In patients with chronic heart failure (HF), the addition of the oral relaxin family peptide receptor 1 (RXFP1) agonist AZD5462 to guideline-directed medical therapies (GDMTs) may help improve cardiac remodelling and haemodynamics across a wide range of left ventricular ejection fraction (LVEF), according to the phase IIb LUMINARA study.
At week 25, after 24 weeks of treatment, the primary endpoint of reductions in end-systolic volume index among patients with LVEF of ≤35 percent (cohort A) were greater by 5.4 mL/m2 with AZD5462 20 mg (p=0.054), 4.4 mL/m2 with 80 mg (p=0.132), and 1.3 mL/m2 with 360 mg (p=0.662) when compared with placebo.
Among patients with LVEF of 41 percent to 55 percent (cohort B), the primary endpoint of changes in systemic vascular resistance (SVR) index at week 25 were smaller with AZD5462 vs placebo, with a difference of 0.81, 0.79, and 0.85 dynes·s−1·cm−5·m−2 in the 20-, 80-, and 360-mg dose groups, respectively (p=0.004, p<0.001, and p=0.021).
“In cohort A, improvement in left ventricular end-systolic volume index from baseline to 6 months appeared greater with AZD5462 treatment. In cohort B, there was a worsening of vascular resistance in placebo and a stabilization and a slight lowering of the SVR index among individuals treated with AZD5462,” reported principal investigator Dr James Januzzi from the Baim Institute for Clinical Research, Massachusetts General Hospital, Harvard Medical School, Boston, US.
“One important finding is an apparent inverse dose relationship where the largest amount of reverse cardiac remodelling among patients in cohort A appeared to be associated with the lowest dose of AZD5462,” Januzzi continued.
For secondary endpoints, results generally favoured AZD5462 over placebo for ventricular function and biomarkers, although none of these differences were statistically significant. However, Januzzi pointed out that the placebo-adjusted reduction in NT-proBNP of approximately 18 percent in the 20-mg dose group was clinically meaningful.
In terms of safety, Januzzi noted that the findings were reassuring and consistent with the expected pharmacology of the agent. The most frequently reported adverse events (AEs) were cardiac failure, dizziness, diarrhoea, and hypotension.
Serious AEs occurred in 18.2 percent of patients in the combined AZD5462 group and 18.6 percent in the placebo group, and death rates were 4 percent and 3.4 percent, respectively. AEs led to treatment discontinuation in 5.7 percent of patients in the combined AZD5462 group and 10.2 percent in the placebo group.
“There were no major safety signals detected across any of the doses, with comparable rates of AEs and no excess discontinuation of study drug. There was evidence for mild haemodilution that was dose-related, typically seen in the higher doses of AZD5462, but there was no excess of AEs related to volume overload,” according to Januzzi.
“As expected, there was mild lowering of blood pressure consistent with the phase I experience with the drug, but there was no meaningful hypotension signal detected,” he said.
Dose-dependent increases in renin concentrations were observed, confirming biological activity. This finding, Januzzi noted, was consistent with vasodilatory physiology and compensatory neurohormonal activation. “And the renin increases seen at the higher doses may help to actually explain why maximal reverse remodelling was seen in the lowest dose of AZD5462 among those with reduced left ventricular ejection fraction,” he added.
“LUMINARA supports relaxin family peptide receptor 1 agonism as a novel mechanistic approach for chronic HF that may provide incremental benefit on top of established background therapy,” Januzzi said. “The encouraging results from this study stand in contrast to results of other recent trials of relaxin-like compounds and provide encouraging support for further exploration of AZD5462 for the treatment of chronic HF.”
Conducted across 57 sites in 10 countries, LUMINARA included 375 chronic HF patients, including 235 with LVEF ≤35 percent (mean age 65 years, 88 percent male) and 140 with LVEF 41 percent to 55 percent (mean age 70 years 69 percent male).
The patients were randomly assigned to receive once-daily treatment with AZD5462 at 20, 80, or 360 mg or placebo. Treatment was administered orally for 24 weeks.