ELONVA Solution for injection Ref.[7198] Active ingredients: Corifollitropin alfa

Pharmacotherapeutic group: sex hormones and modulators of the genital system, gonadotropins
ATC code: G03GA09

Mechanism of action

Corifollitropin alfa is designed as a sustained follicle stimulant with the same pharmacodynamic profile as (rec)FSH, but with a markedly prolonged duration of FSH activity. The long duration of FSH activity was achieved by adding the carboxy-terminal peptide of the β-subunit of human chorionic gonadotropin (hCG) to the β-chain of human FSH. Corifollitropin alfa does not display any intrinsic LH/hCG activity.

In females

Due to corifollitropin alfa’s ability to initiate and sustain multiple follicular growth for an entire week, a single subcutaneous injection of the recommended dose of Elonva may replace the first seven injections of any daily (rec)FSH preparation in a COS treatment cycle.

Paediatric adolescent male population (14 years and older)

Corifollitropin alfa’s sustained FSH activity stimulates the immature Sertoli cells in the testis to initiate gonadal development in support of future spermatogenesis. The combination of FSH with hCG is to initiate puberty with stimulation of Leydig cell function and increase testosterone production until testicular volumes attain adult size.

Clinical efficacy and safety

In three randomized, double-blind, clinical trials, treatment with a single subcutaneous injection of Elonva, 100 micrograms (ENSURE study) or 150 micrograms (ENGAGE and PURSUE study), for the first seven days of COS was compared to treatment with a daily dose of 150, 200, or 300 IU of recFSH, respectively. Pituitary suppression with a GnRH antagonist (ganirelix acetate injection at a daily dose of 0.25 mg) was used in each of the three clinical trials.

In the ENSURE study, 396 healthy normal ovulatory women, aged 18 to 36 years with a body weight less than or equal to 60 kg, were treated for one cycle with 100 micrograms of Elonva and pituitary suppression with a GnRH antagonist as part of an ART program. The primary efficacy endpoint was number of oocytes retrieved. The median total duration of stimulation was 9 days for both groups, indicating that two days of recFSH were required to complete ovarian stimulation from stimulation day 8 onwards (recFSH was given on the day of hCG for this study).

In the ENGAGE Study, 1,506 healthy normal ovulatory women, aged 18 to 36 years with a body weight greater than 60 kg and less than or equal to 90 kg, were treated for one cycle with 150 micrograms of Elonva and pituitary suppression with a GnRH antagonist as part of an ART program. The co-primary efficacy endpoints were ongoing pregnancy rate and number of oocytes retrieved. The median total duration of stimulation was 9 days for both groups, indicating that two days of recFSH were required to complete ovarian stimulation from stimulation day 8 onwards (recFSH was given on the day of hCG for this study).

In the PURSUE study, 1,390 healthy normal ovulatory women, aged 35 to 42 years with a body weight greater than or equal to 50 kg, were treated for one cycle with 150 micrograms of Elonva and pituitary suppression with a GnRH antagonist as part of an ART program. The primary efficacy endpoint was vital pregnancy rate. The number of oocytes retrieved was a key secondary efficacy endpoint. The median total duration of stimulation was 9 days for both groups, indicating that one day of recFSH was required to complete ovarian stimulation from stimulation day 8 onwards (no recFSH was given on the day of hCG for this study).

Number of oocytes retrieved

In all three studies, treatment with a single injection of Elonva, 100 or 150 micrograms, for the first seven days of COS, resulted in a higher number of oocytes retrieved compared with a daily dose of recFSH. However, the differences were within the predefined equivalence (ENGAGE and ENSURE) or non-inferiority (PURSUE) margins. See Table 1 below.

Table 1. Mean Number of Oocytes Retrieved from ENSURE, ENGAGE, and PURSUE Intent-to-Treat Population (ITT):

Pregnancy from the fresh cycles of ENGAGE and PURSUE

In the ENGAGE study, non-inferiority was demonstrated in ongoing pregnancy rates between Elonva and recFSH, with ongoing pregnancy rate defined as presence of at least one foetus with heart activity assessed at least 10 weeks after embryo transfer.

In the PURSUE study, non-inferiority was demonstrated in vital pregnancy rate between Elonva and recFSH, with vital pregnancy rate defined as the percentage of subjects with at least one foetus with heart activity assessed 5 to 6 weeks after embryo transfer.

The pregnancy results from the fresh cycles of ENGAGE and PURSUE are summarized in Table 2 below.

Table 2. Pregnancy Results from the Fresh Cycles of ENGAGE and PURSUE Intent-to-Treat Population (ITT):

^† The primary efficacy endpoint in the ENGAGE study was ongoing pregnancy (assessed at least 10 weeks after embryo transfer).
^‡ The primary efficacy endpoint in the PURSUE study was vital pregnancy rate defined as the percentage of subjects with at least one foetus with heart activity assessed 5 to 6 weeks after embryo transfer.
^* Live birth rate was a secondary efficacy endpoint in ENGAGE and PURSUE.

In these clinical trials, the safety profile of a single injection with Elonva was comparable to daily injections with recFSH.

Pregnancy from the Frozen-Thawed Embryo Transfer (FTET) cycles of ENGAGE and PURSUE

The follow-up FTET trial for ENGAGE included women who had at least one embryo thawed for use up to at least one year after cryopreservation. The mean number of embryos transferred in the FTET cycles of ENGAGE was 1.7 in both treatment groups.

The follow-up FTET trial for PURSUE included women who had at least one embryo thawed for use within two years of the date of the last cryopreservation for this trial. The mean number of embryos transferred in the FTET cycles of PURSUE was 2.4 in both treatment groups. This trial also provided safety data on the infants born from cryopreserved embryos.

The maximum number of FTET cycles was 5 and 4 for the follow-up FTET trial for ENGAGE and PURSUE, respectively. The pregnancy results from the first two FTET cycles of ENGAGE and PURSUE are summarized in Table 3 below.

Table 3. Pregnancy Results from the FTET cycles of ENGAGE and PURSUE Intent-to-Treat Population (ITT):

n = number of subjects with the event; N = total number of subjects
^a Per embryo transfer.

Congenital malformations reported in infants born after a frozen-thawed embryo transfer (FTET) cycle

Following use of Elonva, 61 infants were born after an FTET cycle in the PURSUE study follow-up, and 607 infants were born after fresh ART cycles in the ENSURE, ENGAGE and PURSUE studies combined. The rates for congenital malformations (major and minor combined) reported for infants born after an FTET cycle in the PURSUE study follow-up (16.4%) were similar to those reported for infants born after fresh ART cycles in the ENSURE, ENGAGE and PURSUE studies combined (16.8%).

Immunogenicity

Of the 2,511 women treated with Elonva who were evaluated for the formation of post-treatment antibodies, four (0.16%) had evidence of antibody formation, including three who had been exposed once to Elonva and one who had been exposed twice to Elonva. In each case, these antibodies were non-neutralizing and did not interfere with the response to stimulation or the normal physiologic responses of the Hypothalamic-Pituitary-Ovarian (HPO) axis. Two of these four women became pregnant during the same treatment cycle in which antibodies were detected, suggesting that the presence of non-neutralizing antibodies after stimulation with Elonva is not clinically relevant.

Paediatric population

A single-group, open-label efficacy and safety study was conducted to evaluate the treatment with Elonva in combination with hCG to induce and/or restore puberty and to induce and/or restore spermatogenesis in 17 adolescent males aged 14 years and older for the treatment of hypogonadotropic hypogonadism. A priming period with Elonva instead of hCG in adolescents with HH was included to mimic the gonadotropin pattern of normal puberty, stimulating FSH receptors on Sertoli cells with corifollitropin alfa prior to stimulation of LH receptors on Leydig cells with hCG. The study excluded males who had previously received GnRH, gonadotropins or testosterone treatment. Elonva was administered once every 2 weeks for 64 weeks, alone for the first 12 weeks (priming period), followed by 52 weeks in combination with twice weekly doses of hCG (500 to 5000 IU) (combined treatment period).

The primary endpoint for efficacy was shown by increase in testicular volume, measured as the sum of volumes of left and right testes by ultrasound. During the overall treatment period, the increase noted in testicular volume at Week 64 changed from a geometric mean of 1.4 mL to 12.9 mL, mean fold increase of 9.43 (95% CI: 7.44, 11.97). The primary endpoint for safety showed that corifollitropin alfa was generally well tolerated with no cases of confirmed anti-corifollitropin alfa antibodies, no unexpected values or changes in clinical laboratory data or vitals sign assessments (see also section 4.8).

Additional findings at Week 64 included, increased testosterone levels, growth velocity and progression of puberty (Tanner III, IV and V) indicated appropriate responses to hCG. Decreasing anti-müllerian hormone levels and increases in Inhibin B levels were suggestive of initiation of spermatogenesis.