Safety And Efficacy Of CDR132L, A Novel Antisense Therapeutic Which Targets MicroRNA-132 In Heart Failure Patients
CIRCULATION RESEARCH(2021)
Abstract
Cardiac microRNA-132-3p (miR-132) levels are elevated in people suffering with heart failure (HF) and mechanistically drive remodelling processes in the heart. Here we present CDR132L, a specific antisense oligonucleotide. It is a first-in-class miR-132 inhibitor that attenuates and even reverses HF in preclinical models. The aim of this clinical Phase 1b study was to assess safety, pharmacokinetics, target engagement, and pharmacodynamics of CDR132L in patients on therapy for chronic ischaemic HF in a randomized, placebo-controlled, double-blind, dose-escalation study. Inclusion criteria for participant patients was left ventricular ejection fraction between 30 and 50% or levels of amino terminal fragment of pro-brain natriuretic peptide (NT-proBNP) higher than 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. Randomization separated participants into four cohorts of seven (five verum and two placebo). Results revealed that CDR132L was safe and well tolerated, and there was no detectable dose-limiting toxicity. A pharmacokinetic/pharmacodynamic dose modelling approach suggested an effective dose level of ≥1 mg/kg CDR132L. CDR132L treatment resulted in a dose-dependent, sustained miR-132 reduction in plasma. Patients who were administered ≥1 mg/kg of CDR132L displayed 23.3% NT-proBNP reduction, whereas patients receiving placebo experienced a 0.9% increase. In addition, CDR132L treatment was observed to significantly reduce duration of the QRS interval. This is the first clinical trial in which an antisense oligonucleotide was administered as a therapeutic agent to HF patients. Linear plasma pharmacokinetics were confirmed, and there were no signs of accumulation. The application of this drug suggests cardiac functional improvements and cardiac remodelling. The efficacy of this drug is encouraging, and further clinical work with larger patient populations should follow. Although the study used small patient numbers, results suggest some clinical benefit in chronic HF patients on the top of standard of care. This included an improvement in HF severity and narrowing of the QRS complex. The pharmacodynamic findings presented here are encouraging as they confirm efficacy results seen in animal studies.
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Key words
heart failure patients,novel antisense therapeutic,cdr132l
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