Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1     Pharmacodynamic properties

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 pharmacodynamics profile as (rec)FSH, but with a markedly prolonged duration of FSH activity. Due to its 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. 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.

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)
ENGAGE
PURSUE
ENSURE                  (18-36 years of age)
(35-42 years of age)
(18-36 years of age)      (body weight greater than
Parameter                                                             (body weight greater than (body weight less than or     60 kg and less than or or equal to 50 kg) equal to 60 kg)              equal to 90 kg)

Elonva         recFSH       Elonva           recFSH     Elonva         recFSH 100 µg          150 IU      150 µg            200 IU    150 µg          300 IU N=268           N=128       N=756             N=750     N=694           N=696 Mean number of        13.3           10.6        13.8              12.6      10.7            10.3 oocytes
Difference
[95% CI]            2.5 [1.2; 3.9]                1.2 [0.5, 1.9]           0.5 [-0.2, 1.2] 

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)

Parameter             Fresh Cycles of ENGAGE
†
Fresh Cycles of PURSUE‡
(18-36 years of age)                         (35-42 years of age)
(body weight greater than 60 kg and          (body weight greater than or equal to less than or equal to 90 kg)                            50 kg)

Elonva      recFSH        Difference        Elonva        recFSH        Difference 150 µg       200 IU        [95% CI]         150 µg         300 IU        [95% CI] N=756        N=750                          N=694          N=696
Vital              39.9%        39.1%      1.1 [-3.8, 5.9]     23.9%          26.9%      -3.0 [-7.3, 1.4] pregnancy rate
Ongoing            39.0%        38.1%      1.1 [-3.8, 5.9]     22.2%         24.0%       -1.9 [-6.1, 2.3] pregnancy rate
Live birth         35.6%        34.4%      1.3 [-3.5, 6.1]     21.3%         23.4%       -2.3 [-6.5, 1.9] rate*
†
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)

FTET Cycles of ENGAGE                     FTET Cycles of PURSUE
(18-36 years of age)                     (35-42 years of age)
(body weight greater than 60 kg            (body weight greater than or and less than or equal to 90 kg)                 equal to 50 kg)

Elonva              recFSH               Elonva              recFSH
150 μg                 200 IU               150 μg               300 IU  n      N      %        n      N      %     n     N        %     n     N        % FTET Cycle 1a
Ongoing                   55     148 37.2        45    147 30.6       43    152 28.3       42   145 29.0 pregnancy
Live birth                 -       -      -       -      -       -    43    152 28.3       41   145 28.3 FTET Cycle 2a
Ongoing                    9     38     23.7      9     31     29.0   8     23      34.8   6     14      42.9 pregnancy
Live birth                 -       -      -       -      -       -    8     23      34.8   6     14      42.9 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
The European Medicines Agency has deferred the obligation to submit the results of studies with Elonva in one or more subsets of the paediatric population in hypogonadotrophic hypogonadism. (see section 4.2 for information on paediatric use).

Pharmacokinetic Properties

5.2      Pharmacokinetic properties

Pharmacokinetic parameters of corifollitropin alfa were evaluated after subcutaneous administration in women undergoing a COS treatment cycle.

Due to the long elimination half-life, after administration of the recommended dose, serum concentrations of corifollitropin alfa are sufficient to sustain multiple follicular growth for an entire week. This justifies replacement of the first seven injections of daily (rec)FSH with a single subcutaneous injection of Elonva in COS for the development of multiple follicles and pregnancy in an ART program (see section 4.2).


Body weight is a determinant of exposure to corifollitropin alfa. Corifollitropin alfa exposure after a single subcutaneous injection is 665 hours*ng/mL (AUC, 426-1,037 hours*ng/mL1) and is similar after administration of 100 micrograms corifollitropin alfa to women with a body weight less than or equal to 60 kilograms and of 150 micrograms corifollitropin alfa to women with a body weight greater than 60 kilograms.


Absorption
After a single subcutaneous injection of Elonva, the maximum serum concentration of corifollitropin alfa is 4.24 ng/mL (2.49-7.21 ng/mL1) and is reached 44 hours (35-57 hours1) postdose. The absolute bioavailability is 58% (48-70%1).

Distribution

Distribution, metabolism and elimination of corifollitropin alfa are very similar to other gonadotropins, such as FSH, hCG and LH. After absorption into the blood, corifollitropin alfa is distributed mainly to the ovaries and the kidneys. The steady state volume of distribution is 9.2 L (6.5-13.1 L1). Exposure to corifollitropin alfa increases proportionally with dose within the range of 60 micrograms to 240 micrograms.

Elimination

Corifollitropin alfa has an elimination half-life of 70 hours (59-82 hours1) and a clearance of 0.13 L/h (0.10-0.18 L/h1). Elimination of corifollitropin alfa predominantly occurs via the kidneys, and the rate of elimination may be reduced in patients with renal insufficiency (see sections 4.2 and 4.4). Hepatic metabolism contributes to a minor extent to the elimination of corifollitropin alfa.

Other special populations

Hepatic impairment
Although data in hepatically impaired patients are not available, hepatic impairment is unlikely to affect the pharmacokinetic profile of corifollitropin alfa.