Baxdrostat

There are no available data on the use of baxdrostat during pregnancy to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcome. Hypertension during pregnancy poses a risk to the mother and fetus (see Clinical Considerations). Although studies in animals have shown embryo-fetal toxicity at baxdrostat exposures >29 times the human exposure at the clinical dose of 2 mg, the clinical significance of these findings is unclear.

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Disease-Associated Maternal and/or Embryo/Fetal Risk

Hypertension in pregnancy increases the risk for adverse maternal outcomes including pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section, and post-partum hemorrhage). Hypertension also increases the risk of adverse fetal outcomes including intrauterine growth restriction and stillbirth. Pregnant women with hypertension should be carefully monitored and managed accordingly.

There are no data on the presence of baxdrostat in human milk, the effects on the breastfed infant, or the effects on milk production. Baxdrostat transfers to milk in lactating rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for baxdrostat and any potential adverse effects on the breastfed infant from baxdrostat or from the underlying maternal condition.

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.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of baxdrostat was evaluated over 12 weeks using the randomized, double-blind, placebo-controlled periods from three clinical trials in patients with hypertension not adequately controlled on other antihypertensive medications. Three of these trials [BaxHTN (NCT06034743), BrigHTN (NCT04519658), Bax24 (NCT06168409)] evaluated baxdrostat 2 mg as add-on treatment and two trials [BaxHTN, BrigHTN] evaluated baxdrostat 1 mg as add-on treatment. These data reflect exposure of 441 patients to baxdrostat 2 mg and 333 patients to baxdrostat 1 mg, with a mean treatment duration of 80 days for both baxdrostat 2 mg and 1 mg. Analyses in this section are based on the 12‑week periods in these three trials. Uncontrolled, long-term safety data from 192 patients exposed to baxdrostat 1 mg or 2 mg for a mean of 293 days and 172 patients exposed to baxdrostat 2 mg for a mean of 327 days, were consistent with the safety profile observed during the 12-week, randomized, double-blind, placebo-controlled periods.

Hyperkalemia was the most frequently reported adverse reaction to baxdrostat in the three clinical trials. Hyperkalemia led to permanent discontinuation of treatment in 8 (1.8%) patients in the baxdrostat 2 mg group, 2 (0.6%) patients in the baxdrostat 1 mg group, and none in the placebo group.

Table 1 shows the most frequently reported adverse reactions to baxdrostat during the 12-week period in the three clinical trials.

Table 1. Adverse Reactions Reported in ≥2% of Patients Treated with Baxdrostat and Greater (≥1%) than Placebo During the 12-Week, Randomized, Double-Blind Periods from Three Clinical Trials in Patients with Hypertension:

^* Frequencies derived from the pool of three hypertension studies (BaxHTN, BrigHTN, Bax24) with baxdrostat 2 mg as add-on treatment.
^† Frequencies derived from the pool of two hypertension studies (BaxHTN, BrigHTN) with baxdrostat 1 mg as add-on treatment.
^‡ Frequencies derived from the pool of three hypertension studies (BaxHTN, BrigHTN, Bax24) with baxdrostat 1 mg and/or 2 mg as add‑on treatment.

Laboratory Tests

Serum Potassium

During the 12-week, randomized, double-blind periods from baxdrostat clinical trials in patients with hypertension, increases in serum potassium (>5.5 mEq/L) were reported for 12.2% of patients administered baxdrostat 2 mg, 6.3% of patients administered baxdrostat 1 mg, and 0.9% of placebo-treated patients.

Serum Sodium

During the 12-week, randomized, double-blind periods from baxdrostat clinical trials in patients with hypertension, decreases in serum sodium (<130 mEq/L) were reported for 3.7% of patients administered baxdrostat 2 mg, 3.3% of patients administered baxdrostat 1 mg, and 0.9% of placebo-treated patients.

Estimated Glomerular Filtration Rate (eGFR)

A decrease in mean eGFR was observed in baxdrostat clinical trials in patients with hypertension. At Week 12, the mean placebo-corrected decrease in eGFR was 8.0 mL/min/1.73 m² in the baxdrostat 2 mg group and 7.1 mL/min/1.73 m² in the baxdrostat 1 mg group. In baxdrostat-treated patients, the mean reduction in eGFR appeared to plateau by Week 12 and the mean eGFR increased after baxdrostat discontinuation, suggesting a hemodynamic effect on renal function.