Oral Relaxin Receptor Agonist AZD5462 in Participants With Chronic Heart Failure: Primary Results From the LUMINARA Trial

BACKGROUND: Stimulation of the relaxin family peptide receptor 1 experimentally reduces systemic vascular resistance and afterload, improves organ perfusion, and fosters reverse cardiac remodeling. We hypothesized that AZD5462, an oral once-daily relaxin family peptide receptor 1 agonist, may benefit individuals with chronic heart failure (HF). METHODS: In this international, multicenter, double-blind, placebo-controlled, dose-ranging trial, adults with chronic HF and left ventricular ejection fraction ≤35% (cohort A) or 41% to 55% (cohort B) were randomized 1:1:1:1 to 3 (20, 80, or 360 mg) once-daily oral doses of AZD5462 or placebo. Primary end points were changes in end-systolic volume index (cohort A) and systemic vascular resistance index (cohort B) after at week 25. RESULTS: A total of 235 (cohort A) and 140 (cohort B) participants were randomized across 57 sites in 10 countries. The mean age was 65 and 70 years, and 88% and 69% were male; baseline concomitant guideline-directed medical therapy for HF was excellent. Treatment with AZD5462 was well tolerated compared with placebo. In cohort A, at week 25, treatment with AZD5462 20 mg showed a placebo-adjusted end-systolic volume index change from baseline of −5.4 mL/m 2 (95% CI, −10.9 to 0.1; P =0.054). In cohort B, AZD5462 treatment resulted in significant placebo-adjusted reductions in systemic vascular resistance index at week 25 across all dose groups (all P <0.05). CONCLUSIONS: Among individuals with well-treated chronic HF, the addition of oral AZD5462 was well tolerated and demonstrated encouraging effects on cardiovascular hemodynamic measures across a wide range of left ventricular ejection fraction. Larger and longer duration trials are warranted to assess the impact of AZD5462 on clinical outcomes in HF. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT06299826.