Baxfendy baxdrostat 2 mg Tablet, Film Coated, 7-count — NDC 0310-6002-95 (Billing 00310-6002-95)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Baxdrostat is an inhibitor of human aldosterone synthase. Aldosterone contributes to hypertension by promoting the retention of sodium and water by the kidneys, which increases blood volume and, consequently, raises blood pressure. Aldosterone can cause vascular dysfunction, inflammation, and fibrosis.

Inhibition of aldosterone synthase by baxdrostat decreases plasma aldosterone concentrations, thereby reducing blood pressure. Baxdrostat has a higher potency and selectivity for aldosterone synthase compared to the closely related enzyme 11β-hydroxylase (final enzyme in cortisol synthesis). In nonclinical and clinical studies, baxdrostat significantly lowered aldosterone concentrations without affecting cortisol responses over a wide dose range.

Baxdrostat does not inhibit synthesis of sex hormones such as testosterone and estrone.

12.2Pharmacodynamics In healthy subjects, baxdrostat dosed at 1.5 mg to 2.5 mg with a normal salt diet and 2.5 mg to 5 mg with a low salt diet (0.75 to 2.5 times the maximum recommended dose), resulted in a decrease of up to approximately 70% and 83% in plasma aldosterone concentrations, respectively, after the initial dose. At Day 10, aldosterone concentrations remained up to approximately 68% lower than baseline in the normal salt group and 73% lower than baseline in the low salt group. In hypertensive patients, repeated administration of baxdrostat 0.5 mg (0.5 times the lowest recommended dose), 1 mg and 2 mg caused a sustained dose-dependent decrease in 24-hour urinary excretion of aldosterone, and a decrease in plasma aldosterone concentrations, while plasma renin activity increased.

Decreased plasma aldosterone concentrations were observed up to 32 weeks, the last time point of assessment. No effect on adrenocorticotropic hormone (ACTH) stimulated cortisol secretion was observed during treatment with BAXFENDY in healthy subjects with doses up to 360 mg (180 times the maximum recommended dose) administered as a single dose or with multiple ascending doses up to 10 mg (5 times the maximum recommended dose) at steady state, or in a dedicated randomized, double‑blind, placebo‑controlled trial in patients with hypertension treated with baxdrostat 2 mg for 8 weeks.

Cardiac Electrophysiology Clinically significant QTc interval prolongation was not observed at 16 times the maximum recommended dose.

12.3Pharmacokinetics Baxdrostat geometric mean maximum plasma concentration (C max ) was 19 ng/mL (%CV: 5.4) and the geometric mean area underneath the time concentration curve from time 0 to infinity (AUC 0–inf ) was 711 h*ng/mL (%CV: 32) following a single 2 mg dose. Baxdrostat AUC and C max increased in a dose‑proportional manner for the 1 and 2 mg doses in patients with hypertension, and steady state was reached by Day 8. Absorption Baxdrostat has an absolute bioavailability of 98%.

Under fasted conditions, median time to maximum plasma concentration (t max ) was 2.5 hours (min: 1.0 hours, max: 5.0 hours) for the 2 mg dose. Baxdrostat did not show pH- dependent solubility at pharmacologically relevant concentrations. Effect of Food No clinically significant differences in baxdrostat pharmacokinetics were observed following administration of a high-fat, high-calorie meal (800 to 1000 calories with approximately 50% of the total caloric content from fat) in healthy subjects.

Distribution The volume of distribution of baxdrostat at steady state is 205 L. The plasma protein binding of baxdrostat was 74% and the blood to plasma ratio was 0.95 in vitro . Elimination The mean effective half-life of baxdrostat was approximately 26 hours (range 23 to 32 hours).

The mean total clearance was

2.8 L/h, and the mean renal clearance was

0.46L/h. Metabolism Baxdrostat is primarily metabolized by CYP3A4 to an intermediate ketone metabolite, which is further metabolized by CBR1 (carbonyl reductase 1) to an alcohol metabolite (M2). After a single dose of radiolabeled bax… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Baxdrostat is an inhibitor of human aldosterone synthase. Aldosterone contributes to hypertension by promoting the retention of sodium and water by the kidneys, which increases blood volume and, consequently, raises blood pressure. Aldosterone can cause vascular dysfunction, inflammation, and fibrosis.

Inhibition of aldosterone synthase by baxdrostat decreases plasma aldosterone concentrations, thereby reducing blood pressure. Baxdrostat has a higher potency and selectivity for aldosterone synthase compared to the closely related enzyme 11β-hydroxylase (final enzyme in cortisol synthesis). In nonclinical and clinical studies, baxdrostat significantly lowered aldosterone concentrations without affecting cortisol responses over a wide dose range.

Baxdrostat does not inhibit synthesis of sex hormones such as testosterone and estrone.

12.3Pharmacokinetics Baxdrostat geometric mean maximum plasma concentration (C max ) was 19 ng/mL (%CV: 5.4) and the geometric mean area underneath the time concentration curve from time 0 to infinity (AUC 0–inf ) was 711 h*ng/mL (%CV: 32) following a single 2 mg dose. Baxdrostat AUC and C max increased in a dose‑proportional manner for the 1 and 2 mg doses in patients with hypertension, and steady state was reached by Day 8. Absorption Baxdrostat has an absolute bioavailability of 98%.

Under fasted conditions, median time to maximum plasma concentration (t max ) was 2.5 hours (min: 1.0 hours, max: 5.0 hours) for the 2 mg dose. Baxdrostat did not show pH- dependent solubility at pharmacologically relevant concentrations. Effect of Food No clinically significant differences in baxdrostat pharmacokinetics were observed following administration of a high-fat, high-calorie meal (800 to 1000 calories with approximately 50% of the total caloric content from fat) in healthy subjects.

Distribution The volume of distribution of baxdrostat at steady state is 205 L. The plasma protein binding of baxdrostat was 74% and the blood to plasma ratio was 0.95 in vitro . Elimination The mean effective half-life of baxdrostat was approximately 26 hours (range 23 to 32 hours).

The mean total clearance was

2.8 L/h, and the mean renal clearance was

0.46L/h. Metabolism Baxdrostat is primarily metabolized by CYP3A4 to an intermediate ketone metabolite, which is further metabolized by CBR1 (carbonyl reductase 1) to an alcohol metabolite (M2). After a single dose of radiolabeled baxdrostat, the parent compound accounted for 71% of total radioactivity exposure.

Excretion After administration of a radiolabeled dose of baxdrostat, approximately 69% of the dose was recovered in urine (17% unchanged) and 15% in feces (6% unchanged). Specific Populations There were no clinically relevant effects of age (18 to 90 years), sex (37% females), body weight (43 to 224 kg), or race (White, Asian, and Black or African American) on the pharmacokinetics of baxdrostat. Patients with Renal Impairment In subjects with moderate or severe renal impairment (eGFR 15 to < 60 mL/min, not on dialysis), C max and AUC 0–inf of baxdrostat were similar compared to the control group (eGFR ≥ 60 mL/min), with a geometric mean ratio (95% CI) for baxdrostat C max of 1.02 (0.82, 1.27) and AUC 0–inf of 1.21 (0.81, 1.79).

Compared to the control group, subjects with kidney failure treated with intermittent hemodialysis who were administered baxdrostat on a non-dialysis day had a geometric mean ratio (95% CI) for C max of 0.88 (0.71, 1.09) and AUC 0‑inf of 0.68 (0.46, 0.99) [see Use in Specific Populations (8.6) ] . Patients with Hepatic Impairment In subjects with moderate hepatic impairment (Child-Pugh category B), C max and AUC 0–inf of baxdrostat were similar to control subjects with normal hepatic function, with a geometric mean ratio (95% CI) for baxdrostat C max of 1.13 (0.97, 1.32) and AUC 0–inf of 0.95 (0.73, 1.23).

Baxdrostat has not been studied in patients with severe hepatic impairment. Drug Interaction Studies Clinical Studies There was no clinically significant difference in baxdrostat exposure based on C max (1.30-fold geometric mean increase [95% CI: 1.20, 1.39]) or AUC (1.56-fold geometric mean increase [95% CI: 1.46, 1.66]) when used concomitantly with itraconazole (strong CYP3A and P‑gp inhibitor). There were no differences in the pharmacokinetics of either metformin (MATE1 and MATE2‑K transporter substrate) or the oral contraceptive ethinyl estradiol/levonorgestrel when used concomitantly with baxdrostat.

In Vitro Studies Cytochrome P450 (CYP450) enzymes: Baxdrostat did not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A4/5, and did not induce CYP1A2, CYP2B6, or CYP3A4. Baxdrostat was not a substrate of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A5. UDP-Glucuronosyltransferase (UGT) enzymes: Baxdrostat did not inhibit UGT1A1, UGT1A3… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics In healthy subjects, baxdrostat dosed at 1.5 mg to 2.5 mg with a normal salt diet and 2.5 mg to 5 mg with a low salt diet (0.75 to 2.5 times the maximum recommended dose), resulted in a decrease of up to approximately 70% and 83% in plasma aldosterone concentrations, respectively, after the initial dose. At Day 10, aldosterone concentrations remained up to approximately 68% lower than baseline in the normal salt group and 73% lower than baseline in the low salt group. In hypertensive patients, repeated administration of baxdrostat 0.5 mg (0.5 times the lowest recommended dose), 1 mg and 2 mg caused a sustained dose-dependent decrease in 24-hour urinary excretion of aldosterone, and a decrease in plasma aldosterone concentrations, while plasma renin activity increased.

Decreased plasma aldosterone concentrations were observed up to 32 weeks, the last time point of assessment. No effect on adrenocorticotropic hormone (ACTH) stimulated cortisol secretion was observed during treatment with BAXFENDY in healthy subjects with doses up to 360 mg (180 times the maximum recommended dose) administered as a single dose or with multiple ascending doses up to 10 mg (5 times the maximum recommended dose) at steady state, or in a dedicated randomized, double‑blind, placebo‑controlled trial in patients with hypertension treated with baxdrostat 2 mg for 8 weeks.

Cardiac Electrophysiology Clinically significant QTc interval prolongation was not observed at 16 times the maximum recommended dose.

14 CLINICAL STUDIES The efficacy of BAXFENDY was evaluated in a multipart, phase 3, multicenter trial (BaxHTN, NCT06034743) in adults with systolic blood pressure ≥ 140 and < 170 mmHg who were prescribed at least 2 antihypertensive medications, including one diuretic and who had an eGFR ≥ 45 mL/min/1.73 m 2 and a serum potassium of ≥ 3.5 and < 5.0 mEq/L. Following a 2-week placebo run-in period, 794 patients with a systolic blood pressure ≥ 135 mmHg were randomized equally and treated with BAXFENDY 1 mg, BAXFENDY 2 mg, or placebo once daily during an initial 12‑week double-blind treatment period.

During this period, changes to background antihypertensive medication were prohibited unless patients became hypotensive or required rescue medication. Treatment with potassium supplements and potassium binders was allowed during the trial, but not simultaneous use of both an angiotensin receptor blocker (ARB) and angiotensin‑converting enzyme inhibitor (ACEi), or treatment with a mineralocorticoid receptor antagonist (MRA) or potassium sparing diuretic. At the end of the 12 weeks, patients entered a 12-week, open-label treatment period.

During the open-label period, patients who were on BAXFENDY 2 mg during the double-blind period continued the same dose of BAXFENDY, patients who received BAXFENDY 1 mg were re-randomized 4:1 to either BAXFENDY 2 mg or standard of care, and patients on placebo were re-randomized 1:4 to either BAXFENDY 2 mg or standard of care. At the end of the open-label period, 257 patients who were on BAXFENDY 2 mg in the open-label period were re-randomized 2:1 to receive either BAXFENDY 2 mg (n=172) or placebo (n=85) once daily during an 8-week double-blind, randomized withdrawal period.

The primary endpoints were change from baseline to Week 12 in seated office systolic blood pressure for BAXFENDY 2 mg once daily compared to placebo and for BAXFENDY 1 mg once daily compared to placebo. The key secondary endpoint was change in seated office systolic blood pressure for BAXFENDY 2 mg compared with placebo from the start (Week 24) to the end (Week 32) of the randomized withdrawal double-blind period of the trial. The mean age of the patient population was 61 years, 62% were male, 63% were White, 26% Asian, 7% Black or African American, and 4% other, and 13% were of Hispanic or Latino ethnicity.

The mean body mass index (BMI) at randomization was 31 kg/m 2 . Patient medical history included type 2 diabetes mellitus (37%), heart failure (6%), myocardial infarction (5%), and stroke (4%). Mean eGFR at baseline was 85 mL/min/1.73 m 2 .

Concomitant antihypertensive medicines during the trial included diuretics (100% of patients), either ACEi or ARB (90%), calcium channel blockers (70%), beta‑blockers (34%), and other antihypertensive medicines (17%). Approximately 41% of patients were on 3 background antihypertensive medications. At baseline, the mean systolic blood pressure was 149 mmHg and mean diastolic blood pressure was 87 mmHg.

At Week 12, both BAXFENDY 1 mg and 2 mg were superior to placebo in reducing systolic blood pressure and diastolic blood pressure (Table 2). The mean change from baseline in systolic blood pressure over time in each treatment arm is shown in Figure 1. Table 2: Treatment Effects on Blood Pressure at Week 12 (Full Analysis Set Full analysis set includes all randomized patients who received at least one administration of investigational medicinal product. ), BaxHTN Trial Efficacy Parameter BAXFENDY 2 mg BAXFENDY 1 mg Placebo Systolic Blood Pressure Seated blood pressure measurements were recorded using standardized automated blood pressure machines.

Mean seated blood pressure is defined as the average of the last 2 seated blood pressure measurements of a total of 3 measurements. (mmHg) 1 patient in the placebo group was excluded from the analysis due to a missing baseline measurement. n=266 n=264 n=263 Baseline (mean) 149.1 149.7 149.0 Change from baseline (mean) -15.7 -14.5 -5.8 Difference from… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Baxdrostat was not carcinogenic in a 6‑month carcinogenicity study in rasH2 transgenic mice. Administration of 5, 15, or 45 mg/kg/day of baxdrostat to rasH2 transgenic mice for 6 months did not increase the incidence of neoplastic findings. The exposure margin (based on AUC) was > 260‑fold compared to a human dose of 2 mg.

In a 2‑year carcinogenicity study in rats, baxdrostat was administered at daily doses of 0, 1, 3, or 10 mg/kg/day in males and 0, 0.3, 1, or 3 mg/kg/day in females. An increased incidence of benign and malignant thymoma was observed in males at 10 mg/kg/day. There were no neoplastic effects in males or females at 3 mg/kg/day (at least 36 times the human dose of 2 mg based on AUC).

Mutagenesis Baxdrostat was not genotoxic when tested in a battery of in vitro and in vivo assays. Impairment of Fertility Male and female fertility studies in rats showed no effects of baxdrostat at exposures up to 126- and 218‑fold, respectively the human exposure at 2 mg.