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Results from the phase 2b LUMINARA trial, presented at the European Society of Cardiology Congress and simultaneously published in Circulation, demonstrate that AZD5462—a novel oral relaxin receptor agonist developed by AstraZeneca—was well tolerated and conferred favorable hemodynamic benefits across the heart failure ejection fraction spectrum.
Study Design and Patient Population
The trial evaluated AZD5462 across two distinct patient cohorts receiving background guideline-directed medical therapy (GDMT), which included ACE inhibitors, angiotensin receptor blockers, or angiotensin receptor-neprilysin inhibitors, beta-blockers, mineralocorticoid receptor antagonists, and SGLT2 inhibitors. Patients were randomized to receive once-daily doses of AZD5462 (20 mg, 80 mg, or 360 mg) or placebo.
| Cohort Identifier | Patient Population & Clinical Characteristics | Sample Size (N) | Primary Endpoint (at 24 Weeks) |
| Cohort A | Heart failure with reduced ejection fraction ($\text{LVEF} \le 35\%$); mean age 65 years; 88% men | 235 patients | Change in end-systolic volume index (ESVI) |
| Cohort B | Heart failure with mild-to-moderately preserved ejection fraction ($\text{LVEF} 41\% \text{ to } 55\%$); mean age 70 years; 69% men | 140 patients | Change in systemic vascular resistance index (SVRI) |
Pharmacological Rationale and Mechanism
Explaining the physiological foundation of the therapeutic approach, James L. Januzzi, MD, Hutter Family Professor of Medicine at Massachusetts General Hospital and Harvard Medical School, stated during his presentation:
“Relaxin biology affords a potentially novel approach to improving vascular function and cardiac remodeling in heart failure. Stimulation of the relaxin family peptide receptor 1, or RXFP1, reduces systemic vascular resistance and afterload, improves organ perfusion and fosters reverse cardiac remodeling. So accordingly, relaxin has been studied as a treatment for acute as well as chronic heart failure. To date, however, drugs stimulating RXFP1 have been only administered parenterally, and with variable impact on heart failure. A key innovation here is the development of an oral therapy suitable for testing long-term chronic and perhaps more pulsatile activation of the RXFP1 receptor. Accordingly, AZD5462 is the first and only oral once-daily RXFP1 agonist in clinical development. So we therefore hypothesize that use of this agent may benefit individuals with chronic heart failure.”
Efficacy Outcomes and Hemodynamic Findings
The primary and secondary outcomes evaluated at the 24-week mark revealed differential dose-dependent responses across the trial cohorts.
| Study Arm / Measure | Cohort A Findings (ESVI Change) | Cohort B Findings (SVRI Change) |
| 20 mg AZD5462 Group | Trended toward primary endpoint ($P = .054$) | Reached significance ($P < .05$) |
| 80 mg AZD5462 Group | Trended toward primary endpoint ($P = .132$) | Reached significance ($P < .05$) |
| 360 mg AZD5462 Group | Not significant ($P = .662$) | Reached significance ($P < .05$) |
| Secondary Endpoints | Changes in LVEF and NT-proBNP at 24 weeks were non-significant | Changes in LVEF and NT-proBNP at 24 weeks were non-significant |
In Cohort A, the primary endpoint trended toward statistical significance in the lowest-dose group (20 mg) but failed to reach significance at the highest dose (360 mg). Investigators observed that renin levels increased more substantially at higher doses of AZD5462, which potentially accounts for the superior efficacy demonstrated by the lowest dosage. In Cohort B, the primary endpoint was successfully met across all active treatment arms ($P < .05$). Secondary endpoints tracking changes in left ventricular ejection fraction and N-terminal pro-B-type natriuretic peptide at 24 weeks showed no significant variation across any group.
Safety and Tolerability Profile
Adverse event rates were comparable between the AZD5462 and placebo arms, with no major safety signals identified during the evaluation period. Januzzi highlighted the safety observations:
“There was evidence for mild hemodilution that was dose-related, typically seen in the higher doses of AZD5462, but there was no excess of adverse events related to volume overload. Although, as expected, there was mild lowering of blood pressure, consistent with the phase 1 experience with the drug, there was no meaningful hypotension signal detected.”
Summarizing the clinical implications of the trial, Januzzi concluded:
“Treatment of chronic heart failure with the first oral RXFP1 agonist was well tolerated across a wide LVEF spectrum. AZD5462 treatment resulted in improvement of cardiac remodeling and hemodynamics compared with placebo, despite a high rate of background foundational medical therapy use. Among those individuals with reduced ejection fraction in the trial, there was a greater improvement in end-systolic volume index observed with lower AZD5462 doses. These findings, therefore, justify proceeding forward with further exploration of the drug. It seems clear that the 20 mg dose would be the go-forward dose.”
Expert Commentary and Critical Appraisal
Providing a formal discussant evaluation of the trial, John R. Teerlink, MD, professor of medicine at the University of California, San Francisco, and director of heart failure and of the echocardiography laboratory at the San Francisco Veterans Affairs Medical Center, characterized the investigation as:
“a well-designed and well-conducted phase 2b study with carefully selected and wide dose-ranging assessments. [The researchers] targeted groups of patients across the left ventricular ejection spectrum with excellent background therapy and [the trial] was reasonably well powered for the selected endpoints, given it was a phase 2b study.”
Addressing the unconventional dose-response profile observed in the trial, Teerlink noted:
While “the inverse dose relationship for end systolic volume is rather atypical and needs further discussion … I believe that LUMINARA provides the potential basis for the future development of AZD5462 in heart failure.”
