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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.
Follitropin delta is a recombinant human FSH. The amino acid sequences of the two FSH subunits in follitropin delta 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 follitropin delta produced in a human cell line and recombinant FSH products such as follitropin alfa and follitropin beta produced in Chinese hamster ovary (CHO) cell lines. The glycosylation of FSH in follitropin delta 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 ovarian response (i.e. estradiol, inhibin B and follicular volume and number) was observed in patients after administration of REKOVELLE compared to follitropin alfa.
As the Steelman-Pohley 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 an ovarian response close to that obtained with 150 IU/day follitropin alfa. The recommended REKOVELLE doses in micrograms are not applicable to other recombinant FSH preparations.
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 (see Dosage & Administration).
Clinical efficacy and safety: The ESTHER-1 trial was a randomized, assessor-blinded, controlled trial in 1,326 IVF/ICSI patients. The trial compared the individualized dosing regimen of REKOVELLE where the daily dose is established for each patient and fixed throughout stimulation with no adjustments (see Dosage & Administration) to follitropin alfa filled-by-mass at a 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 in the fresh cycle, 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 impact of the AMH-based dosing regimen of REKOVELLE was also assessed in secondary endpoints, such as ovarian response and OHSS risk management.
In the overall trial population, the mean number of oocytes retrieved was 10.0 ± 5.6 with REKOVELLE (N=636) in the individualised dosing regimen and 10.4 ± 6.5 with follitropin alfa (N=643) at a starting dose of 150 IU followed by dose adjustments.
Among patients with AMH ≥15 pmol/L, the ovarian response with REKOVELLE (N=355) and follitropin alfa (N=353), respectively, was as follows: mean number of oocytes retrieved 11.6 ± 5.9 and 13.3 ± 6.9, and proportion of patients with ≥20 oocytes 10.1% (36/355) and 15.6% (55/353).
In 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.
In a controlled trial evaluating the ovarian response with individualised REKOVELLE dosing in patients with AMH ≤35 pmol/L, the mean number of oocytes was 11.1 ± 5.9 in a GnRH agonist cycle (N=202) compared to 9.6 ± 5.5 in a GnRH antagonist cycle (N=204), and the mean duration of stimulation with REKOVELLE was 10.4 ± 1.9 days in a GnRH agonist cycle compared to 8.8 ± 1.8 days in a GnRH antagonist cycle.
Safety-immunogenicity: 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.
Clinical trial experience with REKOVELLE in the long GnRH agonist protocol is limited.
Pharmacokinetics: The pharmacokinetic profile of follitropin delta 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 follitropin delta are inversely related to the body weight, which supports individualized 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 follitropin delta increases proportionally with the dose.
Elimination: Following intravenous administration, the clearance of follitropin delta 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 follitropin delta with follitropin alfa following daily subcutaneous administration of equal doses of IUs for 7 days, revealed that the AUC and Cmax are 1.7-fold and 1.6-fold higher for follitropin delta than for follitropin alfa. Follitropin delta is expected to be eliminated similarly to other follitropins, i.e. mainly by the kidneys. The fraction of follitropin delta 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 follitropin delta resulted in pharmacological or exaggerated pharmacological actions. Follitropin delta had a negative effect on fertility and early embryonic development in rats when administered in doses ≥0.8 micrograms/kg/day which is above the recommended maximal dose in humans. The relevance of these findings for the clinical use of REKOVELLE is limited.
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