- In a Phase 2 randomized trial, baxdrostat, a highly potent and selective aldosterone synthase inhibitor, had dose-related reductions in blood pressurein patients with resistant hypertension compared to placebo, without any serious adverse events.
Difficult to control hypertension is associated with elevated cardiovascular risk. Spironolactone, a mineralocorticoid receptor antagonist, is recommended by current guidelines for treatment of resistant hypertension. Baxdrostat has been shown in Phase 1 trials to selectively inhibit aldosterone synthase and thereby reduce aldosterone levels without significantly affecting cortisol levels. On November 7, 2022 during the American Heart Association 2022 Late-Breaking Science Session on Resistant Hypertension, Dr. Mason Freeman presented the Phase 2 results of BrgHTN, simultaneously published in the New England Journal of Medicine.1
In this multicenter trial funded by CinCor Pharma, 275 patients on three or more antihypertensive medications (including at least one diuretic) with a blood pressure >=130/80 averaged over three seated measurements 5 minutes apart were randomized in a parallel fashion to once daily baxdrostat 0.5mg (n=69), baxdrostat 1 mg (n=70), baxdrostat 2mg (n= 67), or placebo (n=69) and followed for 12 weeks. Patients with systolic pressure >= 180 mmHg, diastolic pressure >=110mm Hg, estimated glomerular filtration rate of <45 ml/min/1.73 m2, or poorly controlled diabetes were excluded. If patients were on spironolactone at baseline, it was stopped four weeks prior to randomization. In addition, patients had to be at least 70% compliant with their medication regimen based on pill counts during a single blind run-in period prior to randomization. The primary endpoint was change in blood pressure from baseline for each study drug dose compared to placebo.
Overall, participants were in their 60s with a slight male predominance, about 25% were Black and 40% Hispanic or Latino. Over 90% of patients were on an ACE inhibitor or angiotensin receptor blocker.
The trial was stopped early because it met the criteria for overwhelming efficacy. By week 12, the least-squares mean systolic blood pressure decreased in a dose dependent manner: -20.3 mm Hg in the 2mg group, -17.5 mm Hg in the 1mg group, -12.1 mm Hg in the 0.5mg group, and -9.4 mm Hg in the placebo group. There was a significant difference in blood pressure drop between the 2-mg group and the placebo group (-11mm Hg, 95% confidence interval [CI] −16.4 to −5.5, P<0.001) as well as between the 1-mg group and the placebo group (-8.1 mm Hg, 95% CI -13 to -2.8, P=0.003), but not between the 0.5mg group and the placebo group. There were no deaths or episode of adrenal insufficiency. Two patients in the intervention arm had the study drug temporarily held for potassium > 6.0 mmol/L; the values normalized on recheck and the medication was restarted without any recurrence of hyperkalemia.
In conclusion, baxdrostat 2mg significantly lowered blood pressure in patients with resistant hypertension compared to placebo. The secondary analysis showed that baxdrostat reduced aldosterone levels and increased plasma renin activity without changing cortisol levels. “We have beautiful biomarker evidence, not only of blood pressure lowering, but the mechanism by which the blood pressure reduction is occurring,” said Dr. Freeman. “We believe that baxdrostat has the potential to treat disorders associated with aldosterone excess, including primary hyperaldosteronism.”
The authors point out that there has not been a new class of anti-hypertensive medication approved in the United States since 2007. Baxdrostat is a promising novel agent that may safely reduce blood pressure among those that are the hardest to treat. The effect of this medication on cardiovascular outcomes and the safety of this medication in those with chronic kidney disease will be the subject of future studies. Phase 3 trials are planned for 2023.
- Freeman MW, Halvorsen Y-D, Marshall W, et al. Phase 2 Trial of Baxdrostat for Treatment-Resistant Hypertension. N Engl J Med [Internet] 2022;1–11. Available from: http://www.nejm.org/doi/10.1056/NEJMoa2213169