Efficacy and Safety of AZD5462, a Novel Oral Relaxin Receptor Agonist, in Heart Failure: Findings From the Phase 2b LUMINARA Trial
Importance
The management of heart failure (HF) continues to evolve, with novel therapeutic targets emerging to improve hemodynamics and cardiac remodeling. According to findings prese oknted at the European Society of Cardiology (ESC) Congress in Munich and published concurrently in Circulation, a first-in-class oral relaxin receptor agonist has demonstrated favorable hemodynamic profiles across the spectrum of left ventricular ejection fraction (LVEF).
James L. Januzzi, MD, Hutter Family Professor of Medicine at Massachusetts General Hospital and Harvard Medical School, outlined the physiological premise of the therapy during his presentation:
โRelaxin 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.โ
While relaxin has been historically investigated for both acute and chronic HF, prior RXFP1-stimulating therapies were strictly parenteral and yielded inconsistent results. Dr. Januzzi emphasized the therapeutic breakthrough:
โA 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.โ
Objective and Trial Design
The LUMINARA trial (Phase 2b) aimed to evaluate the safety, tolerability, and hemodynamic efficacy of AZD5462 (AstraZeneca) across two distinct heart failure populations over a 24-week period. The majority of enrolled participants were receiving robust, guideline-directed medical therapy, which included SGLT2 inhibitors, beta-blockers, mineralocorticoid receptor antagonists, and ACE inhibitors/ARBs/ARNIs.
Participants were randomly assigned to receive either placebo or one of three once-daily AZD5462 dosing regimens (20 mg, 80 mg, or 360 mg).
| Trial Cohort | Patient Population | Sample Size (N) | Mean Age | Male Representation | Primary Endpoint at 24 Weeks |
| Cohort A | HF with LVEF $\le$ 35% | 235 | 65 years | 88% | Change in end-systolic volume index |
| Cohort B | HF with LVEF 41% to 55% | 140 | 70 years | 69% | Change in systemic vascular resistance index |
Results and Hemodynamic Outcomes
The trial revealed nuanced, dose-dependent hemodynamic benefits. Notably, the lowest investigated dose of AZD5462 demonstrated the most promising clinical profile, particularly in patients with reduced ejection fraction.
In Cohort A, improvements in the end-systolic volume index trended toward statistical significance in the lower-dose arms but lost efficacy at the highest dose. Conversely, in Cohort B, the primary endpoint of improved systemic vascular resistance index was successfully met across all active treatment arms.
Secondary endpoints, including changes in N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and LVEF changes at 24 weeks, did not achieve statistical significance in either cohort.
| AZD5462 Dose Arm | Cohort A Primary Endpoint (P Value) | Cohort B Primary Endpoint (P Value) |
| 20 mg | $P = .054$ (Trended toward significance) | $P < .05$ (Significant) |
| 80 mg | $P = .132$ | $P < .05$ (Significant) |
| 360 mg | $P = .662$ | $P < .05$ (Significant) |
Note: Cohort A endpoint = change in end-systolic volume index; Cohort B endpoint = change in systemic vascular resistance index.
Safety and Tolerability Profile
The safety analysis yielded no major adverse signals. Overall adverse event rates were comparable between the placebo and AZD5462 cohorts. Regarding specific safety parameters, Dr. Januzzi reported:
โThere 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.โ
A notable physiological observation was a dose-dependent elevation in renin levels among patients receiving AZD5462. Dr. Januzzi suggested this compensatory renin increase at higher doses may elucidate why the lowest dose (20 mg) yielded the most favorable efficacy outcomes in Cohort A.
Conclusions and Clinical Implications
The LUMINARA trial provides foundational evidence for the continued investigation of oral RXFP1 agonism in heart failure. Summarizing the clinical takeaways, Dr. Januzzi concluded:
โTreatment 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.โ
Serving as the discussant for the presentation, John R. Teerlink, MD, director of heart failure and the echocardiography laboratory at the San Francisco Veterans Affairs Medical Center, commended the structural integrity of the trial. He characterized LUMINARA as:
โโฆa 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.โ
Dr. Teerlink acknowledged that while โthe inverse dose relationship for end systolic volume is rather atypical and needs further discussion,โ the collective findings ultimately signal that โLUMINARA provides the potential basis for the future development of AZD5462 in heart failure.โ
