Phase I, two-way, crossover study to demonstrate bioequivalence and to compare safety and tolerability of single-dose XM17 vs Gonal-f® in healthy women after follicle-stimulating hormone downregulation

Andreas Lammerich, Arnd Mueller, Peter Bias, Andreas Lammerich, Arnd Mueller, Peter Bias

Abstract

Background: XM17 is a recombinant human follicle-stimulating hormone (rhFSH) intended mainly for use in controlled ovarian hyperstimulation and the treatment of anovulation. The purpose of the current study was to establish bioequivalence, safety and tolerability of single 300-IU subcutaneous (sc) doses of XM17 to that of the reference follitropin alfa (Gonal-f(®)) in healthy young women.

Methods: This open-label, Phase I, single-dose, single-center, two-way crossover study was conducted from February to May 2009. Thirty-six women aged 18-39 years were included, with a study duration of ~27 days per participant. After endogenous FSH downregulation with goserelin (3.6 mg) on study Day 0, XM17 and Gonal-f(®) were administered on Days 11 and 19 in random sequence. Frequent serum samples were drawn for standard pharmacokinetics until 168 h postdosing. Laboratory values, adverse events (AEs) and local tolerability were assessed throughout the study period. Primary endpoints included Cmax and AUC0-t. Secondary endpoints included additional pharmacokinetic (PK) parameters, safety and tolerability.

Results: Ratios of XM17 to Gonal-f(®) for Cmax and AUC0-t equaled 1.017 (90 % confidence interval [CI]: 0.958, 1.080) and 1.028 (90 % CI: 0.931, 1.134), respectively, with the CIs contained within the predefined interval (0.8, 1.25). Ratios for AUC0-168h, AUC0-∞ and t1/2 were also ~1, and no difference in tmax was detected. Both XM17 and Gonal-f(®) were well tolerated, with no detectable anti-FSH antibodies, serious AEs or AEs leading to discontinuation or dose reduction.

Conclusions: PK bioequivalence of single 300-IU sc doses of XM17 to the reference product Gonal-f® was statistically demonstrated. XM17 was well tolerated both systemically and locally.

Trial registration: ClinicalTrials.gov: NCT02592031 ; date of registration: 28 October, 2015.

Figures

Fig. 1
Fig. 1
Subject Disposition. *Or clinically relevant findings in transvaginal ultrasound. †Clinically relevant findings
Fig. 2
Fig. 2
Mean (± SD) serum concentrations of FSH (IU/L) after single sc doses of XM17 or Gonal-f® (corrected for predose FSH levels) in healthy women (linear scale)

References

    1. Daya S. Follicle-stimulating hormone in clinical practice: an update. Treat Endocrinol. 2004;3:161–71. doi: 10.2165/00024677-200403030-00004.
    1. Dhillon S, Keating GM. Lutropin alfa. Drugs. 2008;68:1529–40. doi: 10.2165/00003495-200868110-00005.
    1. Pouwer AW, Farquhar C, Kremer JAM. Long-acting FSH versus daily FSH for women undergoing assisted reproduction. Cochrane Database Syst Rev. 2012;6:CD009577.
    1. European Medicines Agency. Ovaleap (follitropin alfa) [assessment report]. 31 July 2013. (2013). Accessed 25 Feb 2015.
    1. Weise M, Bielsky MC, De Smet K, Ehmann F, Ekman N, Narayanan G, et al. Biosimilars-why terminology matters. Nat Biotechnol. 2011;29:690–3. doi: 10.1038/nbt.1936.
    1. European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP). Guideline on non-clinical and clinical development of similar biological medicinal products containing recombinant human follicle stimulating hormone (r-hFSH). (2013). Accessed 25 Feb 2015.
    1. European Medicines Agency, Committee for Medicinal Products for Human Use (CHMP). Guideline on the investigation of bioequivalence. (2010). Accessed 20 May 2015.
    1. Lammerich A, Bias P, Gertz B. Phase 1 safety, tolerability, and pharmacokinetic study of single ascending doses of XM17 (recombinant human follicle-stimulating hormone) in downregulated healthy women. Int J Womens Health. 2015;7:707–16. doi: 10.2147/IJWH.S83418.
    1. World Medical Association. WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects. Ferney-Voltaire, France, World Medical Association, Inc. 2012.
    1. InternationalConference on Harmonisation. Guideline for Good Clinical Practice (ICH Guideline E6 [R1]. (2012). Accessed 20 May 2015.
    1. le Cotonnec JY, Porchet HC, Beltrami V, Khan A, Toon S, Rowland M. Clinical pharmacology of recombinant human follicle-stimulating hormone (FSH). I. Comparative pharmacokinetics with urinary human FSH. Fertil Steril. 1994;61:669–78.
    1. Matta WHM, Shaw RW, Burford GD. Endocrinologic and clinical evaluation following a single administration of a gonadotrophin-releasing hormone agonist (Zoladex), in a depot formulation, to premenopausal women. Fertil Steril. 1988;49:163–5.
    1. Gonal-f [summary of product characteristics]. London: European Medicines Agency; 2010.

Source: PubMed

Sponsoren und Mitarbeiter

Krankheiten

Drogeninterventionen

3
Abonnieren