Phase 2 Trial of Baxdrostat for Treatment-Resistant Hypertension.

Autor:	Freeman MW; 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.)., Halvorsen YD; 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.)., Marshall W; 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.)., Pater M; 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.)., Isaacsohn J; 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.)., Pearce C; 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.)., Murphy B; 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.)., Alp N; 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.)., Srivastava A; 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.)., Bhatt DL; 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.)., Brown MJ; 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.).
Jazyk:	angličtina
Zdroj:	The New England journal of medicine [N Engl J Med] 2023 Feb 02; Vol. 388 (5), pp. 395-405. Date of Electronic Publication: 2022 Nov 07.
DOI:	10.1056/NEJMoa2213169
Abstrakt:	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.). (Copyright © 2022 Massachusetts Medical Society.)
Databáze:	MEDLINE
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