Perl, Shira

Abstract Disclosure: I. Bancos: AstraZeneca. A. Ben-Shlomo: AstraZeneca. O. Hamidi: Recordati Rare Diseases, Neurocrine Biosciences, Corcept Therapeutics, Crinetics, Camurus, Xeris. A. Hamrahian: AstraZeneca. W. Huang: None. L.S. Kirschner: Corcept Therapeutics, AstraZeneca, Crinetics, Sparrow Pharma, Spruce Biosciences. R. Sam: AstraZeneca. A.F. Turcu: AstraZeneca. A. Lihn: AstraZeneca. A. Mallappa: AstraZeneca. S. Perl: AstraZeneca. B. Tuyishimire: AstraZeneca. M.J. Brown: GlaxoSmithKline, Pfizer, Inc., Bristol-Myers Squibb, AstraZeneca. Introduction: Mineralocorticoid receptor antagonist (MRA) treatment for primary aldosteronism (PA) has limited efficacy in some patients. Highly selective, competitive aldosterone synthase inhibitors (ASIs) offer an alternative therapeutic approach. SPARK (NCT04605549) was a Phase 2, open-label, multicenter trial of the ASI baxdrostat in patients with PA. Methods: Eligibility entailed: aged ≥18 years; diagnosis of PA; willingness to discontinue MRA up to 4 weeks before baxdrostat initiation; and systolic blood pressure (SBP) rise ≥20 mmHg or SBP ≥160 mmHg after discontinuation of MRA, or SBP ≥150 mmHg for patients with newly diagnosed PA who had not taken MRAs in the past 12 weeks. Patients entered a 12-week treatment period (Part 1) of once daily baxdrostat 2 mg, up-titrated to 4 mg or 8 mg at week (W) 4 or W8, respectively, if there was no significant risk of hypotension. Baxdrostat could be down-titrated to 2 mg or continued at 4 mg as needed. After W12, patients could continue baxdrostat up to W72 (Part 2) with doses at investigators’ discretion. Primary endpoints were safety, tolerability and change from baseline in mean seated SBP at W12. Results: Fifteen patients enrolled and completed Part 1; 14 patients continued to Part 2. Median (range) age was 54 (32, 75) years, 67% of patients were male, 47% were White, and median (range) body mass index was 32.0 (24.4, 41.4) kg/m2. At baseline, plasma renin activity (PRA) was <1 ng/mL/h in 12/15 (80%) patients, and 8/15 (53%) patients had hypokalemia (serum potassium <3.5 mmol/L). Mean (range) baseline SBP was 151.5 (130, 174) mmHg; diastolic BP (DBP) was 90.3 (74, 103) mmHg. At W12, mean (range) SBP change from baseline was –29.5 (–47, –12), –24.4 (–31, –17), and –23.9 (–47, –8) mmHg for patients on baxdrostat 2 mg (n=2), 4 mg (n=5), and 8 mg (n=7), respectively; DBP change was –8.0 (–14, –2), –10.4 (–20, 0), and –11.6 (–25, 7) mmHg, respectively. Overall, 11/15 (73%) patients achieved BP <140/90 mmHg and 6/15 (40%) achieved BP <130/80 mmHg at W12; reduced BP persisted in Part 2. No deaths were reported. Nine out of 15 (60%) patients had a treatment-emergent adverse event (TEAE) during W4–W12 of Part 1 (all mild/moderate), including 1/15 (7%) patient with hyperkalemia; no serious TEAEs were reported. In Part 2, 14/14 (100%) patients had a TEAE (most mild/moderate), including 5/14 (36%) patients with hyperkalemia; one serious TEAE of hyperkalemia was reported. Mean (standard deviation, SD) serum potassium levels increased from 3.9 (0.6) mEq/L at baseline to 4.7 (0.5) mEq/L at W12. Mean (SD) 24-h urine aldosterone excretion at baseline and W12 were 30.3 (17.5) and 3.2 (2.7) µg/day, respectively. At W12, 7/15 (47%) patients had achieved unsuppressed PRA (≥1.0 ng/mL/h). Conclusions: Baxdrostat, an ASI, was well tolerated and led to reduced BP and unsuppressed renin in patients with PA. Inhibiting aldosterone synthase may be an alternative to MRAs for treating PA. Presentation: Sunday, July 13, 2025