New gene therapy for HFrEF passes phase 1 testing

The gene therapy AB-1002 was well-tolerated and associated with positive efficacy outcomes in patients with heart failure with reduced ejection fraction (HFrEF). The findings of this phase 1 study led to the development of the phase 2 GenePHIT study, which is currently enrolling.

“AB-1002 is a cardiotropic investigational adeno-associated viral vector (AAV) gene therapy, expressing a constitutively active I-1 protein to inhibit protein phosphatase 1 [PP1] activity,” outlined Dr Roger Hajjar (Mass General Brigham, MA, USA) [1]. “The inhibition of PP1 may restore calcium cycling and improve left ventricular function in patients with chronic HF.” The phase 1 NAN-CS101 study (NCT04179643) tested this treatment in 11 patients with NYHA class III HFrEF.

The therapy was well-tolerated, with no treatment-emergent adverse events deemed related to the intervention. “There was 1 death, but this incident was not attributed to AB-1002 but to substance abuse and non-compliance with other medications,” said Dr Hajjar. Furthermore, there were some cases of self-limiting, asymptomatic elevations in liver enzymes and 1 case of ALT/AST elevation that was associated with an episode of atrial flutter. “This issue was resolved quickly after treatment,” stated Dr Hajjar.

Most participants displayed improvement in NYHA class and left ventricular ejection fraction. Also, quality-of-life measures at 12 months indicated that there was improvement in the majority of participants. The results concerning VO₂ max were mixed, with some participants showing improvement and others deteriorating. Lastly, the 6-minute walk test distance improved or remained stable in most participants.

“Our phase 1 trial showed that intracoronary delivery of AB-1002 was well-tolerated and associated with several positive efficacy outcomes in most patients with HFrEF in the study sample,” concluded Dr Hajjar. “The phase 2 GenePHIT trial (NCT05598333) will further evaluate the safety and efficacy of AB-1002 in patients with chronic HF.”

1. Hajjar RJ, et al. NAN-CS101: a first-in-human phase 1 open-label dose-escalation study of AB-1002 gene therapy for the treatment of NYHA class III HF. Late-breaking clinical trials in chronic heart failure, Heart Failure 2025, 17–20 May, Belgrade, Serbia.

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Posted on 17 July 202525 August 2025