Early evidence of efficacy and safety for a novel sustained-release recombinant human follicle stimulating hormone (FSH-SR)

Abstract

Recombinant hFSH is widely utilized for induction of ovulation in oligo-anovulatory infertility and for stimulation of multiple follicular development in ART. Over the course of a stimulation cycle and depending on the treatment protocol, a patient may self-inject more than 40 times, and have to repeat the process over a number of cycles. A sustained-release (SR) preparation of r-hFSH (follitropin alfa for injection) would offer advantages to the patient, nurse and physician − fewer injections, improved compliance, and a reduced potential for medication errors. FSH-SR was developed in conjunction with Alkermes, Cambridge, MA, USA using follitropin alfa and Alkermes’ patented ProLease® technology. The present study was performed to assess the suitability of this novel formulation of FSH-SR for ovarian stimulation through the monitoring of safety and pharmacodynamic markers (follicle growth and estradiol[E2] production) following its administration to healthy women volunteers. Prospective, open-label, single-center IRB approved study. 36 healthy, normally-cycling women with normal baseline reproductive hormone values were enrolled. Subjects were treated in sequential groups of 4 with a single dose of FSH-SR administered SC. Five groups (n=20) were down-regulated with a GnRH analogue, goserelin acetate, and 4 groups (n=16) were studied in spontaneous cycles. Based on a prospectively defined algorithm, the dose of each group was chosen by a Study Steering Committee. Serum FSH, follicular response as assessed by ultrasound, and serum E2 were assessed at baseline and for 49 days after injection. Safety assessments were performed on each patient visit. The main outcome measure was follicle growth as assessed by the number and size of follicles, and serum E2 over time. Following the dosing algorithm, downregulated subjects were administered single doses of 146 mcg, 73 mcg, 218 mcg (x2) and 328 mcg in groups of 4. Non-downregulated subjects were administered 146 mcg, 218 mcg, 73 mcg and 36 mcg. All dose groups showed evidence of FSH effect with a rise in serum E2 and follicular growth. Higher doses were associated with pre-ovulatory E2 values (>3500 pmol/mL), with follicles of 20 mm diameter and up to 24 responding follicles (>11 mm). Duration of effect, as assessed by days of rising E2 values, was also dose-dependent and up to 10 days (median 4–9 days). Down-regulation was associated with slower increases in serum E2 and follicle number. FSH-SR was well-tolerated in the doses administered, generally and locally, by the study subjects. There were no serious adverse events. A FSH-SR dose-dependent effect is identified on follicular development and E2 production. Pre-ovulatory E2 levels and mature follicle development are achieved with a single dose of FSH-SR. FSH-SR was well tolerated by volunteers and may offer a novel option as initial treatment in both OI and ART.