Phase 2 Trial of Baxdrostat for Treatment-Resistant Hypertension

Freeman, Mason W. M.D.
Halvorsen, Yuan-Di Ph.D.
Marshall, William M.D.
Pater, Mackenzie Ph.D.
Isaacsohn, Jon M.D.
Pearce, Catherine D.H.Sc.
Murphy, Brian M.D., M.P.H.
Alp, Nicholas M.D.
Srivastava, Ajay M.D.
Bhatt, Deepak L. M.D., M.P.H.
Brown, Morris J. M.D.

From CinCor Pharma (M.W.F., Y.-D.H., W.M., C.P.) and Brigham and Women's Hospital, Harvard Medical School (D.L.B.) — both in Boston; CinRx Pharma (M.P., J.I., B.M.) and Medpace (N.A., A.S.) — both in Cincinnati; and the Department of Clinical Pharmacology, William Harvey Research Institute, Queen Mary University of London, London (M.J.B.).

^*The BrigHTN Investigators are listed in the Supplementary Appendix, available at NEJM.org.

Dr. Brown can be contacted at [email protected] or at Queen Mary University of London, Charterhouse Sq., London EC1M 6BQ, United Kingdom.

Supported by CinCor Pharma.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

This article was published on November 7, 2022, and updated on January 6, 2023, at NEJM.org.

A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.

New England Journal of Medicine 388(5):p 395-405, February 2, 2023. | DOI: 10.1056/NEJMoa2213169

ABSTRACT

BACKGROUND

Aldosterone synthase controls the synthesis of aldosterone and has been a pharmacologic target for the treatment of hypertension for several decades. Selective inhibition of aldosterone synthase is essential but difficult to achieve because cortisol synthesis is catalyzed by another enzyme that shares 93% sequence similarity with aldosterone synthase. In preclinical and phase 1 studies, baxdrostat had 100:1 selectivity for enzyme inhibition, and baxdrostat at several dose levels reduced plasma aldosterone levels but not cortisol levels.

METHODS

In this multicenter, placebo-controlled trial, we randomly assigned patients who had treatment-resistant hypertension, with blood pressure of 130/80 mm Hg or higher, and who were receiving stable doses of at least three antihypertensive agents, including a diuretic, to receive baxdrostat (0.5 mg, 1 mg, or 2 mg) once daily for 12 weeks or placebo. The primary end point was the change in systolic blood pressure from baseline to week 12 in each baxdrostat group as compared with the placebo group.

RESULTS

A total of 248 patients completed the trial. Dose-dependent changes in systolic blood pressure of -20.3 mm Hg, -17.5 mm Hg, -12.1 mm Hg, and -9.4 mm Hg were observed in the 2-mg, 1-mg, 0.5-mg, and placebo groups, respectively. The difference in the change in systolic blood pressure between the 2-mg group and the placebo group was -11.0 mm Hg (95% confidence interval [CI], -16.4 to -5.5; P<0.001), and the difference in this change between the 1-mg group and the placebo group was -8.1 mm Hg (95% CI, -13.5 to -2.8; P=0.003). No deaths occurred during the trial, no serious adverse events were attributed by the investigators to baxdrostat, and there were no instances of adrenocortical insufficiency. Baxdrostat-related increases in the potassium level to 6.0 mmol per liter or greater occurred in 2 patients, but these increases did not recur after withdrawal and reinitiation of the drug.

CONCLUSIONS

Patients with treatment-resistant hypertension who received baxdrostat had dose-related reductions in blood pressure. (Funded by CinCor Pharma; BrigHTN ClinicalTrials.gov number, NCT04519658.)

Phase 2 Trial of Baxdrostat for Treatment-Resistant Hypertension

ABSTRACT

BACKGROUND

METHODS

RESULTS

CONCLUSIONS

Baxdrostat for Treatment-Resistant Hypertension

Decreasing the Effects of Aldosterone in Resistant Hypertension — A Success Story

Aldosterone and Treatment-Resistant Hypertension