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

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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 C _max and AUC _0-t. Secondary endpoints included additional pharmacokinetic (PK) parameters, safety and tolerability.

Results

Ratios of XM17 to Gonal-f ^® for C _max and AUC _0-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 AUC _0-168h, AUC _0-∞ and t _1/2 were also ~1, and no difference in t _max 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.

Related collections

Most cited references 8

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Biosimilars-why terminology matters.

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Follicle-stimulating hormone (FSH), a glycoprotein produced by the anterior pituitary gland, plays an important role in the regulation of fertility in both men and women. FSH is used clinically to treat women with anovulatory infertility, for controlled ovarian stimulation in women being treated with assisted reproductive technologies (ART), and in the treatment of male hypogonadotrophic hypogonadism. Urine-derived gonadotropin preparations containing variable amounts of FSH together with urinary proteins have been available for many years. More recently, FSH preparations produced using recombinant DNA technology have become available. Recombinant FSH has a high specific activity, high purity, and guaranteed consistency among batches. Two recombinant FSH preparations have been available for clinical use for some years: follitropin-alpha and follitropin-beta. The continuing development of recombinant FSH has recently resulted in a new presentation (follitropin-alpha filled by mass [FbM]). This product can be filled by mass (microg) with an activity (IU), reflecting exceptional consistency as a result of refinement and improvement in the manufacturing process, allowing the clinician to deliver a guaranteed dose of FSH. Experience with recombinant FSH in the treatment of male hypogonadotrophic hypogonadism is limited, but the available data suggest that recombinant FSH has a similar efficacy to urine-derived preparations (urofollitropin). In patients with WHO group I anovulatory infertility, the use of recombinant FSH to stimulate follicular development is effective and well tolerated. In patients with WHO group II anovulation, protocols based on recombinant FSH are more effective than conventional protocols using urofollitropin. Comparative studies and a meta-analysis have shown that recombinant FSH is more effective than urofollitropin for controlled ovarian stimulation in women undergoing ART. Pharmacoeconomic modeling indicates that follitropin-alpha is more cost effective than urofollitropin in a range of different healthcare systems. The available evidence from comparative studies of the two recombinant FSH preparations suggests that follitropin-alpha may have an advantage over follitropin-beta in terms of efficacy. Follitropin-alpha is superior to follitropin-beta in terms of local tolerability. Recent preliminary studies suggest an efficacy advantage for follitropin-alpha FbM compared with standard follitropin-alpha. The FbM presentation appears to represent an advance on standard preparations of recombinant FSH in terms of consistency and clinical efficacy.

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Katherine Y. Le, A. K. Azad Khan, S Toon … (1994)

To assess and compare the pharmacokinetics of recombinant human FSH with those of a reference preparation of urinary human FSH. Urinary human FSH and recombinant human FSH (Metrodin and Gonal-F; Laboratoires Serono, Aubonne, Switzerland) were administered in a balanced, random order, crossover sequence as a single i.v. dose of 150 or 300 IU separated by 1 week of washout to 12 pituitary down-regulated, healthy female volunteers. Serum FSH concentrations were measured by an immunoradiometric assay (IRMA) and by an in vitro rat granulosa cell aromatase bioassay. Urine FSH concentrations were measured by IRMA. The mean concentration-time profiles after 150 IU of urinary human FSH and recombinant human FSH were superimposed, and the mean profile after 300 IU of recombinant human FSH was double that of the 150 IU dose. The data for both FSH preparations were well described by a biexponential equation. Total clearance of the preparations was comparable, judging from immunoassay and bioassay data (0.5 and 0.15 L/h, respectively). Based on the immunoassay, renal clearance of urinary human FSH was 0.1 L/h, whereas for recombinant human FSH it was slightly lower at 0.07 L/h, indicating that less than one fifth of the administered dose was excreted in the urine. Immunoassay showed that the two preparations were similar in terms of initial and terminal half-lives (2 and 17 hours, respectively). The volumes of distribution at steady state (11 L) were similar. The results of the in vitro bioassay confirmed this pharmacokinetic analysis. Just after i.v. administration, an initial decrease in the serum bioassay:immunoassay ratio was observed because of dilution of urinary human FSH or of recombinant human FSH in the residual endogenous FSH pool. Then the ratio increased progressively with time, suggesting either metabolic selection or activation of both types of injected human FSH toward forms with greater in vitro bioactivity. The bioassay:immunoassay ratio returned to baseline by day 7. The results obtained in this study indicate that the following [1] the pharmacokinetic characteristics of recombinant human FSH are similar to those of urinary human FSH; [2] the terminal half-life of human FSH is approximately 1 day; [3] after a single i.v. injection of human FSH a progressive increase in FSH bioassay: immunoassay ratio is observed; and [4] clinical use of recombinant human FSH could follow protocols and treatment regimens currently applied to urinary human FSH.

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Author and article information

Contributors

Andreas Lammerich: +49 (0)731 402 3891 , andreas.lammerich@ratiopharm.de

Arnd Mueller: Arnd.Mueller@ratiopharm.de

Peter Bias: Peter.Bias@ratiopharm.de

Journal

Journal ID (nlm-ta): Reprod Biol Endocrinol

Journal ID (iso-abbrev): Reprod. Biol. Endocrinol

Title: Reproductive Biology and Endocrinology : RB&E

Publisher: BioMed Central (London )

ISSN (Electronic): 1477-7827

Publication date (Electronic): 1 December 2015

Publication date PMC-release: 1 December 2015

Publication date Collection: 2015

Volume: 13

Electronic Location Identifier: 130

Affiliations

Merckle GmbH, Member of the Teva Group, Graf-Arco-Str. 3, 89079 Ulm, Germany

Article

Publisher ID: 124

DOI: 10.1186/s12958-015-0124-y

PMC ID: 4665917

PubMed ID: 26621118

SO-VID: 3a672490-da3b-4057-b1a2-b6e9224e0807

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 8 July 2015

Date accepted : 20 August 2015

Custom metadata

ScienceOpen disciplines: Human biology

Keywords: recombinant human follicle-stimulating hormone,infertility,pharmacokinetics

Data availability:

ScienceOpen disciplines: Human biology

Keywords: recombinant human follicle-stimulating hormone, infertility, pharmacokinetics