J1 - Gene Therapy Trials - In-Vivo Modification
9: Safety and Efficacy of AB-1002 Gene Therapy in Patients with Advanced Heart Failure: Results from an Ongoing Phase 1 Clinical Trial
Type: Oral Abstract Session
Presentation Details
Session Title: Clinical Trials Spotlight Symposium
Congestive heart failure (CHF) is a progressive disease in need of innovative therapies. A key characteristic of failing hearts is abnormal intracellular Ca2+ handling and increased protein phosphatase 1 activity (PP1). Inhibition of PP1 by a constitutively active inhibitor-1 (I-1c) has been shown to enhance cardiac function in pre-clinical models of heart failure. We developed a novel cardiotropic and liver de-targeted capsid, AAV2i8, designed to overcome poor transduction in cardiac tissue. In a Phase 1 clinical trial the AAV2i8 capsid delivered a constitutively active I-1c protein to cardiac tissue via a single intracoronary infusion of AB-1002 (AAV2i8.I-1c). Eligible patients were >18yrs with non-ischemic cardiomyopathy, New York Heart Association (NYHA) class III with Left Ventricular Ejection Fraction (LVEF) of ≥15% to ≤35%. Efficacy measures included changes from baseline to month 12 in NYHA classification, Peak VO2, 6-minute walk test (6MWT), LVEF and Minnesota Living with Heart Failure Questionnaire (MLHFQ). Safety and tolerability were assessed by collection of AEs and SAEs, laboratory tests, vital signs and ECGs. Eleven patients have received either 3.25E13 (Cohort 1; n=6) or 1.08E14 (Cohort 2; n=5) viral genomes (vg) of AB-1002. Three patients in cohort 1 have completed at least 36 months follow up and a further three have completed 3 months follow up. Three patients in cohort 2 have completed at least 30-months observation, and one completed 24 months of observation. Patients were aged between 53 and 76yrs, with 9 males and 2 females. Mean LVEF at baseline was 30.33% (SD 3.88; cohort 1) and 23.28% (SD 5.92; cohort 2). The first 3 participants in Cohort 1, showed clinically meaningful improvements in LVEF, NYHA Class, MLHFQ, Peak VO2 and 6MWT at 12 months. Of the 3 remaining patients in cohort 1, two have shown initial improvement in NYHA Class, 6MWT and MLHFQ score at 3 months post administration. Among participants in Cohort 2, four of the 5 patients enrolled could be evaluated. Two of 4 patients showed improvements in MLHFQ and NYHA score, and all 4 showed improvements in LVEF at 12 months, compared to baseline. Peak VO2 declined in three but improved in one at 12 months while 6MWT declined in one patient, worsened in one, and was stable in two at 12 months. In support of this encouraging early clinical efficacy signal, left ventricular cardiac tissue was obtained from 1 patient in cohort 2 who underwent left ventricular assist device (LVAD) placement 13 months post-intracoronary gene transfer. AB-1002 demonstrated high myocardial transduction efficiency at 1.19 vg per cardiomyocyte and phosphorylation levels of phospholamban similar to normal hearts. To date AB-1002 has been well tolerated. Over the total follow up time available, 4 of 6 patients experienced 25 treatment emergent adverse events (TEAEs) and 5 patients experienced 56 TEAEs in cohorts 1 and 2 respectively, most of which were mild or moderate in severity. There was 1 fatal event in cohort 2 not considered related to investigational product. We believe our Phase 1 clinical trial demonstrates that AB-1002 is well-tolerated and results in positive efficacy outcomes in patients with non-ischemic HF. Further development of AB-1002 will be conducted in a phase 2 trial of up to 150 patients, GenePHIT, which is currently ongoing.
Luke Roberts1, Timothy Henry2, Eugene Chung2, Monica Alvisi1, Ferzin Sethna1, David Murray3, Jay Traverse4, Lothar Roessig1, Tugba Ozkan1, Stacy Webb1, Monika Mittal1, Leigh Ervin1, Kaitlyn Walker1, Hesham Sadek5, Sheila Mikhail6, Kobra Haghighi7, Canwen Jiang1, R. Jude Samulski6, Evangelia G. Kranias7, Anna Tretiakova1, Roger Hajjar8
1Asklepios BioPharmaceutical, Inc, Durham, NC,2Christ Hospital, Cincinnati, OH,3University of Wisconsin, Madison, WI,4The Minneapolis Heart Institute, Minneapolis, MN,5UT Southwestern Medical Center, Dallas, TX,6Asklepios BioPharmaceutical, Inc., Durham, NC,7University of Cincinnati, Cincinnati, OH,8Massachusetts General Brigham, Cambridge, MA"
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