Study objectives and parameters measured
The primary objectives were to assess the PK (ie, bioequivalence) and safety in terms of both systemic and local tolerability of single 300-IU sc doses of XM17 (Ovaleap®; follitropin alfa, Teva Pharmaceuticals Europe B.V., Utrecht, The Netherlands) and Gonal-f®. The primary PK parameters measured for XM17 and Gonal-f® included area under the serum concentration vs time curve (AUC) from time 0 to the last concentration observed above predose levels (AUC0-t) and maximum predose-corrected serum concentration (Cmax). Secondary PK parameters included AUC from time 0 to 168 h (AUC0-168h), AUC extrapolated to infinity (AUC0-∞), apparent terminal rate constant (λZ), apparent volume of distribution during the terminal phase (Vz/F where F = fraction absorbed), time at which Cmax occurred (tmax), apparent terminal elimination half-life (t1/2), and apparent clearance (CL/F).
Safety in terms of systemic and local tolerability (ie, injection-site reactions) was monitored in all participants who received at least one dose of either study drug. Treatment-emergent adverse events (TEAEs) and adverse reactions, changes in laboratory parameters (hematology, clinical chemistry, coagulation parameters, urinalysis), changes in vital signs and electrocardiogram (ECG), presence of anti-FSH antibodies and changes in participants’ physical or gynecological examination were collected.
Participant eligibility
Nonpregnant, non–breast-feeding women aged 18–39 years of any race, with a body mass index (BMI) between 18 and 29 kg/m2 and weighing ≥50 kg were included. Participants could be either non- or moderate smokers (<10 cigarettes/day). All must have used oral contraceptives (OCs) for ≥3 months for contraception, had a normal uterus and two functioning ovaries, and agreed to use double-barrier contraceptive methods during the study and resume OCs after end of study. Participants must have been healthy by medical history, physical examination, ECG, blood pressure (BP), pulse rate, blood laboratory profile, including coagulation factors and urinalysis. Participants must have tested negative for HIV and hepatitis C virus, and were excluded if they had a history of or current polycystic ovary syndrome, class III or IV endometriosis, Papanicolaou (PAP) smear ≥3 within 3 years of screening, submucosal myoma uteri, endocrine abnormalities with treatment within 6 months of screening, drug or alcohol abuse, high caffeine consumption (>5 coffee equivalents/day), or treatment with an investigational drug or a drug with known potential organ toxicity within 60 or 90 days, respectively.
Study assessments and design
The study consisted of a screening visit within 21 days before the start of a 10-day run-in period to downregulate endogenous FSH, an experimental period of 16 days (Day 11 until Day 26) that included rhFSH dosing on Days 11 and 19, and an end-of-study visit on Day 26.
At screening, gynecological examinations, including breast examination, transvaginal sonography and PAP smear were performed by an experienced gynecologist. Serum FSH levels were determined at screening and at Days 0 and 10. Fourteen ± 3 days into a cycle of OCs (study Day 0), the GnRH agonist (Zoladex
® [goserelin acetate implant 3.6 mg, 1-month depot], AstraZeneca GmbH, 22876 Wedel, Germany) was implanted sc to downregulate endogenous FSH [
11]. Participants could continue into the treatment period only if downregulation of plasma FSH to <4 IU/L was confirmed 10 days after goserelin administration. Based on previous reports of an initial rise in FSH and luteinizing hormone levels after beginning downregulation [
12], participants took their own OCs for another 4–7 days to ensure pregnancy prevention. Participants had to discontinue concomitant prescribed and over-the-counter medications 4 weeks and 2 weeks before XM17 or Gonal-f
® administration, respectively, until the final study visit. Grapefruit- and quinine-containing products were not permitted within 72 h before XM17 or Gonal-f
® administration to the completion of the end-of-study visit. Participants had to abstain from drinking alcoholic beverages for 72 h both before the screening visit and before Day 0 and from Day 11 to the completion of the end-of-study visit.
All participants fasted for 10 h before rhFSH dosing and until 2 h after dosing. Participants resided in the clinic from the evening before dosing (Days 10 and 18) until the morning of Days 13 and 21, respectively. All other study visits occurred as outpatient visits.
XM17 and Gonal-f® were administered in a two-way crossover design on Days 11 and 19. On the morning of Day 11 (PK period 1), participants received either a single 300-IU sc dose of XM17 or a single 300-IU sc dose of Gonal-f® (according to the randomization scheme), followed by the same sets of participants receiving single doses of Gonal-f® and XM17, respectively, on the morning of Day 19 (PK period 2).
Blood sampling for PK of XM17 and Gonal-f® was performed 10 min predose on Days 11 and 19, then at 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 24, 36, 48, 72, 96, 120, 144 and 168 h postdose. Participants were monitored predose and at regular intervals postdose for ECG and vital signs (pulse rate and BP; temperature was also taken but predose only). Routine laboratory testing was performed on Days 11, 12, 19, 20 and 26. Blood was sampled to monitor for XM17 or Gonal-f® antibodies on Days 11, 19 and 26. A second gynecological exam was performed at the Final Study Visit (Day 26) immediately after which participants were to resume taking OCs. Excluding screening, the study duration was about 27 days per participant.
Drug product and drug concentration measurements
XM17, produced and tested according to Good Manufacturing Practice and relevant European Pharmacopoeia monographs, was provided in vials of 1.0 mL containing 600 IU XM17 and administered at a dose of 300 IU XM17, which corresponded to an injection volume of 0.5 mL. Commercially available Gonal-f® was provided in pens with integrated vials of 0.5 mL containing 300 IU Gonal-f®. During screening and on days 0 and 10, endogenous FSH levels were determined at Medizinisches Versorgungszentrum (MVZ) für Laboratoriumsmedizin und Mikrobiologie GbR (Ulm, Germany) using an electrochemiluminescent immunoassay (ECLIA; Elecsys testkit, Roche Diagnostics, Indianapolis, IN, USA). All PK samples and downregulated endogenous FSH (measured predose on Days 11 and 19) were measured by a validated, double-sandwich, bioanalytical method (MSD® platform) at MDS Pharma Services Switzerland AG. Serum anti-FSH antibodies were determined by ECLIA at MDS Pharma Services Switzerland AG.