Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1     Pharmacodynamic properties

Pharmacotherapeutic group: Other gynaecologicals, other gynaecologicals, ATC code: G02CX06.

Mechanism of action
Fezolinetant is a non-hormonal selective neurokinin 3 (NK3) receptor antagonist. It blocks neurokinin B (NKB) binding on the kisspeptin/neurokinin B/dynorphin (KNDy) neuron, which is postulated to restore the balance in KNDy neuronal activity in the thermoregulatory centre of the hypothalamus.

Pharmacodynamic effects

In postmenopausal women, with fezolinetant treatment, a transient decrease of luteinizing hormone (LH) levels was observed. No clear trends or clinically relevant changes in sex hormones measured (follicle-stimulating hormone (FSH), testosterone, oestrogen, and dehydroepiandrosterone sulphate) in postmenopausal women were observed.


Clinical efficacy and safety
Efficacy: Effects on VMS
The effects of fezolinetant were studied in postmenopausal women with moderate to severe VMS in two 12-week, randomised, placebo-controlled, double-blind phase 3 studies of identical design, followed by a 40-week extension treatment period (SKYLIGHT 1 – 2693-CL-0301 and SKYLIGHT 2 – 2693-CL-0302). Women who had a minimum average of 7 moderate to severe VMS per day were enrolled in the studies.

The study population included postmenopausal women defined as having amenorrhoea for ≥ 12 consecutive months (70.1%) or amenorrhoea for ≥ 6 months with FSH > 40 IU/l (4.1%) or having had bilateral oophorectomy ≥ 6 weeks prior to the screening visit (16.1%).

The study population included postmenopausal women with one or more of the following: prior hormone replacement therapy (HRT) use (19.9%), prior oophorectomy (21.6%), or prior hysterectomy (32.1%).

In the studies, a total of 1022 postmenopausal women (81% Caucasian, 17% Black, 1% Asian, 24% Hispanic/Latina ethnicity, and aged ≥ 40 years and ≤ 65 years with an average age of 54 years) were randomised and stratified by smoking status (17% smokers).

The 4 co-primary efficacy endpoints for both studies were the change from baseline in moderate to severe VMS frequency and severity to weeks 4 and 12 as defined in the Food and Drug Administration (FDA) and European Medicines Agency (EMA) guidelines. Each study demonstrated a statistically significant and clinically meaningful (≥ 2 hot flashes per 24 hours) reduction from baseline in the frequency of moderate to severe VMS to weeks 4 and 12 for fezolinetant 45 mg compared to placebo.
Data from the studies showed a statistically significant reduction from baseline in the severity of moderate to severe VMS to weeks 4 and 12 for fezolinetant 45 mg compared to placebo.

Results of the co-primary endpoint for change from baseline to weeks 4 and 12 in mean frequency of moderate to severe VMS per 24 hours from SKYLIGHT 1 and 2 and from pooled studies are shown in Table 2.

Table 2. Mean baseline and change from baseline to weeks 4 and 12 for mean frequency of moderate to severe VMS per 24 hours
Pooled studies
SKYLIGHT 1                      SKYLIGHT 2
(SKYLIGHT 1 and 2)
Parameter                Fezolinetant      Placebo       Fezolinetant      Placebo       Fezolinetant    Placebo 45 mg                           45 mg                           45 mg (n=174)          (n=175)        (n=167)         (n=167)         (n=341)       (n=342) Baseline
Mean (SD)                          10.44 (3.92) 10.51 (3.79) 11.79 (8.26) 11.59 (5.02) 11.10 (6.45)               11.04 (4.46) Change from baseline to week 4
LS Mean (SE)                       -5.39 (0.30)   -3.32 (0.29) -6.26 (0.33)      -3.72 (0.33) -5.79 (0.23)        -3.51 (0.22) Mean % Reduction2                     50.63%        30.46%          55.16%          33.60%           52.84%         31.96% Difference vs Placebo (SE)         -2.07 (0.42)        --         -2.55 (0.46)         --          -2.28 (0.32)        -- P-value                              < 0.0011          --           < 0.0011           --            < 0.001           -- Change from baseline to week 12
LS Mean (SE)                       -6.44 (0.31)   -3.90 (0.31) -7.50 (0.39)      -4.97 (0.39) -6.94 (0.25)        -4.43 (0.25) Mean % Reduction2                     61.35%        34.97%          64.27%          45.35%           62.80%         40.18% Difference vs Placebo (SE)         -2.55 (0.43)        --         -2.53 (0.55)         --          -2.51 (0.35)        -- P-value                              < 0.0011          --           < 0.0011           --            < 0.001           -- 1 Statistically significantly superior compared to placebo at the 0.05 level with multiplicity adjustment.

LS Mean: Least Squares Mean estimated from a mixed model for repeated measures analysis of covariance; SD: Standard Deviation; SE: Standard Error.
2 Mean % Reduction is a descriptive statistic and not from the mixed model.


Results of the co-primary endpoint for change from baseline to weeks 4 and 12 in mean severity of moderate to severe VMS per 24 hours from SKYLIGHT 1 and 2 and from pooled studies are shown in Table 3.

Table 3. Mean baseline and change from baseline to weeks 4 and 12 for mean severity of moderate to severe VMS per 24 hours
Pooled studies
SKYLIGHT 1                      SKYLIGHT 2
(SKYLIGHT 1 and 2)
Parameter                Fezolinetant      Placebo       Fezolinetant      Placebo      Fezolinetant    Placebo 45 mg                           45 mg                          45 mg
(n=174)          (n=175)        (n=167)         (n=167)        (n=341)       (n=342) Baseline
Mean (SD)                           2.40 (0.35)   2.43 (0.35)      2.41 (0.34)    2.41 (0.32)      2.40 (0.35)   2.42 (0.34) Change from baseline to week 4
LS Mean (SE)                       -0.46 (0.04) -0.27 (0.04) -0.61 (0.05)        -0.32 (0.05) -0.53 (0.03)       -0.30 (0.03) Difference vs Placebo (SE)         -0.19 (0.06)        --         -0.29 (0.06)         --         -0.24 (0.04)        -- 1                               1
P-value                               0.002            --           < 0.001            --            < 0.001          -- Change from baseline to week 12
LS Mean (SE)                       -0.57 (0.05)   -0.37 (0.05) -0.77 (0.06)      -0.48 (0.06) -0.67 (0.04)       -0.42 (0.04) Difference vs Placebo (SE)         -0.20 (0.08)        --         -0.29 (0.08)         --         -0.24 (0.06)        -- 1                               1
P-value                               0.007            --           < 0.001            --            < 0.001          -- 1 Statistically significantly superior compared to placebo at the 0.05 level with multiplicity adjustment.

LS Mean: Least Squares Mean estimated from a mixed model for repeated measures analysis of covariance; SD: Standard Deviation; SE: Standard Error.

Safety: Endometrial safety
In the long-term safety data (SKYLIGHT 1, 2, and 4), endometrial safety of fezolinetant 45 mg was assessed by transvaginal ultrasound and endometrial biopsies (304 women had baseline and post- baseline endometrial biopsies during 52 weeks of treatment).

Endometrial biopsy assessments did not identify an increased risk of endometrial hyperplasia or malignancy according to pre-specified criteria for endometrial safety. Transvaginal ultrasound did not reveal increased endometrial thickness.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with fezolinetant in all subsets of the paediatric population for the treatment of moderate to severe VMS associated with menopause (see section 4.2 for information on paediatric use).

Pharmacokinetic Properties

5.2       Pharmacokinetic properties

In healthy women, fezolinetant Cmax and AUC increased proportionally with doses between 20 and 60 mg once daily.

After once-a-day dosing, steady-state plasma concentrations of fezolinetant were generally reached by day 2, with minimal fezolinetant accumulation. The pharmacokinetics of fezolinetant do not change over time.

Absorption

Fezolinetant Cmax is usually achieved at 1 to 4 hours post-dose. No clinically significant differences in fezolinetant pharmacokinetics were observed following administration with a high-calorie, high-fat meal. Veoza may be administered with or without food (see section 4.2).


Distribution

The mean apparent volume of distribution (Vz/F) of fezolinetant is 189 l. The plasma protein binding of fezolinetant is low (51%). The distribution of fezolinetant into red blood cells is almost equal to plasma.

Biotransformation

Fezolinetant is primarily metabolised by CYP1A2 to yield oxidised major metabolite ES259564.
ES259564 is approximately 20-fold less potent against human NK3 receptor. The metabolite-to-parent ratio ranges from 0.7 to 1.8.

Elimination

The apparent clearance at steady-state of fezolinetant is 10.8 l/h. Following oral administration, fezolinetant is mainly eliminated in urine (76.9%) and to a lesser extent in faeces (14.7%). In urine, a mean of 1.1% of the administered fezolinetant dose was excreted unchanged and 61.7% of the administered dose was excreted as ES259564. The effective half-life (t1/2) of fezolinetant is 9.6 hours in women with VMS.

Special populations

Effects of age, race, body weight, and menopause status
There are no clinically relevant effects on age (18 to 65 years), race (Black, Asian, Other), body weight (42 to 126 kg), or menopause status (pre-, post-menopause) on the pharmacokinetics of fezolinetant.

Hepatic impairment
Following single-dose administration of 30 mg fezolinetant in women with Child-Pugh Class A (mild) chronic hepatic impairment, mean fezolinetant Cmax increased by 1.2-fold and AUCinf increased by 1.6- fold, relative to women with normal hepatic function. In women with Child-Pugh Class B (moderate) chronic hepatic impairment, mean fezolinetant Cmax decreased by 15% and AUCinf increased by 2-fold.
The Cmax of ES259564 decreased in both mild and moderate chronic hepatic impairment groups while AUCinf and AUClast slightly increased less than 1.2-fold.

Fezolinetant has not been studied in individuals with Child-Pugh Class C (severe) chronic hepatic impairment.

Renal impairment
Following single-dose administration of 30 mg fezolinetant, there was no clinically relevant effect on fezolinetant exposure (Cmax and AUC) in women with mild (eGFR 60 to less than 90 ml/min/1.73 m2) to severe (eGFR less than 30 ml/min/1.73 m2) renal impairment. The AUC of ES259564 was not changed in women with mild renal impairment but increased approximately 1.7- to 4.8-fold in moderate (eGFR 30 to less than 60 ml/min/1.73 m2) and severe renal impairment. Veoza is not recommended for use in women with severe renal impairment or with end-stage renal disease because of lack of long-term safety data in this population.

Fezolinetant has not been studied in individuals with end-stage renal disease (eGFR less than 15 ml/min/1.73 m2).