AB-1002 gene therapy expressing active protein phosphatase inhibitor-1 in heart failure: rationale and study design of the GenePHIT trial

BACKGROUND AND AIMS: AB-1002 is an investigational, cardiotropic adeno-associated viral vector gene therapy expressing constitutively active form of protein phosphatase inhibitor-1 intended to restore cardiomyocyte calcium handling and improve cardiac contractility. METHODS: GenePHIT is an adaptive, double-blinded, placebo-controlled, randomized multicentre Phase 2 trial evaluating the efficacy, safety, and tolerability of AB-1002 in adults with non-ischaemic cardiomyopathy with left ventricular ejection fraction 15%-35% and New York Heart Association class III symptoms despite standard of care therapy. GenePHIT includes a 52-week observation period and 4-year long-term follow-up. Participants are randomized 1:1:1 (n=30-50/group) to receive a single antegrade intracoronary infusion of AB-1002 at 1 of 2 doses (7.15E13 or 1.43E14 viral genomes/participant), or placebo. The primary endpoint will be assessed at 52 weeks and will comprise a hierarchical composite of cardiovascular death, change from baseline in New York Heart Association class, left ventricular ejection fraction improvement of ≥5%, and six-minute walk test improvement of >30m, with pooled active doses compared to placebo via a win ratio estimate using Finkelstein-Schoenfeld methodology. Several other secondary efficacy, safety, and exploratory endpoints will be assessed at 52 weeks and through long-term follow-up. CONCLUSIONS: This Phase 2, placebo-controlled trial will further elucidate the risk-benefit characterization of single-dose AB-1002 in patients with non-ischaemic heart failure.