Phase 1 safety, tolerability, and pharmacokinetic study of single ascending doses of XM17 (recombinant human follicle-stimulating hormone) in downregulated healthy women

Abstract

Background: XM17 is a recombinant human follicle-stimulating hormone (follitropin alfa) for stimulation of multifollicular development in women undergoing controlled ovarian hyper-stimulation during assisted reproductive therapy and for treatment of anovulation. Manufactured using Chinese hamster ovary cells transfected with the human follicle-stimulating hormone gene, XM17 has an identical amino acid sequence to that of the human protein as well as to those of the other approved recombinant human follicle-stimulating hormone products. Glycosylation patterns may differ slightly between products. The objectives of this first-in-human study were to assess the safety, tolerability, pharmacokinetics, and dose-proportionality of single ascending subcutaneous doses of XM17 in healthy young female volunteers.

Methods: Endogenous follicle-stimulating hormone was downregulated by implanting a 1-month depot of goserelin acetate 3.6 mg on day 0 in eligible subjects. On day 14 of the experimental period, subjects received one of four ascending doses of XM17. Blood sampling to obtain the pharmacokinetic profile of XM17 was done at frequent intervals until 168 hours post-dose.

Results: Following downregulation of endogenous follicle-stimulating hormone to <4 IU/L, 40 subjects (of mean age 29±5.4 years) received single subcutaneous doses of 37.5 (n=4, pilot group), 75, 150, or 300 IU (n=12 each) of XM17. The mean serum concentration-time profiles of XM17 revealed dose-related increases in maximum concentration (Cmax) within 24 hours followed by monoexponential decay for the three higher dose levels. Slopes estimated by linear regression for Cmax and AUC0-168h were ~1.0 (0.9052 IU/L and 1.0964 IU·h/L, respectively). For each IU of XM17 administered, Cmax and AUC0-168h rose by 0.032 IU/L and 2.60 IU·h/L, respectively. Geometric mean elimination half-life ranged from 54 to 90 hours. No antibodies to XM17 were detected. The most common treatment-emergent adverse events were headache (12 events in eleven [27.5%] subjects) and dizziness (four events in four [10%] subjects); two subjects (5%) reported mild pain on touch at the injection site.

Conclusion: Single subcutaneous doses of XM17 up to 300 IU in healthy young women exhibited dose-proportional pharmacokinetics with good safety and tolerability.

Keywords: anovulation; assisted reproductive technology; biosimilar; follitropin alfa.

Figure 1

Study schema and schedule of events. Abbreviations: ECG, electrocardiogram; FSH, follicle-stimulating hormone; PK, pharmacokinetic.

Figure 2

Mean (standard deviation) serum concentrations of XM17 after single ascending doses administered subcutaneously to healthy females. Values are corrected for pre-dose follicle-stimulating hormone levels (linear scale).

Figure 3

Mean serum concentrations of XM17 after single ascending doses administered subcutaneously to healthy females. Values are corrected for pre-dose follicle-stimulating hormone levels (log-linear scale).

Figure 4

Individual pre-dose corrected values for XM17 C_max (IU/L) (A) and AUC_0–168h (IU·h/L) (B) versus XM17 dose (IU). Abbreviations: C_max, maximum XM17 concentration; AUC_0–168h, area under the XM17 concentration-time curve from time zero to 168 hours post-dose.