Lynkuet elinzanetant 60 mg Capsule, 60-count — NDC 50419-475-05 (Billing 50419-0475-05)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action LYNKUET is a neurokinin 1 (NK1) and neurokinin 3 (NK3) receptor antagonist. Inhibition of Substance P and Neurokinin B through antagonism of NK1 and NK3 receptor signaling on kisspeptin/neurokinin B/dynorphin (KNDy) neurons can modulate neuronal activity in thermoregulation associated with hot flashes. Elinzanetant has higher affinity for human NK1 receptors (pKi values of 8.7 to 10.2) and NK3 receptors (pKi values of 8.0 to 8.8) than for human NK2 receptors (pKi values of approximately 6.0).

12.2Pharmacodynamics Cardiac Electrophysiology No clinically relevant prolongation of the QTc interval was observed after single oral administration of elinzanetant at doses up to 5 times the maximum recommended dose. However, QTc prolongation effect of elinzanetant when co-administered with strong CYP3A4 inhibitors has not been sufficiently characterized.

12.3Pharmacokinetics Elinzanetant C max and AUC increased in a greater than dose-proportional manner (20% to 50%) over the dose range from 40 to 160 mg once daily (0.33 to 1.33 times the highest recommended dose). Elinzanetant steady state plasma concentrations were reached in 5 to 14 days after daily dosing. Elinzanetant accumulation is <2-fold at the approved recommended dosage.

Absorption Elinzanetant median (min-max) time to maximum plasma concentration (T max ) is 1.0 hours (1-2.5 hours) at steady state. Elinzanetant absolute bioavailability is 52% following oral administration. Effect of Food No clinically significant differences in elinzanetant pharmacokinetics were observed following administration with a high-calorie, high-fat meal containing approximately 1000 calories (500-600 calories from fat, 250 calories from carbohydrates, and 150 calories from protein).

Distribution The mean volume of distribution after intravenous administration at steady state of elinzanetant is 137 L. The plasma protein binding of elinzanetant is 99.7%. The blood-to-plasma ratio is between 0.6 and 0.7.

Elimination Elinzanetant elimination half-life was approximately 45 hours in women with vasomotor symptoms. The clearance of elinzanetant after a single intravenous dose was

8.77L/h. Metabolism Elinzanetant is primarily metabolized by CYP3A4 to yield three major active metabolites, M18/21, M27, and M30/34. These metabolites have similar potency for the human NK1 and NK3 receptors as compared to elinzanetant.

The ratio of these metabolites to parent in plasma is approximately 0.39. Excretion Following a single oral dose of radiolabeled elinzanetant in healthy subjects, approximately 90% of the dose was recovered in feces (50% unchanged) and less than 1% with urine. Specific Populations No clinically significant differences in the pharmacokinetics of LYNKUET were observed based on race.

Patients with Renal Impairment In patients with mild (eGFR 60 to <90 mL/min) renal impairment, mean elinzanetant C max increased 1.9-fold and AUC increased 1.6-fold. In patients with moderate (eGFR 30 to <60 mL/min) renal impairment, mean elinzanetant C max increased 1.8-fold and AUC increased 1.7-fold. In patients with severe (eGFR< 30 mL/min) renal impairment, mean elinzanetant C max increased 1.2-fold and AUC increased 1.1-fold.

Population pharmacokinetic analysis of the clinical trial data indicate similar exposure of elinzanetant in patients with mild and moderate renal impairment compared to patients with normal renal function. Elinzanetant has not been studied in patients with end-stage renal disease (eGFR <15 mL/min) [see Use in Specific Populations (8.7) ]. Patients with Hepatic Impairment In patients with Child-Pugh Class A (mild) hepatic impairment, mean elinzanetant C max increased 1.2-fold and AUC (0-24) increased 1.5-fold.

In patients with Child-Pugh Class B (moderate) hepatic impairment, mean elinzanetant C max and AUC (0-24) increased by 2.3-fold. Elinzanetant has not been studied in patients with Child-Pugh Class C (severe) hepatic impairment [see Use i… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action LYNKUET is a neurokinin 1 (NK1) and neurokinin 3 (NK3) receptor antagonist. Inhibition of Substance P and Neurokinin B through antagonism of NK1 and NK3 receptor signaling on kisspeptin/neurokinin B/dynorphin (KNDy) neurons can modulate neuronal activity in thermoregulation associated with hot flashes. Elinzanetant has higher affinity for human NK1 receptors (pKi values of 8.7 to 10.2) and NK3 receptors (pKi values of 8.0 to 8.8) than for human NK2 receptors (pKi values of approximately 6.0).

12.3Pharmacokinetics Elinzanetant C max and AUC increased in a greater than dose-proportional manner (20% to 50%) over the dose range from 40 to 160 mg once daily (0.33 to 1.33 times the highest recommended dose). Elinzanetant steady state plasma concentrations were reached in 5 to 14 days after daily dosing. Elinzanetant accumulation is <2-fold at the approved recommended dosage.

Absorption Elinzanetant median (min-max) time to maximum plasma concentration (T max ) is 1.0 hours (1-2.5 hours) at steady state. Elinzanetant absolute bioavailability is 52% following oral administration. Effect of Food No clinically significant differences in elinzanetant pharmacokinetics were observed following administration with a high-calorie, high-fat meal containing approximately 1000 calories (500-600 calories from fat, 250 calories from carbohydrates, and 150 calories from protein).

Distribution The mean volume of distribution after intravenous administration at steady state of elinzanetant is 137 L. The plasma protein binding of elinzanetant is 99.7%. The blood-to-plasma ratio is between 0.6 and 0.7.

Elimination Elinzanetant elimination half-life was approximately 45 hours in women with vasomotor symptoms. The clearance of elinzanetant after a single intravenous dose was

8.77L/h. Metabolism Elinzanetant is primarily metabolized by CYP3A4 to yield three major active metabolites, M18/21, M27, and M30/34. These metabolites have similar potency for the human NK1 and NK3 receptors as compared to elinzanetant.

The ratio of these metabolites to parent in plasma is approximately 0.39. Excretion Following a single oral dose of radiolabeled elinzanetant in healthy subjects, approximately 90% of the dose was recovered in feces (50% unchanged) and less than 1% with urine. Specific Populations No clinically significant differences in the pharmacokinetics of LYNKUET were observed based on race.

Patients with Renal Impairment In patients with mild (eGFR 60 to <90 mL/min) renal impairment, mean elinzanetant C max increased 1.9-fold and AUC increased 1.6-fold. In patients with moderate (eGFR 30 to <60 mL/min) renal impairment, mean elinzanetant C max increased 1.8-fold and AUC increased 1.7-fold. In patients with severe (eGFR< 30 mL/min) renal impairment, mean elinzanetant C max increased 1.2-fold and AUC increased 1.1-fold.

Population pharmacokinetic analysis of the clinical trial data indicate similar exposure of elinzanetant in patients with mild and moderate renal impairment compared to patients with normal renal function. Elinzanetant has not been studied in patients with end-stage renal disease (eGFR <15 mL/min) [see Use in Specific Populations (8.7) ]. Patients with Hepatic Impairment In patients with Child-Pugh Class A (mild) hepatic impairment, mean elinzanetant C max increased 1.2-fold and AUC (0-24) increased 1.5-fold.

In patients with Child-Pugh Class B (moderate) hepatic impairment, mean elinzanetant C max and AUC (0-24) increased by 2.3-fold. Elinzanetant has not been studied in patients with Child-Pugh Class C (severe) hepatic impairment [see Use in Specific Populations (8.6) ]. Drug Interaction Studies Clinical Studies and Model-Informed Approaches No clinically significant differences in elinzanetant pharmacokinetics were observed when used concomitantly with esomeprazole (proton pump inhibitor).

No clinically significant differences in the pharmacokinetics of the following oral drugs were observed when used concomitantly with elinzanetant: tamoxifen (substrate of CYP2D6, CYP3A4 and P-gp) and rosuvastatin (substrate of BCRP, OATP1B1/OATP1B3, and OAT3). Strong CYP3A4 and P-gp inhibitors: Elinzanetant C max increased approximately 3.3-fold and AUC increased 6.3-fold following concomitant use with itraconazole 200 mg (strong CYP3A4 and P-gp inhibitor). Moderate CYP3A4 Inhibitors: Elinzanetant C max and AUC are predicted to increase 2.0-fold and 3.0-fold, respectively, following concomitant use of elinzanetant 120 mg with erythromycin (mode… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Cardiac Electrophysiology No clinically relevant prolongation of the QTc interval was observed after single oral administration of elinzanetant at doses up to 5 times the maximum recommended dose. However, QTc prolongation effect of elinzanetant when co-administered with strong CYP3A4 inhibitors has not been sufficiently characterized.

14 CLINICAL STUDIES

14.1Effects on Vasomotor Symptoms (VMS) in Postmenopausal Women The efficacy of LYNKUET for the treatment of moderate to severe vasomotor symptoms due to menopause was demonstrated in the first 12 weeks of two randomized, double-blind, placebo-controlled, multicenter clinical trials. In OASIS 1 (NCT05042362) and OASIS 2 (NCT05099159), 796 menopausal women were randomized 1:1 to receive LYNKUET 120 mg or placebo once daily at bedtime for 12 weeks. In each of these two trials, after the first 12 weeks, women on placebo were switched over to LYNKUET and all women were then treated with LYNKUET for a 14-week extension for up to 26 weeks total exposure.

Women who had at least 50 moderate to severe hot flashes (HFs), including night-time HFs, per week, were enrolled in OASIS 1 and 2. In these trials, postmenopausal status was defined as at least 12 months of spontaneous amenorrhea, or at least 6 months of spontaneous amenorrhea with serum follicle stimulating hormone levels >40 mIU/mL and a serum estradiol concentration of <30 pg/mL, or at least 6 months after hysterectomy with serum follicle-stimulating hormone >40 mIU/mL and serum estradiol <30 pg/mL, or at least 6 weeks post-surgical bilateral oophorectomy with or without hysterectomy.

In OASIS 1 and OASIS 2, the mean age of women was 54.6 years (range 40-65). The racial distribution was 80.4% White, 17.1% Black or African American, and 0.5% Asian. About 8.5% women were of Hispanic or Latino ethnicity.

The study population included women with prior hysterectomy (38.8%), prior uni-/bilateral oophorectomy (20.6%), or prior menopausal hormone therapy (MHT) use (31.4%). The primary efficacy endpoints in both trials were the mean change in frequency and severity of moderate to severe vasomotor symptoms from baseline to Weeks 4 and 12, including day and night HFs measured using the Hot Flash Daily Diary (HFDD). In both trials, LYNKUET treatment groups showed statistically significant and clinically meaningful reduction (≥ 2 hot flashes over 24 hours) in the frequency of moderate to severe HFs from baseline to Weeks 4 and 12 compared to placebo.

In both trials, LYNKUET treatment groups showed a statistically significant reduction in severity of moderate to severe vasomotor symptoms from baseline to Weeks 4 and 12 compared to placebo. Results of the co-primary endpoints for change from baseline to Weeks 4 and 12 in mean frequency and severity of moderate to severe vasomotor symptoms over 24 hours from OASIS 1 and OASIS 2 are shown in Tables 4 and 5. Table 4: Mean Baseline and Mean Change in Frequency of Moderate to Severe VMS over 24 hours from Baseline to Weeks 4 and 12 (OASIS 1 and 2) OASIS 1 OASIS 2 Parameter LYNKUET 120 mg (N= 199) Placebo (N= 197) LYNKUET 120 mg (N= 200) Placebo (N= 200) CI = Confidence Interval, LS-Means = Least Squares Means estimated from a mixed model for repeated measures analysis of covariance, SD = standard deviation, SE = Standard Error Baseline Mean (SD) 13.38 (6.57) 14.26 (13.94) 14.66 (11.08) 16.16 (11.15) Change from Baseline to Week 4 LS-Means (SE) Difference vs.

Placebo (95% CI) P-value - one-sided p-value. -7.60 (0.43) -3.29 (-4.47, -2.10) <0.0001 -4.31 (0.43) -8.58 (0.49) -3.04 (-4.40, -1.68) <0.0001 -5.54 (0.49) Change from Baseline to Week 12 LS-Means (SE) Difference vs. Placebo (95% CI) P-value -8.66 (0.58) -3.22 (-4.81, -1.63) <0.0001 -5.44 (0.59) -9.72 (0.50) -3.24 (-4.60, -1.88) <0.0001 -6.48 (0.49) Table 5: Mean Baseline and Mean Change in Severity of Moderate to Severe VMS over 24 hours from Baseline to Weeks 4 and 12 (OASIS 1 and 2) Trial 1 Trial 2 Parameter LYNKUET 120 mg (N= 199) Placebo (N= 197) LYNKUET 120 mg (N= 200) Placebo (N= 200) CI = Confidence Interval, LS-Means = Least Squares Means estimated from a mixed model for repeated measures analysis of covariance, SD = standard deviation, SE = Standard Error Baseline Mean (SD) 2.56 (0.22) 2.53 (0.23) 2.53 (0.24) 2.54 (0.24) Change from Baseline to Week 4 LS-Means (SE… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis In a 2-year carcinogenicity study in female rats, oral doses of elinzanetant ≥60 mg/kg/day (29-fold the total AUC (0-24) at the human therapeutic dose) increased the incidence of endometrial adenocarcinoma, the combination of malignant and benign endometrial tumors and squamous cell carcinoma of the uterus, and lymphomas of the hematolymphoid system. These effects were not observed at a dose representing 7-fold the total AUC (0-24) at the human therapeutic dose.

The clinical significance of these findings is unknown. In a 26-week carcinogenicity study in rasH2 transgenic mice, there was no evidence of drug-related carcinogenicity at 85 or 70 mg/kg/day in males or females, respectively. Mutagenesis Elinzanetant showed no genotoxic potential in bacterial mutation assay (Ames test), mouse lymphoma assay, and in-vivo bone marrow micronucleus test in rats.

Additionally, the principal human metabolites of elinzanetant were negative for genotoxicity in vitro in the Ames and micronucleus test.

13.2Animal Toxicology and/or Pharmacology Repeat dose toxicity studies were conducted in rats and cynomolgus monkeys. The findings of clinical relevance are described below: Reproductive organs (female) In female rats, daily oral administration of elinzanetant for 4 weeks at 100 mg/kg (40-fold the AUC (0-24) at the human therapeutic dose) induced mucification of the vaginal epithelium, uterine atrophy, and persistent corpora lutea. In monkeys, twice daily oral administration of elinzanetant for 39 weeks at doses ≥60 mg/kg/day (2-fold the human therapeutic exposure) reduced cyclical ovarian activity.

Central Nervous System (CNS) In male and female rats, twice daily oral administration of elinzanetant for 13 weeks induced involuntary muscle contractions starting around treatment day 24 and convulsions starting around day 34, when exposures in male and female rats were estimated to be ≥4-fold the AUC (0-24) at the human therapeutic dose. In female rats, twice daily oral administration of elinzanetant for 2 years induced convulsions starting around treatment day 106, when exposures were estimated to be ≥17-fold the AUC (0-24) at the human therapeutic dose.

Skeletal muscle In rats, twice daily oral administration of elinzanetant for 13 weeks at ≥100 mg/kg/day (equivalent to ≥16-fold the AUC (0-24) at human therapeutic dose) induced skeletal muscle degeneration and necrosis. These findings were not related to the convulsions presented by elinzanetant-treated rats in the same 13-week toxicity study (described under CNS above). A longer duration (26-week) toxicity study in rats as well as a follow up mechanistic study in male rats did not have any skeletal muscle findings.

The clinical relevance of these findings is unknown. Gastrointestinal system In male and female monkeys, once daily oral administration of elinzanetant for 4 weeks at 60 mg/kg/day (4-fold the AUC (0-24) at human therapeutic exposure) caused loose/watery fecal consistency and reduced food intake. In three studies of male and female monkeys treated orally with elinzanetant for 13 to 39 weeks, gastrointestinal disturbances characterized by diarrhea were observed at doses ≥30 mg/kg/day (0.2-fold the AUC (0-24) at human therapeutic exposure).

Diarrhea eventually led to dehydration, weight loss, and general ill-health in animals at doses of ≥60 mg/kg/day. Photosensitivity An in-vitro study demonstrated that elinzanetant has some potential for photosensitization. While studies of photosensitivity in animals were not conducted, there is evidence that elinzanetant distributes to and accumulates in melanin-containing tissues in the rats.