AZD5462 / AstraZeneca - LARVOL DELTA

Oral Relaxin Receptor Agonist AZD5462 in Participants With Chronic Heart Failure: Primary Results From the LUMINARA Trial. (PubMed, Circulation) - P2 | "Larger and longer duration trials are warranted to assess the impact of AZD5462 on clinical outcomes in HF. URL: https://www.clinicaltrials.gov; Unique identifier: NCT06299826."

Journal • Cardiovascular • Congestive Heart Failure • Heart Failure

Divergent activation of the RXFP1 relaxin receptor by protein and small molecule agonists. (PubMed, bioRxiv) - "Here, we present three cryo-electron microscopy structures of RXFP1: ligand-free, bound to the native agonist relaxin-2, and bound to the small-molecule drug candidate AZD5462...Both mechanisms are distinctive from the "push-pull" mechanism of glycoprotein hormone receptors. Altogether, our findings define divergent activation mechanisms for protein and small-molecule agonists of RXFP1 and provide structural framework for next-generation drug discovery targeting relaxin receptors and their relatives."

Journal • Cardiovascular • Congestive Heart Failure • Fibrosis • Heart Failure • Immunology

The first oral relaxin receptor RXFP1 agonist for heart failure treatment: Translational studies from non-human primates to humans. (PubMed, Mol Ther Adv) - "Prior clinical studies using injectable short- or long-acting relaxin analogues have not delivered sustained benefits. These findings support AZD5462 as a promising novel therapy for chronic heart failure. A phase 2 study of AZD5462 is currently underway in patients with chronic heart failure."

Journal • Cardiovascular • Congestive Heart Failure • Heart Failure • Hypotension

Phase 2b trial of an oral RXFP1 agonist in patients with chronic heart failure: rationale and design. (PubMed, ESC Heart Fail) - "This study will evaluate AZD5462 as a novel oral therapy for patients with chronic HF, aiming to improve symptoms as well as haemodynamic and cardiorenal biomarkers. The findings may provide insights on the development of AZD5462 in a future phase 3 trial."

Journal • P2b data • Cardiovascular • Congestive Heart Failure • Heart Failure

LUMINARA: A Phase IIb Study of AZD5462 in Patients With Chronic Heart Failure (clinicaltrials.gov) - P2 | N=375 | Completed | Sponsor: AstraZeneca | Active, not recruiting ➔ Completed

Trial completion • Cardiovascular • Congestive Heart Failure • Heart Failure

Biased small molecule RXFP1 agonists ameliorate experimental pulmonary hypertension and RV hypertrophy (AHA 2025) - "Serum and PDGF-BB-induced migration of PASMC were inhibited by RLN2, ML290 and derivatives. Humanized RXFP1 knock-in (hRXFP1-KI) mice subjected to SU5416 and hypoxia (FiO2=0.1) for three weeks and treated with ML290, TRND8394, AZD5462 (10 mg/kg/d p.o.), or ACTRIIA-Fc (a.k.a., sotatercept, 2.2 mg/kg/twice weekly i.p.) had comparable improvements in right ventricular systolic pressure (RVSP) vs. disease controls, while treatment with biased compounds ML290 and TRND8394, and ACTRIIA-Fc elicited potent decreases in RV hypertrophy (RV/LV+S).ConclusionSmall molecule RXFP1 agonists with biased GPCR signaling may elicit more potent effects in experimental PH upon right ventricular hypertrophy than non-biased RXFP1 agonists and represent a promising therapeutic strategy for cardiopulmonary disease."

Cardiovascular • Congestive Heart Failure • Heart Failure • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • ACVR2A • CALD

AURORA: A Phase Ib Study of AZD5462 on Top of Dapagliflozin in Participants With Heart Failure and Moderate Renal Impairment (clinicaltrials.gov) - P1 | N=8 | Terminated | Sponsor: AstraZeneca | Completed ➔ Terminated; Sponsor Decision

Trial termination • Cardiovascular • Congestive Heart Failure • Heart Failure • Renal Disease

A Phase 1b Randomized Clinical Trial of AZD5642 and Dapagliflozin in Patients with Heart Failure and Moderate Renal Impairment. (PubMed, Am J Cardiol) - "The safety and tolerability of AZD5462 will be further evaluated compared with placebo on top of dapagliflozin. AURORA is a phase 1b pharmacodynamic, pharmacokinetic, and safety study of AZD5462 on top of dapagliflozin in patients with heart failure and renal impairment."

Clinical • Journal • P1 data • Cardiovascular • Congestive Heart Failure • Heart Failure • Renal Disease

LUMINARA: A Phase IIb Study of AZD5462 in Patients With Chronic Heart Failure (clinicaltrials.gov) - P2 | N=375 | Active, not recruiting | Sponsor: AstraZeneca | Recruiting ➔ Active, not recruiting

Enrollment closed • Cardiovascular • Congestive Heart Failure • Heart Failure

A Study Designed to Assess the Mass Balance Recovery, Absorption, Metabolism, Excretion of [14C]AZD5462 and the Absolute Bioavailability of AZD5462 (clinicaltrials.gov) - P1 | N=8 | Completed | Sponsor: AstraZeneca | Not yet recruiting ➔ Completed

Trial completion • Cardiovascular • Heart Failure

AURORA: A Phase Ib Study of AZD5462 on Top of Dapagliflozin in Participants With Heart Failure and Moderate Renal Impairment (clinicaltrials.gov) - P1 | N=8 | Completed | Sponsor: AstraZeneca | Active, not recruiting ➔ Completed | Trial completion date: Dec 2025 ➔ May 2025 | Trial primary completion date: Dec 2025 ➔ May 2025

Trial completion • Trial completion date • Trial primary completion date • Cardiovascular • Congestive Heart Failure • Heart Failure • Renal Disease

A Study Designed to Assess the Mass Balance Recovery, Absorption, Metabolism, Excretion of [14C]AZD5462 and the Absolute Bioavailability of AZD5462 (clinicaltrials.gov) - P1 | N=8 | Not yet recruiting | Sponsor: AstraZeneca

New P1 trial • Cardiovascular • Heart Failure

AURORA: A Phase Ib Study of AZD5462 on Top of Dapagliflozin in Participants With Heart Failure and Moderate Renal Impairment (clinicaltrials.gov) - P1 | N=8 | Active, not recruiting | Sponsor: AstraZeneca | Recruiting ➔ Active, not recruiting | N=40 ➔ 8

Enrollment change • Enrollment closed • Cardiovascular • Congestive Heart Failure • Heart Failure • Renal Disease

Liquid Chromatography Combined With Electrospray Ionization Tandem Mass Spectrometry for the Determination and Identification of AZD5462 and Its Metabolites in Rat Plasma. (PubMed, Biomed Chromatogr) - "The metabolic pathways of AZD5462 include oxygenation and glucuronidation. This study is the first report on the pharmacokinetics and metabolism of AZD5462, which would provide insights into the effectiveness and toxicity of this drug candidate."

Journal • Preclinical • Cardiovascular • Congestive Heart Failure • Heart Failure

GLITTER: A Study to Investigate the Pharmacokinetics, Safety and Tolerability of AZD5462 in Participants With Renal Impairment (clinicaltrials.gov) - P1 | N=16 | Completed | Sponsor: AstraZeneca | Recruiting ➔ Completed | N=25 ➔ 16 | Trial completion date: Apr 2025 ➔ Dec 2024 | Trial primary completion date: Apr 2025 ➔ Dec 2024

Enrollment change • Trial completion • Trial completion date • Trial primary completion date • Renal Disease

GLITTER: A Study to Investigate the Pharmacokinetics, Safety and Tolerability of AZD5462 in Participants With Renal Impairment (clinicaltrials.gov) - P1 | N=25 | Recruiting | Sponsor: AstraZeneca | Not yet recruiting ➔ Recruiting

Enrollment open • Renal Disease

GLITTER: A Study to Investigate the Pharmacokinetics, Safety and Tolerability of AZD5462 in Participants With Renal Impairment (clinicaltrials.gov) - P1 | N=25 | Not yet recruiting | Sponsor: AstraZeneca

New P1 trial • Renal Disease

AURORA: A Phase Ib Study of AZD5462 on Top of Dapagliflozin in Participants With Heart Failure and Moderate Renal Impairment (clinicaltrials.gov) - P1 | N=40 | Recruiting | Sponsor: AstraZeneca

New P1 trial • Cardiovascular • Congestive Heart Failure • Heart Failure • Renal Disease

LUMINARA: A Phase IIb Study of AZD5462 in Patients With Chronic Heart Failure (clinicaltrials.gov) - P2 | N=360 | Recruiting | Sponsor: AstraZeneca | Not yet recruiting ➔ Recruiting

Enrollment open • Cardiovascular • Congestive Heart Failure • Heart Failure

Renal expression pattern of the relaxin receptor, RXFP1, and effects of the RXFP1 agonist, AZD5462, on renin in non-human primates and humans (ERA-EDTA 2024) - "Human RXFP1 kidney glomerular expression is conserved with NHPs but not rodent, thus highlighting the translational and pharmacological challenges in studying RXFP1/relaxin biology across species. The concordant ability of AZD5462 to induce elevations in renin and reduction in serum creatinine, together with relaxin's reported renal-hemodynamic activity in humans, may underlie a previously unappreciated renal-intrinsic RXFP1 target engagement mechanism driving its hemodynamic and renal effects. The potential therapeutic benefits of RXFP1 agonism are the subject of on-going clinical trials in heart failure patients."

Cardiovascular • Congestive Heart Failure • Heart Failure

Discovery of Clinical Candidate AZD5462, a Selective Oral Allosteric RXFP1 Agonist for Treatment of Heart Failure. (PubMed, J Med Chem) - "AZD5462 was well tolerated in both rat and cynomolgus monkey and has successfully completed phase I studies in healthy volunteers. In summary, AZD5462 is a small molecule pharmacological mimetic of relaxin H2 signaling at RXFP1 and holds promise as a potential therapeutic approach to treat heart failure patients."

Journal • Cardiovascular • Congestive Heart Failure • Heart Failure

LUMINARA: A Phase IIb Study of AZD5462 in Patients With Chronic Heart Failure (clinicaltrials.gov) - P2 | N=360 | Not yet recruiting | Sponsor: AstraZeneca

New P2 trial • Cardiovascular • Congestive Heart Failure • Heart Failure

Safety, tolerability, and pharmacokinetics of AZD5462, a small molecule agonist of the RXFP1 relaxin receptor (ESC 2023) - "Introduction: Despite multiple new drug advancements for patients with heart failure in recent years (specifically, sodium-glucose co-transporter-2 and sacubitril/valsartan), morbidity and mortality remain high. AZD5462 was generally well tolerated at all dose levels in this phase 1 study. These data pave the way for development of a chronic oral relaxin therapy for patients with heart failure."

Clinical • PK/PD data • Cardiovascular • Congestive Heart Failure • Heart Failure • Hypotension • Ventricular Tachycardia

Pharmacokinetics of AZD5462 in Healthy Participants (clinicaltrials.gov) - P1 | N=8 | Completed | Sponsor: AstraZeneca | Active, not recruiting ➔ Completed

Trial completion

Pharmacokinetics of AZD5462 in Healthy Participants (clinicaltrials.gov) - P1 | N=8 | Active, not recruiting | Sponsor: AstraZeneca | Recruiting ➔ Active, not recruiting | N=16 ➔ 8

Enrollment change • Enrollment closed