Novel antisense therapy targeting microRNA-132 in patients with heart failure: results of a first-in-human Phase 1b randomized, double-blind, placebo-controlled study

Abstract

Aims: Cardiac microRNA-132-3p (miR-132) levels are increased in patients with heart failure (HF) and mechanistically drive cardiac remodelling processes. CDR132L, a specific antisense oligonucleotide, is a first-in-class miR-132 inhibitor that attenuates and even reverses HF in preclinical models. The aim of the current clinical Phase 1b study was to assess safety, pharmacokinetics, target engagement, and exploratory pharmacodynamic effects of CDR132L in patients on standard-of-care therapy for chronic ischaemic HF in a randomized, placebo-controlled, double-blind, dose-escalation study (NCT04045405).

Methods and results: Patients had left ventricular ejection fraction between ≥30% and <50% or amino terminal fragment of pro-brain natriuretic peptide (NT-proBNP) >125 ng/L at screening. Twenty-eight patients were randomized to receive CDR132L (0.32, 1, 3, and 10 mg/kg body weight) or placebo (0.9% saline) in two intravenous infusions, 4 weeks apart in four cohorts of seven (five verum and two placebo) patients each. CDR132L was safe and well tolerated, without apparent dose-limiting toxicity. A pharmacokinetic/pharmacodynamic dose modelling approach suggested an effective dose level at ≥1 mg/kg CDR132L. CDR132L treatment resulted in a dose-dependent, sustained miR-132 reduction in plasma. Patients given CDR132L ≥1 mg/kg displayed a median 23.3% NT-proBNP reduction, vs. a 0.9% median increase in the control group. CDR132L treatment induced significant QRS narrowing and encouraging positive trends for relevant cardiac fibrosis biomarkers.

Conclusion: This study is the first clinical trial of an antisense drug in HF patients. CDR132L was safe and well tolerated, confirmed linear plasma pharmacokinetics with no signs of accumulation, and suggests cardiac functional improvements. Although this study is limited by the small patient numbers, the indicative efficacy of this drug is very encouraging justifying additional clinical studies to confirm the beneficial CDR132L pharmacodynamic effects for the treatment of HF.

Keywords: Cardiac remodelling; Clinical trial Phase 1b study; Heart failure; microRNAs.

Graphical abstract

Figure 1

Study profile.

Figure 2

Study participant flow chart.

Figure 3

Selected safety variables over time. Data are mean (95% confidence interval). KIM-1, kidney injury molecule-1; QTc, corrected QT interval; bpm, beats per minute.

Figure 4

Plasma CDR132L concentrations through 48 h after CDR132L administrations. Data are mean (95% confidence interval). Measurements were taken 9 min and 1, 3, 9, 24, and 48 h after CDR132L administration. *CDR132L concentration fell below the lower limit of quantification at subsequent time points.

Figure 5

Plasma miR-132 levels in patients after CDR132L treatment. (A) Median with 25%/75% interquartile ranges of plasma miR-132 levels in patients over the study course (pre = immediately before, post = 1h after administration). (B) Individual median miR-132 levels in healthy subjects (n = 30; blood bank samples) and in patients (n = 25) at study end (Day 112). P-value: Mann–Whitney U test comparing to the placebo group.

Figure 6

Changes in exploratory pharmacodynamic variables, before first study treatment vs. end of study (Day 112). ‘Non-PD active’: patients receiving placebo or the 0.32 mg/kg CDR132L, ‘PD active’: patients receiving 1, 3, or 10 mg/kg CDR132L. (A) Median (circles) and 25%/75% interquartile ranges (bars) for relative changes in NT-proBNP from baseline to Day 112. (B) Percentages of patients with a >2% absolute increase in left ventricular ejection fraction and a >10% reduction in NT-proBNP, or both. (C) Corresponding mean ± SEM end-of-study plasma miR-132 levels. (D) Mean ± SEM changes in galectin-3, suppression of tumourgenicity-2, lipocalin-2, and matrix metallopeptidase-1. (E) Mean ± SEM changes in QRS narrowing normalized to pre-dosing measurements. P-values: Fisher's exact test (A, B, D, and E) or Mann–Whitney U test (C) comparing to ‘non-PD active’. Gal-3, galectin-3; MMP-1, matrix metallopeptidase-1; NGAL, lipocalin-2; ST-2, suppression of tumourgenicity-2.

Take home figure

This first-in-human study confirmed that the novel treatment concept with an antisense oligonucleotide directed against miR-132 is safe and well-tolerated and provided indicative beneficial pharmacodynamic effects for the treatment of heart failure.