Novel Relaxin Receptor RXFP1 Agonist AZD3427 in the Treatment of Heart Failure: A Phase 1a/b, First-in-Human, Randomized, Single-Blind, Placebo-Controlled Study

Abstract

Background: Heart failure mortality remains high despite recent progress in pharmacological treatment. AZD3427 is a selective long-acting analog of relaxin, a vasodilatory hormone with antifibrotic effects. We assessed the safety, pharmacokinetics, and pharmacodynamics of AZD3427 in healthy volunteers and patients with heart failure on standard-of-care therapy.

Methods and results: In this first-in-human, phase 1a/b, randomized, single-blind, placebo-controlled study, healthy volunteers were randomized 6:2 to receive a single dose of AZD3427 or placebo by subcutaneous injection in 5 mixed-ethnicity cohorts (5, 10, 30, 90, or 270 mg) and 1 Japanese-descent cohort (270 mg), or by intravenous injection in 1 cohort (15 mg). After confirming safety and tolerability in healthy volunteers, 3 cohorts of patients with heart failure and left ventricular ejection fraction ≤40% and 3 cohorts with ejection fraction ≥41% were randomized 6:2 to receive 5 weekly doses of AZD3427 (5, 15, or 45 mg) or placebo by subcutaneous injection. In total, 56 healthy volunteers and 48 patients with heart failure were randomized. AZD3427 was well tolerated at all doses. After subcutaneous administration, AZD3427 was absorbed slowly, and exposure was approximately linear across the dose range. In patients with heart failure, AZD3427 terminal half-life was 13 to 14 days and there were numerical increases in stroke volume and estimated glomerular filtration rate. No treatment-emergent antidrug antibodies were detected.

Conclusions: AZD3427 had favorable safety and pharmacokinetic profiles. Hemodynamic changes in patients with heart failure were consistent with the anticipated effects of a relaxin analog. These findings support further development of AZD3427 as a novel long-term treatment for patients with heart failure.

Registration: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT04630067.

Keywords: AZD3427; HFmrEF; HFpEF; HFrEF; RXFP1; relaxin.

Figure 1. Study design for (A) healthy volunteers and (B) patients with heart failure.

D indicates day; EF, ejection fraction; FU, follow‐up; IV, intravenous; JPN, Japanese descent; and SC, subcutaneous.

Figure 2. Serum AZD3427 concentration–time profile in (A) healthy volunteers and (B) patients with heart failure.

Serum concentration of AZD3427 from day 32 was not included due to deviations between actual and nominal sampling time. EF indicates ejection fraction; IV, intravenous; JPN, Japanese descent; and SC, subcutaneous.

Figure 3. Change from baseline in (A) systolic blood pressure, (B) diastolic blood pressure, and (C) heart rate in patients with heart failure.

EF indicates ejection fraction; and SC, subcutaneous.

Figure 4. Change from baseline in (A) stroke volume, (B) cardiac output, and (C) estimated glomerular filtration rate in patients with heart failure.

EF indicates ejection fraction; SC, subcutaneous.