2 Nelson SM, Larsson P, Mannaerts B, et al. AMH variability and its implications for the number of oocytes retrieved following individualized dosing with follitropin delta [abstract]: 34th Annual Meeting of the European Society of Human Reproduction and Embryology (ESHRE); 2018; Barcelona, Spain. Abstract no P-651.
3 Fauser BC, Diedrich K, Devroey P. Evian Annual Reproduction Workshop Group 2007. Hum Reprod Update; 2008 02 [cited 2018 Jun 14];14:1–14.
4 La Marca A, Sunkara SK. Individualization of controlled ovarian stimulation in IVF using ovarian reserve markers: from theory to practice. Hum Reprod Update. 2014 01 [cited 2018 Jun 14;20:124–40.
5 Steward RG, Lan L, Shah AA, et al. Oocyte number as a predictor for ovarian hyperstimulation syndrome and live birth: an analysis of 256,381 in vitro fertilization cycles. Fertil Steril. 2014 04 [cited 2018 Jun 14];101:967–973.
6 Drakopoulos P, Blockeel C, Stoop D, et al. Conventional ovarian stimulation and single embryo transfer for IVF/ICSI. How many oocytes do we need to maximize cumulative live birth rates after utilization of all fresh and frozen embryos? Hum Reprod. 2016 02 [cited 2018 Jun 14];31(2):370-376.
7 Ji J, Liu Y, Hong Tong X, et al. The optimum number of oocytes in IVF treatment: an analysis of 2455 cycles in China. Hum Reprod. 2013 10 [cited 2018 Jun 14];28(10):2728-2734.
8 Rekovelle® Summmary of Product Characteristics. Date of publication 2016 12 [cited 2018 Jun 14]. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Summary_for_the_public/human/003994/WC500220238.pdf.
9 Olsson H, Sandström 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. Journal of Clinical Pharmacology. 2014 11 [cited 2018 Jun 14];54(11):1299–307.
10 Arce JC, Nyboe Andersen A, Fernandez Sanchez M, et al. Ovarian response to recombinant human follicle stimulating hormone: a randomized, anti-Müllerian hormone–stratified, dose–response trial in women undergoing in vitro fertilization/intracytoplasmic sperm injection. Fertility and Sterility. 2014 12 [cited 2018 Jun 14];102(6):1633–1640.
11 La Marca A, Sighinolfi G, Radi D, et al. Anti-Mullerian hormone (AMH) as a predictive marker in assisted reproductive technology (ART). Hum Reprod Update. 2010 03 [cited 2018 Jun 14];16(2):113-130.
12 Deeks ED. Elecsys® AMH assay: a review in anti-Müllerian hormone quantification and assessment of ovarian reserve. Molecular Diagnosis & Therapy. 2015 07 [cited 2018 Jun 14];19: 245-249.
13 Roche Diagnostics. Elecsys® AMH (anti-Müllerian hormone): Method sheet. (2015). Date of publication 2014 [cited 2018 Jun 14]. Available from: http://www.cobas.com/content/dam/cobas_com/pdf/product/Elecsys%20AMH/Elecsys%20AMH%20FactSheet.pdf.
14 Buur Rasmussen A, Mannaerts B, Klein BM, et al. Low immunogenicity potential of follitropin delta, a recombinant FSH preparation produced from a human cell line: Results from phase 3 trials (ESTHER-1 and ESTHER-2). Human Reproduction. 2016 07 [cited 2018 Jun 14];31:385.
15 Gassner D. & Jung R. First fully automated immunoassay for anti-Müllerian hormone. Clinical Chemistry and Laboratory Medicine. 2014 08 [cited 2018 Jun 14];52(8):1143-1152.
16 Anderson RA, Anckaert E, Bosch E, et al. Prospective study into the value of the automated Elecsys® Anti-Müllerian Hormone assay for the assessment of the ovarian growing follicle pool. Fertility and Sterility. 2015 04 [cited 2018 Jun 14];103(4):1074–1080.e4.
17 Nelson SM, Pastuszek E, Kloss G, et al. Two new automated, compared with two enzyme-linked immunosorbent anti-Müllerian hormone assays. Fertility and Sterility. 2015 07 [cited 2018 Jun 14];104(4):1016-1021.e6.
18 Hyldgaard J, Bor P, Ingerslev HJ, et al. Comparison of two different methods for measuring anti-Müllerian hormone in a clinical series. Reproductive Biology and Endocrinology. 2015 09 [cited 2018 Jun 14];13(1):107.
* A sub-analysis of the ESTHER-1 study population including 1,326 women (aged 18-40 years). Serum AMH was measured at a random day at screening and at cycle day 2-3 prior to stimulation using the Elecsys® AMH Plus immunoassay (Roche). Limitations: A centralised AMH measuring laboratory was used which may give rise to reduced AMH variability. AMH measurements were compared with samples taken within 3 months prior to ovarian stimulation, longer time intervals may have shown different variability due to the age-related decline in AMH.
ƗGONAL-f®, registered trademark of Merck KGaA, Darmstadt, Germany.
ǂ Conventional dosing of follitropin alfa is 150 IU/d for 5 days, with potential subsequent dose adjustments at a maximum of 450 IU/d.1
§ ESTHER-1 was neither designed nor powered to assess results based on secondary endpoints. Predefined secondary endpoints are used as a measurement to yield supportive evidence to evaluate additional effects relevant to informing the Rekovelle individualised dosing regimen. No confirmatory conclusions can be derived.
** AMH is measured by a companion diagnostic, the Elecsys® AMH Plus immunoassay from F. Hoffmann-La Roche Ltd (Roche).