A Phase IIb Two-Cohort, Randomised, Placebo-controlled, Double-blind, Multi-centre, Dose-ranging Study of AZD5462 in Stable Patients With Chronic Heart Failure

doi:10.1161/circulationaha.126.082763

LUMINARA

Paziente / Popolazione Intervento / Esposizione Confronto Esito

In 375 patients with chronic heart failure, AZD5462, an oral relaxin agonist improved the change in LV end-systolic volume index or systemic vascular resistance at 24 weeks compared with placebo.

N

375pazienti

Disegno

phase 2b, randomised 1:1:1:1 (stratified by cohort), double-blind, placebo-controlled, multicentre (57 sites in 10 countries), dose-ranging; two cohorts — A: LVEF ≤35 % (≈220 planned), B: LVEF 41–55 % (≈140 planned); three once-daily oral doses of AZD5462 vs placebo for 24 weeks, plus 4-week follow-up

Esito

Cohort A — change from baseline in left ventricular end-systolic volume index after 24 weeks of treatment; Cohort B — change from baseline in systemic vascular resistance index after 24 weeks of treatment (echocardiographic, week 25 visit)

Rilevanza

3Complementare — contesto, non conoscenza imprescindibile.

RisultatoCohort A (LVEF ≤ 35%): change in LV end-systolic volume index vs placebo P = 0.054, 0.132 and 0.662 for 20, 80 and 360 mg. Cohort B (LVEF 41-55%): change in systemic vascular resistance index P = 0.004, < 0.001 and 0.021. Every key secondary — NT-proBNP, LVEF, KCCQ, eGFR — was P > 0.05. Serious adverse events 18.2% vs 18.6% in cohort A; renin rose with dose.

Januzzi JL, et al. Circulation. 2026; published online 30 August. 10.1161/circulationaha.126.082763

Discussione e critica

An oral relaxin agonist reaches its target: vascular resistance falls where resistance was the endpoint, and renin rises with dose, so the drug is doing what the receptor predicts. What it does not yet do is anything a patient would notice — every secondary endpoint, including symptoms and natriuretic peptides, came back above 0.05, and the remodelling signal in the reduced-ejection-fraction cohort was strongest at the lowest dose and absent at the highest. Phase 2b, 375 patients, mechanistic endpoints; it earns an outcomes trial rather than a conclusion.