Nereus Tradipitant 85 mg Capsule, 36-count — NDC 43068-585-02 (Billing 43068-0585-02)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Tradipitant is a selective, high-affinity antagonist of human substance P/neurokinin 1 (NK1) receptors. Tradipitant does not have affinity for NK2 and NK3 receptors, serotonin (5-HT3), dopamine (D2), cholinergic, or histamine (H1) receptors. Tradipitant has been shown in animal models to inhibit drug induced emesis.

Human Positron Emission Tomography (PET) studies with tradipitant have shown that tradipitant crosses the blood brain barrier and occupies brain NK-1 receptors. The exact mechanism by which tradipitant exerts its therapeutic effect is not fully established.

12.2Pharmacodynamics Tradipitant inhibits the NK1 receptor with a K i of 0.062 ± 0.01 nM and inhibits substance P (SP) induced intracellular calcium mobilization with a K b of 0.095 ± 0.025 nM. The major metabolites of tradipitant (M2, M3, M4, and M8) showed a similar degree of binding at the NK-1 receptor. NK1 Receptor Occupancy A clinical study using PET imaging demonstrated a dose- and concentration-dependent increase in frontal cortex NK-1 receptor occupancy of tradipitant.

The maximum receptor occupancy was 93% after multiple administrations of 100 mg NEREUS. Cardiac Electrophysiology At the mean maximum concentration provided by the maximum recommended single dose (170 mg) administered without food, clinically significant QTc prolongation was not observed.

12.3Pharmacokinetics Absorption Absolute oral bioavailability has not been studied in humans. Following a single dose of 85 mg tradipitant in healthy subjects under fasting conditions, tradipitant geometric mean C max was 84.7 ng/mL, AUC 0-inf was 1839 ng*h/mL, and the median T max was 2.0 hours. Following a single dose of 170 mg tradipitant in healthy subjects under fasting conditions, tradipitant geometric mean C max was 112 ng/mL, AUC 0-inf was 3,526 ng*h/mL, and the median T max was 1.50 hours.

Effect of food Tradipitant C max and AUC 0-inf increased approximately 4.7-fold and 2.4-fold, respectively, and T max was delayed by 2 hours, when 85 mg tradipitant was administered with a high-fat meal (800 to 1,000 calories, 50% fat) compared to fasted conditions in healthy subjects. After administration of 170 mg tradipitant with a high-fat meal, C max and AUC 0-inf increased approximately 6.9-fold and 2.9-fold, respectively, and T max was delayed by 2.5 hours [see Dosage and Administration (2.1) ] . Distribution The apparent volume of distribution (Vd/F) of tradipitant is 1956 L in healthy subjects.

Tradipitant plasma protein binding ranged from 96% to >99% in vitro. Elimination The observed mean elimination half-life for tradipitant is approximately 34 hours and apparent oral clearance of tradipitant is

41.7L/hour in healthy subjects. Metabolism Tradipitant is extensively metabolized; however, the metabolic pathways have not been fully characterized. In vitro findings suggest that non-CYP450-mediated processes and CYP enzymes (CYP3A4, CYP2C19, and to a lesser extent by CYP2C8) are involved in the metabolism of tradipitant.

Tradipitant is also glucuronidated by UGT1A4 and UGT2B7. Four major metabolites (M2, M3, M4, and M8) were identified in plasma. Following a single dose of 85 mg tradipitant in healthy subjects under fasting conditions, the AUCs of M2, M3, M4, and M8 represent 40%, 33%, 43%, and 42% of the parent AUC, respectively.

Excretion Following a single oral dose of radiolabeled tradipitant 25 mg, approximately 88% of the dose was recovered, with 80% of the dose in feces and 7% in urine. Unchanged tradipitant was minimal in feces and was not detected in urine. Specific Populations Patients with Renal Impairment Based on population pharmacokinetic analysis, no clinically significant difference was observed in pharmacokinetics of tradipitant between subjects with normal renal function and subjects with mild to moderate renal impairment (estimated glomerular filtration rate (eGFR) of at least 30 mL/minute/1.73m 2 ).

The impact of severe renal impai… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Tradipitant is a selective, high-affinity antagonist of human substance P/neurokinin 1 (NK1) receptors. Tradipitant does not have affinity for NK2 and NK3 receptors, serotonin (5-HT3), dopamine (D2), cholinergic, or histamine (H1) receptors. Tradipitant has been shown in animal models to inhibit drug induced emesis.

Human Positron Emission Tomography (PET) studies with tradipitant have shown that tradipitant crosses the blood brain barrier and occupies brain NK-1 receptors. The exact mechanism by which tradipitant exerts its therapeutic effect is not fully established.

12.3Pharmacokinetics Absorption Absolute oral bioavailability has not been studied in humans. Following a single dose of 85 mg tradipitant in healthy subjects under fasting conditions, tradipitant geometric mean C max was 84.7 ng/mL, AUC 0-inf was 1839 ng*h/mL, and the median T max was 2.0 hours. Following a single dose of 170 mg tradipitant in healthy subjects under fasting conditions, tradipitant geometric mean C max was 112 ng/mL, AUC 0-inf was 3,526 ng*h/mL, and the median T max was 1.50 hours.

Effect of food Tradipitant C max and AUC 0-inf increased approximately 4.7-fold and 2.4-fold, respectively, and T max was delayed by 2 hours, when 85 mg tradipitant was administered with a high-fat meal (800 to 1,000 calories, 50% fat) compared to fasted conditions in healthy subjects. After administration of 170 mg tradipitant with a high-fat meal, C max and AUC 0-inf increased approximately 6.9-fold and 2.9-fold, respectively, and T max was delayed by 2.5 hours [see Dosage and Administration (2.1) ] . Distribution The apparent volume of distribution (Vd/F) of tradipitant is 1956 L in healthy subjects.

Tradipitant plasma protein binding ranged from 96% to >99% in vitro. Elimination The observed mean elimination half-life for tradipitant is approximately 34 hours and apparent oral clearance of tradipitant is

41.7L/hour in healthy subjects. Metabolism Tradipitant is extensively metabolized; however, the metabolic pathways have not been fully characterized. In vitro findings suggest that non-CYP450-mediated processes and CYP enzymes (CYP3A4, CYP2C19, and to a lesser extent by CYP2C8) are involved in the metabolism of tradipitant.

Tradipitant is also glucuronidated by UGT1A4 and UGT2B7. Four major metabolites (M2, M3, M4, and M8) were identified in plasma. Following a single dose of 85 mg tradipitant in healthy subjects under fasting conditions, the AUCs of M2, M3, M4, and M8 represent 40%, 33%, 43%, and 42% of the parent AUC, respectively.

Excretion Following a single oral dose of radiolabeled tradipitant 25 mg, approximately 88% of the dose was recovered, with 80% of the dose in feces and 7% in urine. Unchanged tradipitant was minimal in feces and was not detected in urine. Specific Populations Patients with Renal Impairment Based on population pharmacokinetic analysis, no clinically significant difference was observed in pharmacokinetics of tradipitant between subjects with normal renal function and subjects with mild to moderate renal impairment (estimated glomerular filtration rate (eGFR) of at least 30 mL/minute/1.73m 2 ).

The impact of severe renal impairment (eGFR ≤29 mL/min/1.73m 2 ) on the pharmacokinetics of tradipitant is unknown [see Use in Specific Populations (8.6) ] . Patients with Hepatic Impairment Tradipitant has not been studied in subjects with any degree of hepatic impairment (Child-Pugh Class A to C). The impact of mild, moderate, or severe hepatic impairment on the pharmacokinetics of tradipitant is unknown. [see Use in Specific Populations (8.7) ] Drug Interaction Studies Clinical Studies Midazolam (CYP3A4 Substrate) Co-administration of tradipitant did not result in clinically significant change in pharmacokinetics of midazolam or 1-OH-midazolam.

Ethanol Co-administration of tradipitant with ethanol (20% w/v alcohol in orange juice (240 mL for men and 200 mL women) increased tradipitant C max by 9% and AUC 0-24s by 14%. This increase in exposure is not considered to be clinically relevant. In Vitro Studies Based on in vitro studies, tradipitant does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, nor induces CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19.

Based on in vitro studies, tradipitant may inhibit and induce CYP3A4. However, an in vivo study showed no clinically significant differences in midazolam pharmacokinetics when co-administered with tradipitant. Tradipitant is a P-gp substrate and is not a substrate of BCRP, OATP1B1, OATP1B3, MATE1 or MATE2-K.

In vitro, tradipitant did not inhibit P-gp,… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Tradipitant inhibits the NK1 receptor with a K i of 0.062 ± 0.01 nM and inhibits substance P (SP) induced intracellular calcium mobilization with a K b of 0.095 ± 0.025 nM. The major metabolites of tradipitant (M2, M3, M4, and M8) showed a similar degree of binding at the NK-1 receptor. NK1 Receptor Occupancy A clinical study using PET imaging demonstrated a dose- and concentration-dependent increase in frontal cortex NK-1 receptor occupancy of tradipitant.

The maximum receptor occupancy was 93% after multiple administrations of 100 mg NEREUS. Cardiac Electrophysiology At the mean maximum concentration provided by the maximum recommended single dose (170 mg) administered without food, clinically significant QTc prolongation was not observed.

14 CLINICAL STUDIES The efficacy of NEREUS for the prevention of vomiting induced by motion was evaluated in two randomized, double-blind, placebo-controlled studies: Study 1 (NCT04327661) and Study 2 (NCT05903924). In both studies, subjects were randomized 1:1:1 to receive a single dose of NEREUS 85 mg, 170 mg, or placebo approximately 60 minutes prior to a boat trip scheduled to last approximately 2 to 5 hours. Subjects with conditions causing chronic nausea were not eligible for enrollment.

Subjects were instructed to take study medication without food. Use of anti-nausea or anti-emetic medications was not allowed during the studies. The efficacy of NEREUS for the treatment of established nausea and vomiting was not evaluated in the studies.

There were 365 subjects in Study 1 and 316 in Study 2 with a mean age of 48 years (range from 18 to 75 years), 62% were female, 12% identified as Hispanic or Latino, 81% identified as White, 9% as Asian, 5% as Black or African American, and 4% identified as another racial group. The duration of the boat trip in these studies ranged from 2 to 4.4 hours. The peak wave height ranged from 0.3 to 2.5 meters.

The primary endpoint in both studies was the percentage of subjects with vomiting during the boat trip. Vomiting was assessed every 30 minutes using a 1-item questionnaire completed by subjects indicating whether they had vomited in the last 30 minutes. Prevention of Vomiting Endpoint Results The percentage of subjects with vomiting during a boat trip in Studies 1 and 2, is shown in Table 2 .

Table 2: Percentage of Subjects with Vomiting During a Boat Trip CI = confidence interval a NEREUS was administered as a single 85 mg or 170 mg dose approximately 60 minutes prior to a boat trip and without food. b The difference (%) for NEREUS minus placebo is based on the unadjusted risk difference. The 95% CI is calculated using the Wald method. NEREUS 85 mg a NEREUS 170 mg a Placebo Study 1 N=123 N=120 N=122 Incidence of Vomiting (%) 20% 18% 44% Treatment -25% -26% Difference (95% CI) b (-36%, -14%) (-37%, -15%) Study 2 N=104 N=106 N=106 Incidence of Vomiting (%) 18% 10% 38% Treatment -19% -27% Difference (95% CI) b (-31%, -8%) (-38%, -16%) Prevention of Nausea Endpoint Results In Study 1 and Study 2 during a boat trip, a secondary endpoint of worst nausea score, assessed over the preceding 30 minutes on a 5-point scale where 0 indicates no nausea and 4 indicates very severe nausea, was 2.4 for NEREUS 85 mg and 2.3 for NEREUS 170 mg compared to 2.4 for placebo in Study 1 and 2.5 for NEREUS 85 mg and 2.2 for NEREUS 170 mg compared to 2.4 for placebo in Study 2.

These differences did not reach statistical significance in either study.

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis In transgenic rasH2 mice orally administered tradipitant (15, 50, or 1500 mg/kg/day) for 26 weeks, there was no increase in tumors. In rats orally administered tradipitant (10, 30, or 150 mg/kg/day) for at least 104 weeks, a dose- related increase in the incidence of thyroid follicular cell tumors (adenomas or adenomas combined with carcinomas), correlating with the findings of thyroid masses and cysts, was observed at all tested doses in both males (less than the exposure at the MRHD) and females (1.4 times the exposure to tradipitant at the MRHD).

These findings in the thyroid are likely rodent specific, secondary to the induction of hepatic metabolic enzymes and not relevant to humans. Mutagenesis Tradipitant was not genotoxic in a battery of in vitro (Ames, chromosomal aberration in human peripheral blood lymphocytes) and in vivo (mouse micronucleus) assays. Impairment of Fertility In a combined fertility and embryofetal development study, no effects were observed on fertility or reproductive performance in male or female rats administered oral doses of tradipitant at 10, 100, or 1000 mg/kg/day (up to 2.2 times the exposure to tradipitant at the MRHD) prior to and through mating, conception, and implantation.