Abstract 4119680: First-in-Man Treatment of Heart Failure by Repeated Intravenous Infusions of a Cardiovascular Cell-Derived Extracellular Vesicle-Enriched Secretome

Background: Most of the effects of intramyocardially transplanted stem cells can be duplicated by the sole administration of their secretome but this approach has not yet been tested in heart failure (HF). Methods: The SECRET-HF phase I trial (NCT05774509) was designed according to a Bayesian optimal interval scheme to assess the effects of repeated intravenous infusions of a cellular secretome in 12 patients with a non-ischemic dilated cardiomyopathy. The main inclusion criteria are severe symptoms (NYHA Class III despite an optimal guideline-directed medical therapy), a reduced left ventricular (LV) ejection fraction (EF ≤40%) and ineligibility for a heart transplant. The Investigational Medicinal Product was derived from human induced pluripotent stem cells reprogrammed from a healthy donor and differentiated in cardiovascular progenitor cells (CPC). Following CPC culture in a dedicated "vesiculation" medium, the conditioned media were collected, filtered, enriched for extracellular vesicles, concentrated by tangential flow filtration and scaled out into glass vials stored at -80°C. Quality controls were implemented throughout the whole process which was conducted according to current Good Manufacturing Practices. Results: Three patients, out of the 4 of the initial low-dose cohort, have now been treated. All had been previously fitted with an automatic internal cardioverter defibrillator (AICD). The secretome was delivered intravenously 3 times, 3 weeks apart, at a dose of 20 x10 9 particles/kg for each infusion. By November, 2024, the follow-up will be 16, 9, 6 and 2 months for each of them (mean: 8 months). So far, none of the treated patients has experienced a dose-limiting toxicity; in particular, there have been no post-treatments ventricular arrhythmia detected by the AICD, no allo-immunization and no inflammation based on the enumeration of lymphocyte subpopulations by flow cytometry. At 6 months, the first patient improved to NYHA Class II with a decrease in echographic LVEDV and LVESV (from 108 mL/m 2 to 87 mL/m 2 and from 80 mL/m 2 to 60 mL/m 2 , respectively) and a concomitant increase in LVEF from 25% to 32%. At 1 month post-treatment, the second patient also reports a symptomatic improvement (NYHA Class II) with an increase in EF from 21% to 28%. Conclusions: This initial experience supports the safety of repeated intravenous administrations of a cardiovascular cellular secretome as a potential noninvasive and user-friendly treatment of severe HF.