GenePHIT Phase 2 baseline characteristics: a double blind, placebo-controlled trial to assess safety and efficacy of AB-1002 gene therapy in heart failure with reduced ejection fraction

Introduction Morbidity and mortality in heart failure (HF) remains high despite guideline directed medical therapy (GDMT). AB-1002 is an investigational adeno-associated virus (AAV) gene therapy optimised for cardiac delivery. It delivers a transgene that encodes for a constitutively active form of the endogenous protein I-1 (I-1c), with the goal of improving cardiac contractility by restoring intracellular calcium signalling. GenePHIT (NCT05598333) is a placebo-controlled, randomised, multicentre Phase 2 trial evaluating efficacy, safety, and tolerability of AB-1002 in heart failure with reduced ejection fraction (HFrEF). Adult patients with non-ischemic cardiomyopathy, New York Heart Association (NYHA) Class III, and left ventricular ejection fraction (LVEF) 15-35% were enrolled. GenePHIT was conducted in multiple countries across 96 sites. Patients are followed up for 52 weeks following intracoronary infusion of AB-1002 or placebo, and the primary endpoint is a hierarchy of cardiovascular death, change from baseline in NYHA Class, LVEF, and 6-minute walk distance (6MWD), analysed by win-ratio. Following completion of enrolment, we hereby report the baseline characteristics of patients enrolled in GenePHIT. Methods All randomised and treated patients were included in the baseline characteristics analysis. Patient demographics, baseline characteristics, past medical history, and concomitant medications were assessed. Results In total, 223 patients were screened, 173 were randomised (without screening for pre-existing immunity to AAV2/8 chimeric capsid), and 157 were treated with AB-1002/placebo (Table). At baseline, the mean patient age was 62.4 years, with 14.6% aged ≤50 years and 26.8% aged >70 years. Most patients identified as White (88.5%) and 22.9% were female. With a mean BMI of 30.1 kg/m2, the study population was consistent with a typical HFrEF population in which patients are generally overweight. Patients were well-treated with contemporary GDMT, with 6.4% on angiotensin converting enzyme inhibitors, 81.5% on angiotensin receptor-neprilysin inhibitors, 87.9% on mineralocorticoid receptor antagonists, 84.1% on sodium-glucose transporter 2 inhibitors and 94.9% on beta-blockers. Mean LVEF at screening was 33.2%, median N-Terminal ProB-type natriuretic peptide was 955.1 pg/mL and mean 6MWD was 336.0 meters. 44.6% had an implantable cardioverter defibrillator in situ, while 45.9% had a medical history of atrial fibrillation. Conclusions GenePHIT is a large, multinational trial demonstrating the feasibility of conducting intracoronary administration of gene therapy in a HFrEF patient population. The enrolled population reflects symptomatic non-ischemic cardiomyopathy patients well-treated on standard of care. These baseline population characteristics demonstrate that the study population is appropriate for future clinical evaluation. Efficacy and safety outcomes of this trial are expected in 2027.