HAYA Therapeutics has dosed the first cohort in the Phase I/IIa clinical trial of HTX-001, an antisense oligonucleotide targeting WISPER lncRNA in patients with nonobstructive hypertrophic cardiomyopathy (nHCM), marking the first time a therapy designed to directly reprogram cardiac fibroblasts has entered human testing. The announcement positions HTX-001 as the first clinical-stage asset to address the fibrotic pathology of nHCM rather than its haemodynamic consequences.
The Phase Ia/b study follows a multiple-ascending dose design, enrolling healthy volunteers before advancing to nHCM patients. Primary endpoints cover safety, tolerability, pharmacokinetics, and pharmacodynamics. HAYA Therapeutics, headquartered in Lausanne, Switzerland, with laboratory operations at Lilly Gateway Labs in San Diego, has not disclosed the total number of participants or an anticipated completion date.
HTX-001 is the lead asset from HAYA's regulatory genome platform, which maps long non-coding RNA (lncRNA) targets that govern pathological cell states. WISPER — first characterised by HAYA co-founder and CEO Samir Ounzain in 2017 — is a heart stress-specific lncRNA overexpressed in hypertrophic cardiomyopathy tissue. The antisense oligonucleotide HTX-001 is designed to silence WISPER expression in cardiac myofibroblasts, promoting their reprogramming toward a non-fibrotic state.
Scientific and clinical context
nHCM accounts for an estimated 30–60% of all HCM cases and is characterized by left ventricular hypertrophy, impaired diastolic function, and diffuse myocardial fibrosis — the last of which is increasingly recognized as an independent driver of arrhythmia, diastolic dysfunction, and progression to advanced heart failure. Unlike the discrete scar tissue of ischaemic disease, fibrosis in HCM is diffuse and interstitial, making it a poor candidate for device-based or surgical intervention and a compelling target for molecular therapy.
Current pharmacological options do not address this fibrotic process. Beta-blockers, calcium channel blockers, and disopyramide manage symptoms but leave the underlying remodelling untouched. The two most recent approvals in HCM — mavacamten (Camzyos, Bristol Myers Squibb) in 2022 and aficamten (Myqorzo, Cytokinetics) in late 2025 — are cardiac myosin inhibitors indicated specifically for obstructive HCM, where their mechanism of reducing left ventricular outflow tract obstruction is directly relevant. Neither is indicated for nHCM, and neither targets fibrosis.
WISPER was identified through a screen of super-enhancer-associated lncRNAs in injured myocardium, a class of regulatory elements that tend to govern cell identity. Its expression is cardiac fibroblast-specific — not observed in cardiomyocytes — which offers a degree of cellular selectivity that upstream pathway inhibitors lack. Mechanistically, WISPER promotes myofibroblast activation partly through its interaction with TIAR, a protein that controls splicing of lysyl hydroxylase 2, an enzyme central to collagen cross-linking and extracellular matrix stabilisation.