VEOZAH (Page 3 of 5)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

In a 2-year female rat carcinogenicity study and a 26-week carcinogenicity study in rasH2 transgenic mice, there was no evidence of drug-related carcinogenicity at 186-fold and 47-fold the human AUC₂₄ at the human therapeutic dose of 45 mg, respectively.

Mutagenesis

Fezolinetant showed no genotoxic potential by the bacterial reverse mutation test, chromosomal aberration test, or in vivo micronucleus test.

Impairment of Fertility

Fezolinetant had no effect on female fertility or early embryonic development up to 100 mg/kg/day in rats (143-fold the human AUC₂₄ at the human therapeutic dose). In the pre- and post-natal development study in rats, the F₁ male showed incomplete balanopreputial separation at doses greater than or equal to 30 mg/kg/day (36-fold the human AUC₂₄ at the human therapeutic dose), which delayed male reproductive maturation and affected fertility. These effects were not observed following dosing at 10 mg/kg/day (11-fold the human AUC₂₄ at the human therapeutic dose) [see Pregnancy (8.1)].

13.2 Animal Toxicology and/or Pharmacology

Repeat dose toxicity studies were conducted in intact female rats and cynomolgus monkeys. In female rats, daily administration of fezolinetant for 26 weeks at doses equal to or greater than 30 mg/kg/day (56-fold the human AUC₂₄ at the human therapeutic dose) showed uterine atrophy and epithelial mucification of the vagina and cervix. In female cynomolgus monkeys, daily administration for 39 weeks at doses equal to or greater than 10 mg/kg/day (19-fold the human AUC₂₄ at the human therapeutic dose) showed reduced ovarian activity.

14 CLINICAL STUDIES

14.1 Effects on Vasomotor Symptoms in Postmenopausal Women

The efficacy of VEOZAH for the treatment of moderate to severe vasomotor symptoms due to menopause was evaluated in the first 12-week, randomized, placebo-controlled, double-blind portion of each of two phase 3 clinical trials. In each of these two trials, after the first 12 weeks, women on placebo were then re-randomized to VEOZAH for a 40-week extension to evaluate safety for up to 52 weeks total exposure.

In Trials 1 (NCT04003155) and 2 (NCT04003142), 1022 women (522 in Trial 1 and 500 in Trial 2) who had a minimum average of 7 moderate to severe vasomotor symptoms per day were randomized to one of two doses of fezolinetant (including the 45 mg dosage strength) or placebo. Randomization was stratified by smoking status.

The mean age of the postmenopausal women was 54 years. Women self-identified as Caucasian (81%), African American (17%), Asian (1%), and Hispanic/Latina ethnicity (24%). The study population included menopausal women with one or more of the following: prior hysterectomy (32.1%), prior oophorectomy (21.6%), or prior hormone therapy use (19.9%). Those who were on prior hormone therapy underwent a wash-out period prior to trial participation.

The co-primary efficacy endpoints for both trials were the mean change from baseline in moderate to severe vasomotor symptoms frequency and severity to Weeks 4 and 12. Data from each trial demonstrated statistically significant and clinically meaningful (≥ 2 hot flashes over 24 hours) reduction from baseline in the frequency of moderate to severe vasomotor symptoms for VEOZAH 45 mg compared to placebo at Weeks 4 and 12. Data from each trial also demonstrated a statistically significant reduction from baseline in the severity of moderate to severe vasomotor symptoms (over 24 hours) at Weeks 4 and 12 for VEOZAH 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 vasomotor symptoms over 24 hours from Trials 1 and 2 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 Vasomotor Symptoms over 24 Hours in Women Treated with VEOZAH in Trials 1 and 2

* 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.
Parameter	Trial 1		Trial 2
	VEOZAH 45 mg (n=174)	Placebo (n=175)	VEOZAH 45 mg (n=167)	Placebo (n=167)
Baseline Mean (SD)	10.4 (3.92)	10.5 (3.79)	11.8 (8.26)	11.6 (5.02)
Change from Baseline to Week 4 LS Mean (SE) Difference vs Placebo (95% CI) P-value	-5.4 (0.30) -2.1 (-2.9, -1.3) < 0.001*	-3.3 (0.29) — —	-6.3 (0.33) -2.6 (-3.5, -1.6) < 0.001*	-3.7 (0.33) — —
Change from Baseline to Week 12 LS Mean (SE) Difference vs Placebo (95% CI) P-value	-6.4 (0.31) -2.6 (-3.4, -1.7) < 0.001*	-3.9 (0.31) — —	-7.5 (0.39) -2.5 (-3.6, -1.5) < 0.001*	-5.0 (0.39) — —

Results of the co-primary endpoint for change from baseline to Weeks 4 and 12 in mean severity of moderate to severe vasomotor symptoms over 24 hours from Trials 1 and 2 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 Vasomotor Symptoms over 24 Hours in Women Treated with VEOZAH in Trials 1 and 2

* 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.
Parameter	Trial 1		Trial 2
	VEOZAH 45 mg (n=174)	Placebo (n=175)	VEOZAH 45 mg (n=167)	Placebo (n=167)
Baseline Mean (SD)	2.4 (0.35)	2.4 (0.35)	2.4 (0.34)	2.4 (0.32)
Change from Baseline to Week 4 LS Mean (SE) Difference vs Placebo (95% CI) P-value	-0.5 (0.04) -0.2 (-0.3, -0.1) 0.002*	-0.3 (0.04) — —	-0.6 (0.05) -0.3 (-0.4, -0.2) < 0.001*	-0.3 (0.05) — —
Change from Baseline to Week 12 LS Mean (SE) Difference vs Placebo (95% CI) P-value	-0.6 (0.05) -0.2 (-0.4, -0.1) 0.007*	-0.4 (0.05) — —	-0.8 (0.06) -0.3 (-0.5, -0.1) < 0.001*	-0.5 (0.06) — —