Tuyishimire, Bonifride

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

Abstract Background Community-acquired pneumonia (CAP) in children is usually treated with 10 days of antibiotics. Shorter antibiotic courses may be beneficial if proven effective, with potentially fewer antibiotic adverse effects and decreased antibiotic exposure. Methods This randomized, double-blind, placebo-controlled superiority trial (NCT02891915) compared a strategy of short vs standard course ß-lactam therapy for outpatient CAP in children ages 6–71 months. Children demonstrating clinical improvement by day 3–5 of initial therapy were considered for enrollment. Enrolled children were randomized 1:1 to receive either 5 additional days of the originally prescribed antibiotic (standard) or matching placebo (short). The Desirability of Outcome Ranking (DOOR; PMID: 26113652) was the primary outcome, and was defined by classifying the global experience of children into an ordinal clinical response (OCR) that combined the response to CAP treatment and antibiotic adverse effects 11–15 days after the start of therapy. For those subjects with equivalent OCR, documented days of antibiotic administration was used to further rank the desirability of the outcome with the a priori assumption that shorter antibiotic exposure was more desirable. The OCR was a secondary outcome. The intention to treat population was used to estimate the probability of a more desirable outcome for the strategy of short vs. standard course therapy for both outcomes. Results 385 children were enrolled; 380 had complete data for analysis. Baseline characteristics were similar between the two strategies. In both strategies, > 90% of children had an adequate response to CAP treatment and most antibiotic adverse effects were minor (Table). In the OCR analysis, short course therapy had a 48% probability (95% CI: 42%-53%) of a more desirable outcome. In the DOOR analysis, short course therapy was superior to standard therapy with a 69% probability (95% CI: 63%-72%; p< 0.001) of a more desirable outcome. Conclusion Among children with CAP demonstrating initial clinical improvement with outpatient therapy, both strategies had a similar response to CAP treatment and antibiotic adverse effects, but short course therapy was superior in our a priori defined outcome that incorporated decreased antibiotic exposure. Disclosures Emmanuel B. Walter, MD, MPH, Moderna (Grant/Research Support)Pfizer (Grant/Research Support) Jason Newland, MD, MEd, FPIDS, Merck (Grant/Research Support)Pfizer (Other Financial or Material Support, Industry funded clinical trial) Vance G. Fowler, Jr., MD, MHS, Achaogen (Consultant)Actavis (Grant/Research Support)Advanced Liquid Logics (Grant/Research Support)Affinergy (Consultant, Research Grant or Support)Affinium (Consultant)Allergan (Grant/Research Support)Ampliphi Biosciences (Consultant)Basilea (Consultant, Research Grant or Support)Bayer (Consultant)C3J (Consultant)Cerexa (Consultant, Research Grant or Support)Contrafect (Consultant, Research Grant or Support)Cubist (Grant/Research Support)Debiopharm (Consultant)Destiny (Consultant)Durata (Consultant)Forest (Grant/Research Support)Genentech (Consultant, Research Grant or Support)Integrated Biotherapeutics (Consultant)Janssen (Consultant, Research Grant or Support)Karius (Grant/Research Support)Locus (Grant/Research Support)Medical Biosurfaces (Grant/Research Support)Medicines Co. (Consultant)Medimmune (Consultant, Research Grant or Support)Merck (Consultant, Research Grant or Support)NIH (Grant/Research Support)Novadigm (Consultant)Novartis (Consultant, Research Grant or Support)Pfizer (Grant/Research Support)Regeneron (Consultant, Research Grant or Support)Tetraphase (Consultant)Theravance (Consultant, Research Grant or Support)Trius (Consultant)xBiotech (Consultant) W. Charles Huskins, MD, MSc, ADMA Biologics (Consultant)Pfizer, Inc (Consultant)