A Phase 1b Randomized Clinical Trial of AZD5462 and Dapagliflozin in Patients with Heart Failure and Moderate Renal Impairment

AZD5462 is the first oral selective relaxin/insulin-like family peptide receptor 1 agonist in clinical development. The aim of this mechanistic study is to investigate the renal effects of AZD5462 when administered on top of the sodium–glucose cotransporter 2 inhibitor dapagliflozin in participants with heart failure and moderate renal impairment. AURORA is a phase 1b, placebo-controlled, double-blind, 2-centre study of AZD5462 on top of dapagliflozin as standard of care in 2 arms. Approximately 40 participants with heart failure with ejection fraction ≤50% and moderate renal impairment (estimated glomerular filtration rate of 30–60 mL/min/1.73 m 2, inclusive) will be randomized 1:1 to AZD5462 or placebo tablets for a treatment period of 4 weeks. All participants will be standardized to 10 mg dapagliflozin prior to AZD5462 administration, and dapagliflozin as standard of care will continue until the end of the follow-up period. The objectives of the study are to evaluate the renal and haemodynamic effects of AZD5462 compared with placebo on top of dapagliflozin on natriuresis, albuminuria, haematocrit, fluid balance, cardiorenal biomarkers, and systemic hemodynamics. 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.

Graphical Abstract

Heart failure (HF) and kidney disease, when occurring together, significantly worsens their individual prognosis. In patients with severe chronic kidney disease (CKD), the use of guideline-directed medical therapies for HF are progressively infrequent. In a study published in 2021, only 5%–15% of patients hospitalized with HF with estimated glomerular filtration rate (eGFR) 30–44 mL/min/1.73 m 2 or <30 mL/min/1.73 m 2 received the evidence-based triple therapy recommended at the time. Therefore, drugs that can treat both conditions have the potential to significantly improve prognosis and reduce mortality.

AZD5462 is the first oral relaxin receptor agonist that stimulates the relaxin/insulin-like family peptide receptor 1 (RXFP1). The relaxin RFXP1 receptor is located in the kidney glomeruli of humans. Relaxin is an endogenous hormone that stimulates the RXFP1 receptor causing increases of up to 50% in glomerular filtration and renin release throughout pregnancy. Relaxin also causes a gradual reduction in systemic vascular resistance of up to 30%, without causing a reduction in blood pressure throughout pregnancy. , AZD5462 has been developed to target the RXFP1 receptor mimicking the effects of naturally occurring relaxin. In healthy humans AZD5462 has been demonstrated to reduce systemic vascular resistance without causing blood pressure alterations whilst also causing natriuresis due to increases in filtration (increased eGFR) (AstraZeneca data on file), making it attractive for patients with congestive HF. It is currently unknown whether the eGFR increase is solely due to increases in renal blood flow or the result of increases in intraglomerular pressure and in turn increased filtration. However, in a study in healthy volunteers with a recombinant human relaxin, glomerular hydrostatic pressure remained unchanged despite increased renal plasma flow.

One of the newer drug therapies for patients with both HF and CKD is the selective SGLT2is. Despite SGLT2is causing short-term decline in eGFR, they have been demonstrated to significantly lower the risk of a composite of kidney outcomes, including the sustained decline in eGFR, end-stage kidney disease, death from renal or cardiovascular causes, and hospitalization for HF, leading to longer patient survival. ,,, Another feature of SGLT2is is that they have minor blood pressure (BP)-lowering effects, allowing SGLT2i treatment to be initiated earlier in the treatment paradigm to avoid hypotension in patients with HF with reduced ejection fraction (HFrEF). As SGLT2is are not considered to be haemodynamic drugs, they could be favourably administered with a haemodynamic drug with similar beneficial profiles.

Study Design

Overview

AURORA is a phase 1b, randomized, double-blind, placebo-controlled study to evaluate the pharmacodynamic, pharmacokinetic, and safety effects of AZD5462 on top of dapagliflozin as standard of care (SoC) in participants with HF (EF≤ 50%) and moderate renal impairment (defined as an eGFR of 30–60 mL/min/1.73 m 2, inclusive). All participants will be standardized to daily doses of 10 mg dapagliflozin for a period of 4 weeks to minimize potential variability caused by SGLT2i dose or type before the oral administration of AZD5462; dapagliflozin treatment will continue until the end of the follow-up period ( Figure 1 ). Additionally, participants will be asked to maintain a stable dietary sodium intake from visit 2 until the end of the study. The study will aim to randomize (1:1) approximately 40 participants to 2 treatment arms (20 evaluable participants per arm), AZD5462 or placebo once daily, on top of 10 mg dapagliflozin for 4 weeks.

Figure 1

Schematic representation of the AURORA phase 1b study design. D = day; dapa = dapagliflozin; OD = once daily; R = randomization; SoC = standard of care; V = visit.

The study will consist of 5 study periods with 9 study visits ( Figure 1 ): 1) an outpatient screening period (28 days, visit 1); 2) an outpatient dapagliflozin and dietary salt run-in period (26 days, visit 2), to stabilize all participants on dapagliflozin as part of the HF SoC and a standardized dietary sodium intake; 3) an inpatient treatment period (4 days, visit 3); 4) an outpatient treatment period (27 days, visits 4–6); and 5) an outpatient follow-up period (28 days, visits 7–9).

The total duration of the study is expected to be 113 days per participant. The safety of the participants will be monitored during the study through safety assessments at all visits, including 3 visits after the end of treatment (follow-up period).

Conduct and ethics

This study is being conducted in accordance with the protocol and international guidelines including the Declaration of Helsinki and Council for International Organizations of Medical Sciences, and all applicable ethical and regulatory requirements. All patients will provide written informed consent before participating and can withdraw their consent at any time. The study is registered with ClinicalTrials.gov (NCT06639087). Everyone involved in the conduct of the study will remain blinded to treatment assignment throughout the duration of the study.

Study population

The study population will consist of males and females of nonchildbearing potential, 18–85 years of age (inclusive), with a minimum body mass index (BMI) of 18 kg/m 2, a pre-existing diagnosis of HF with an LVEF of ≤50%, and an eGFR of 30–60 mL/min/1.73 m 2 (inclusive). Participants must be receiving stable HF SoC medication and stable SGLT2i treatment for at least 4 and 12 weeks prior to screening, respectively. Participants with a current diagnosis of type 1 or type 2 diabetes mellitus are excluded from the study. A comprehensive list of the inclusion and exclusion criteria for this study is presented in Table 1 .

Table 1

Participant inclusion and exclusion criteria in the AURORA study

Inclusion criteria
  • •

    Males and females of nonchildbearing potential, capable of giving and willing to give signed informed consent.

  • •

    18–85 years of age, inclusive.

  • •

    Minimum BMI of 18 kg/m 2 at screening.

  • •

    Pre-existing diagnosis of HF.

  • •

    LVEF of ≤50% based on echocardiography taken within the past 9 months.

  • •

    eGFR of 30–60 mL/min/1.73 m 2 (inclusive) at screening (CKD-EPI 2021 creatinine equation).

  • •

    Participants must be receiving stable HF SoC medication for at least 4 weeks prior to screening. If the participant is currently taking diuretics, diuretics must also be stable for at least 1 week prior to screening.

  • •

    Participants must be receiving stable SGLT2 inhibitor treatment for at least 12 weeks prior to screening.

  • •

    NT-pro-BNP >300 pg/mL for participants in sinus rhythm, or NT-proBNP >600 pg/mL for participants with atrial fibrillation.

  • •

    Female participants must not be pregnant or lactating and must be of nonchildbearing potential, confirmed at screening.

  • •

    Male participants should refrain from fathering a child or donating sperm until 3 months after the final study follow-up visit. The female partner of the study participant has to be either of nonchildbearing potential or has to use a highly effective contraception form of birth control until 3 months after the final study follow-up visit.

Exclusion criteria
  • •

    Historical or current evidence of a clinically significant disease or disorder including but not limited to: (1) myocardial infarction, stroke, transient ischaemic attack, coronary artery bypass grafting, or percutaneous coronary intervention within 12 weeks prior to screening or transcatheter structural heart interventions or cardiac valve surgery within 6 months prior to screening; (2) current diagnosis of T1DM or T2DM; (3) sarcoidosis, restrictive cardiomyopathy, active myocarditis, constrictive pericarditis, or hypertrophic (obstructive) cardiomyopathy; (4) history of untreated clinically significant valve disease or a screening confirmation of severe aortic stenosis, severe mitral stenosis, moderate or severe aortic insufficiency or severe mitral insufficiency; (5) amyloidosis, Fabry disease, or haemochromatosis; (6) pericardial disease (i.e. visually significant white pericardium on echocardiogram); (7) acute renal injury or primary kidney injury (true renal disease) not related to HF; (8) known coagulation disorders; (9) current diagnosis of active hepatitis; (10) severe pulmonary disease that is not expected to improve over time, as assessed by the Investigator; (11) decompensated HF or any cardiopulmonary hospitalization, except planned hospitalization without worsening of cardiac or pulmonary functions, within 4 weeks prior to screening; (12) history of active malignancy within 2 years, except for fully excised or treated basal cell carcinoma, or ≤2 squamous cell carcinomas of the skin. Participants who are under investigation for breast or cervical cancer, including participants with a pap smear of grade ≥3. All investigations must be resolved as negative for breast or cervical cancer at least 12 weeks before screening.

  • •

    Participants with a known hypersensitivity to AZD5462 or dapagliflozin, or to any of the excipients of these drug products.

  • •

    Known history of drug or alcohol abuse within 24 months of screening.

  • •

    Congenital long QT syndrome or history of QT prolongation associated with other medications that required discontinuation of that medication.

  • •

    Cardiac ventricular arrhythmia that requires treatment. However, participants with atrial fibrillation or flutter and controlled ventricular rate (e.g., resting HR <110 bpm) are permitted. Participants with cardiac ventricular arrhythmia that is treated with antiarrhythmic agents (e.g. amiodarone) and is stable are permitted.

  • •

    History of or anticipated heart transplant.

  • •

    Any planned highly invasive cardiovascular procedure (e.g., coronary revascularization, valve repair/replacement, aortic aneurysm surgery).

  • •

    Any evidence of clinically important disease or disorder which in the Investigator’s opinion makes it undesirable for the participant to participate in the study.

  • •

    Positive hepatitis C antibody, hepatitis B virus surface antigen, or hepatitis B virus core antibody at screening.

  • •

    Known to have historically tested positive for HIV.

  • •

    Participants requiring iron infusion during the study.

  • •

    Strong CYP3A4/P-gp inhibitors and inducers.

  • •

    Rosuvastatin doses >10 mg once daily.

  • •

    Digoxin.

  • •

    Plasma donation within 1 month prior to screening or any blood donation/blood loss >500 mL during the 3 months prior to screening.

  • •

    Participation in another clinical study with an IMP administered in the last month prior to screening, or planned participation in such study prior to the end of the follow-up period.

  • •

    Abnormal vital signs defined as any of the following at screening (following 5 minutes of seated rest): (a) sitting SBP >160 mmHg or sitting DBP >100 mmHg; (b) sitting SBP <100 mmHg or sitting DBP <50 mmHg; (c) resting HR of <50 bpm or >110 bpm.

  • •

    Judgement by the investigator that the participant should not participate in the study if the

  • •

    participant is unlikely to comply with study procedures, restrictions, and requirements.

  • •

    Previous enrolment or randomization in the present study.

  • •

    For females only: currently pregnant (confirmed with positive pregnancy test) or breastfeeding.

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Jun 16, 2026 | Posted by in CARDIOLOGY | Comments Off on A Phase 1b Randomized Clinical Trial of AZD5462 and Dapagliflozin in Patients with Heart Failure and Moderate Renal Impairment

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