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Pharmacology: Pharmacodynamics: Mechanism of action: The most important effect resulting from parenteral administration of FSH is the development of multiple mature follicles.
REKOVELLE is a recombinant human FSH produced in a human cell line by recombinant DNA technology. The amino acid sequences of the two FSH subunits in REKOVELLE are identical to the endogenous human FSH sequences. The expressing cell line can influence the characteristics of the recombinant FSH, and differences in glycosylation profile, sialic acid pattern and isoform profile have been documented between REKOVELLE and recombinant FSH products such as follitropin alfa and follitropin beta produced in Chinese hamster ovary (CHO) cell lines. The glycosylation of FSH in REKOVELLE contains both α2,3 and α2,6-linked sialic acid (2,6-linked sialic acid is absent in CHO-derived recombinant FSH), different sugars such as N-acetylgalactosamine, additional linkages between carbohydrates such as bisecting N-acetylglucosamine, and a higher proportion of tetra-antennary structures and higher overall sialic acid content than CHO-derived recombinant FSH.
Pharmacodynamic effects: Comparisons of REKOVELLE versus follitropin alfa indicate that the differences in glycosylation influence both the pharmacokinetic and pharmacodynamic profile. Following daily administration of equal IU doses of REKOVELLE and follitropin alfa as determined in the rat in vivo bioassay (Steelman-Pohley assay), higher FSH exposure and higher ovarian response (i.e. estradiol, inhibin B and follicular volume) were observed in patients after administration of REKOVELLE compared to follitropin alfa. As the rat bioassay might not fully reflect the potency of the FSH in REKOVELLE in humans, REKOVELLE is dosed in micrograms and not in IU. The clinical trial data suggest that a daily dose of 10.0 [95% CI 9.2; 10.8] micrograms REKOVELLE provides, for the majority of patients, an ovarian response close to that obtained with 150 IU/day follitropin alfa.
The number of oocytes retrieved increases with the dose of REKOVELLE and serum AMH concentration. Conversely, increasing body weight leads to a decrease in the number of oocytes retrieved (only clinically relevant for REKOVELLE doses below 12 micrograms). Consequently, the REKOVELLE dosing regimen is based on serum AMH concentration and furthermore on body weight for doses lower than 12 micrograms.
Clinical efficacy and safety: ESTHER-1 clinical trial: The ESTHER-1 trial was a randomised, assessor-blinded, controlled trial in 1,326 IVF/ICSI patients. Comparing the individualised dosing regimen of REKOVELLE (with fixed dose) to a standard dosing regimen of follitropin alfa filled-by-mass (starting dose of 11 micrograms (150 IU) for the first five days followed by dose adjustments from day 6 of stimulation based on follicular development) in a GnRH antagonist protocol. The patients were up to 40 years of age and had regular menstrual cycles presumed to be ovulatory. Single blastocyst transfer on day 5 was compulsory with the exception of patients 38-40 years in whom double blastocyst transfer was performed if no good-quality blastocysts were available. The two co-primary endpoints were ongoing pregnancy rate and ongoing implantation rate, defined as at least one intrauterine viable fetus 10-11 weeks after transfer and number of intrauterine viable fetuses 10-11 weeks after transfer divided by number of blastocysts transferred, respectively.
The trial demonstrated that REKOVELLE was at least as effective as follitropin alfa in terms of ongoing pregnancy rate and ongoing implantation rate, as shown in Table 1. (See Table 1.)
Click on icon to see table/diagram/imageThe clinical value of the AMH-based dosing regimen of REKOVELLE was also assessed in secondary endpoints, such as ovarian response, OHSS risk management and gonadotropin consumption.
Ovarian response and total FSH dose: Excessive ovarian response leading to triggering with GnRH agonist occurred for fewer patients with the individualised REKOVELLE dosing regimen compared to the follitropin alfa dosing regimen (p<0.05). Low ovarian response leading to cycle cancellation occurred at comparable rates with REKOVELLE and follitropin alfa.
The probability of patients achieving 8-14 oocytes was increased for patients with low or high AMH treated with individualised REKOVELLE dosing regimen compared to follitropin alfa at a starting dose of 11 micrograms (150 IU) and adjustments during stimulation (p<0.05). The average REKOVELLE daily dose was 0.16 μg/kg. The ovarian response and total FSH dose overall and according to AMH concentration are displayed in Table 2. (See Table 2.)
Click on icon to see table/diagram/imageSafety-OHSS risk management: The incidence of patients who required preventive interventions for early OHSS, such as triggering with GnRH agonist or administration of dopamine agonist, was reduced by 50% in the REKOVELLE treated patients compared to the follitropin alfa treated patients (p<0.05). The risk of early OHSS and/or preventive interventions as well as the risk of early and late OHSS and/or preventive interventions was higher by increasing AMH with the standard follitropin alfa dosing regimen compared to the individualised REKOVELLE dosing regimen (p<0.05). OHSS risk management parameters are summarised in Table 3. (See Table 3.)
Click on icon to see table/diagram/imageIn ovulatory patients with polycystic ovaries undergoing a GnRH antagonist cycle, the incidence of early moderate/severe OHSS and/or preventive interventions for early OHSS was 7.7% with REKOVELLE and 26.7% with follitropin alfa.
ESTHER-2 clinical trial: Safety-immunogenicity: The ESTHER-2 trial included patients who participated in the ESTHER-1 trial who failed to achieve an ongoing pregnancy. These patients were eligible for cycle 2, and those who failed to achieve an ongoing pregnancy in cycle 2, were eligible for cycle 3. Patients with severe OHSS in a previous cycle, or patients with any clinically relevant change to any of the eligibility criteria or any clinically relevant medical history since the previous cycle were not eligible for participation in the trial. Treatment allocation to either REKOVELLE or follitropin alfa remained the same as in the ESTHER-1 trial. The treatment dose in both groups could be adjusted based on the ovarian response obtained in the previous cycle(s). Surplus blastocysts could be cryopreserved for use after trial completion. A post-trial follow-up evaluated the cryopreserved cycles initiated within one year after randomisation for patients participating in ESTHER-1, and within one year after start of stimulation of the last repeated controlled ovarian stimulation cycle for subjects enrolled in ESTHER-2.
Anti-FSH antibodies were measured pre-dosing and post-dosing in patients undergoing up to three repeated treatment cycles with REKOVELLE (665 patients in cycle 1 in the ESTHER 1 trial as well as 252 patients in cycle 2 and 95 patients in cycle 3 in the ESTHER 2 trial). The incidence of anti-FSH antibodies after treatment with REKOVELLE was 1.1% in cycle 1, 0.8% in cycle 2 and 1.1% in cycle 3. These rates were similar to the incidence of pre-existing anti-FSH antibodies before exposure to REKOVELLE in cycle 1 which was 1.4%, and comparable to the incidences of anti-FSH antibodies after treatment with follitropin alfa. In all patients with anti-FSH antibodies, titres were undetectable or very low and without neutralising capacity. Repeated treatment with REKOVELLE of patients with pre-existing or treatment-induced anti-FSH antibodies did not increase the antibody titre, was not associated with decreased ovarian response, and did not induce immune-related adverse events.
ESTHER-1 and ESTHER-2 clinical trials combined analyses: ESTHER-1 and ESTHER-2 trials combined include data from 1,027 controlled ovarian stimulation cycles and 692 frozen cycles. The 665 women randomised and exposed to REKOVELLE conducted 1,012 controlled ovarian stimulation cycles and initiated 341 frozen cycles, and the 661 women randomised and exposed to follitropin alfa conducted 1,015 treatment cycles and initiated 351 frozen cycles.
The overall live birth rate and the live neonate rate at 4 weeks after birth after fresh and frozen cycles were comparable for REKOVELLE and follitropin alfa for women who participated in the ESTHER trials. (See Table 4.)
Click on icon to see table/diagram/imageThe cumulative incidence of moderate/severe OHSS and/or preventive interventions for early OHSS across three controlled ovarian stimulation cycles were significantly lower for REKOVELLE compared to follitropin alfa (p<0.05), as displayed in Table 5. (See Table 5.)
Click on icon to see table/diagram/imageBEYOND Phase 3b trial, 000304: In an open-label, controlled trial 435 IVF/ICSI patients with AMH ≤35 pmol/L were randomised to either individualised REKOVELLE dosing in a protocol using down-regulation with a GnRH agonist or to a GnRH antagonist. The maximum allowed REKOVELLE dose was 12 micrograms. The primary endpoint was number of oocytes retrieved. The mean number of oocytes retrieved among patients who started controlled ovarian stimulation with REKOVELLE was 11.1 ± 5.9 in the GnRH agonist cycle compared to 9.6 ± 5.5 in the GnRH antagonist cycle. The mean number of stimulation days in the GnRH agonist cycle was 10.4 ± 1.9 days compared to 8.8 ± 1.8 days in the GnRH antagonist cycle. The live birth rate per started cycle was 35.1% in the GnRH agonist cycle compared to 28.9% in the GnRH antagonist cycle. The proportion of patients with early OHSS was 4.0% in the GnRH agonist cycle and 2.5% in the GnRH antagonist cycle, and the proportion of patients with early moderate/severe OHSS was 1.5% in the GnRH agonist cycle and 2.5% in the GnRH antagonist cycle. The proportion of patients with late OHSS was 2.0% in the GnRH agonist cycle and 2.9% in the GnRH antagonist cycle, and the proportion of patients with late moderate/severe OHSS was 1.5% in the GnRH agonist cycle and 3.0% in the GnRH antagonist cycle.
Pharmacokinetics: The pharmacokinetic profile of REKOVELLE has been investigated in healthy female subjects and in IVF/ICSI patients undergoing COS. Following repeated daily subcutaneous administrations, REKOVELLE reaches steady-state within 6 to 7 days with a threefold higher concentration compared with the concentration after the first dose. Circulating levels of REKOVELLE is inversely related to the body weight, which supports individualised dosing based on body weight. Follitropin delta leads to greater exposure than follitropin alfa.
Absorption: After daily subcutaneous administration of REKOVELLE, the time to maximum serum concentration is 10 hours. The absolute bioavailability is about 64%.
Distribution: The volume of distribution at steady state is about 9 L. Within the therapeutic dose range, exposure to REKOVELLE increases proportionally with the dose.
Elimination: Following intravenous administration, the clearance of REKOVELLE is 0.3 L/h. The terminal elimination half-life after single subcutaneous administration is 40 hours and after multiple subcutaneous administration is 28 hours. Comparison of the pharmacokinetics of REKOVELLE with follitropin alfa following daily subcutaneous administration of equal doses of IUs for 7 days, revealed that the apparent clearance is 1.6 fold lower and accordingly the AUC and Cmax are 1.7-fold and 1.6-fold higher for REKOVELLE than for follitropin alfa. REKOVELLE is expected to be eliminated similarly to other follitropins, i.e. mainly by the kidneys. The fraction of REKOVELLE excreted unchanged in the urine was estimated to 9%.
Toxicology: Preclinical safety data: Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and local tolerance. The overdose of REKOVELLE resulted in pharmacological or exaggerated pharmacological actions. REKOVELLE had a negative effect on fertility and early embryonic development in rats when administered in doses ≥0.8 μg/kg/day which is above the recommended maximal dose in humans. Since REKOVELLE is contraindicated during pregnancy, these observations are of limited clinical significance.
