Clin Res Cardiol (2022). https://doi.org/10.1007/s00392-022-02002-5

First-In-Human Phase 1b Trial in Heart Failure Patients for CDR132L, a Novel Antisense microRNA-132 Inhibitor Targeting Cardiac Remodelling
J. Täubel1, W. Hauke1, S. Rump1, J. Viereck1, S. Batkai1, J. Poetzsch1, L. Rode1, H. Weigt1, C. Genschel1, C. Theek2, J. Bauersachs3, S. D. Solomon4, R. Agrawal1, T. Thum5
1Cardior Pharmaceuticals GmbH, Hannover; 2Witten/Herdecke University, Witten; 3Kardiologie und Angiologie, Medizinische Hochschule Hannover, Hannover; 4Cardiovascular Division, Brigham and Women's Hospital, Boston MA, US; 5Institut für Molekulare und Translationale Therapiestrategien, OE-8886, Medizinische Hochschule Hannover, Hannover;

Background and Results: Despite the availability of approved therapies, there is still unmet need for mechanistic based therapeutic approaches for heart failure (HF). Dysregulation of cardiac microRNA-132-3p (miR-132) is a key driver of adverse cardiac remodeling in heart failure. CDR132L was developed as a first-in-class antisense oligonucleotide miR-132 inhibitor that is well tolerated and improves HF in preclinical models. In a first-in-human phase 1b trial in heart failure patients (mixed cohort of HFrEF and HFpEF patients) on standard-of-care therapy, CDR132L was safe and well tolerated, without apparent dose-limiting toxicity. CDR132L treatment resulted in a dose-dependent, sustained miR-132 reduction in plasma, confirming target engagement and long-lasting effect. The HF patients given CDR132L ≥1 mg/kg displayed at the endpoint of 16 weeks 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 in the chronic HF patients.

Subgroup analysis revealed that HFrEF patients (LVEF<45%) receiving 1mg/kg or more CDR132L (PD active) showed a significant decrease of 54.8 % in NT-proBNP levels, in comparison to non-PD active patients (p<0.022).

Conclusion: This study was a first-in-human trial of a novel antisense oligonucleotide drug in heart failure patients. CDR132L was safe and well tolerated, with favorable PK profile without any signs of tissue accumulation. The result also suggests beneficial effects, in particular in HFrEF patients. Although this study is limited by nature due to small patient numbers, the observed indicative beneficial effects of CDR132L justifies subsequent clinical studies to confirm efficacy for the treatment of heart failure.


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