Preclinical Evaluation of HTX-001 as a Novel Anti-fibrotic Therapy for non-obstructive HCM

• Published in: Journal of cardiac failure 2024-09, Vol.30, p.S9-S10
• Main Authors: Karras, James, Kling, Fanny, Marcuello, Maria, Cruz, Joaquim, Tien, Chih-Liang, Roberts, Claire, Gentry, Kristen, Watson, Audrey, Loetscher, Alexis, Rauleac, Tudor, Rochat, Mary-Aude, Nguyen, Chi Tam, Jusic, Amela, Silva, Ana Catarina, Mina, Marco, Micheletti, Rudi, Blessing, Daniel, Ounzain, Samir
• Format: Article
• Language: English
• ISSN: 1071-9164
• DOI: 10.1016/j.cardfail.2024.08.015

We have identified WISPER, a cardiac fibroblast-specific lncRNA overexpressed in human cardiovascular diseases, including hypertrophic cardiomyopathy (HCM), and shown to promote transcriptional activation of the myofibroblast cell-state, resulting in pathological fibrosis in preclinical models. High WISPER expression driving excessive interstitial fibrosis is thought to highly contribute to the underlying pathophysiology of HCM, especially in non-obstructive HCM (nHCM). In turn, interstitial and replacement fibrosis are known to lead to worse outcomes, including diastolic dysfunction, arrythmias, heart failure and death. HTX-001 is a synthetic antisense oligonucleotide (ASO) which was developed to suppress WISPER RNA expression, produce a reduction in myocardial fibrosis, reverse existing cardiac interstitial fibrosis, and bring an effective and targeted anti-fibrotic therapy to patients with HCM. Prior work in heart failure with preserved ejection fraction demonstrates that small reductions in myocardial fibrosis are associated with reductions in natriuretic peptide levels, indicating decreased wall stress and the expanded interstitial space, which can result in improved outcomes. WISPER expression was validated in patient datasets. In vivo efficacy studies using ASOs targeting Wisper were performed in mouse myocardial infarction (MI) and transaortic constriction models (references in Figure) and in the Göttingen minipig post-MI model (data to be presented). Study readouts included histology, echocardiography and transcriptomics analysis. We show that HTX-001 treatment in preclinical animal models of pathological cardiac remodelling reduces cardiac fibrosis and improves heart function. Multi-omics analysis demonstrates WISPER-mediated control of extracellular matrix levels, pro-fibrotic and pro-inflammatory gene expression, resulting in a switch in cardiac tissue metabolism from healthy fatty acid metabolism to glycolytic metabolism. Pharmacokinetic and pharmacodynamic analyses indicate suitable drug-like characteristics of HTX-001, including target engagement in cardiac tissue that is also measurable using WISPER mechanism of action-related biomarkers in plasma or serum. Overall, preclinical data suggest that HTX-001 is expected to be efficacious as a single agent with a unique mechanism of action that is non-overlapping with other currently available or investigational agents for HCM. We intend to develop HTX-001 for nHCM as the first indication given t