Cardiac and skeletal muscle effects in the randomized HOPE-Duchenne trial

Abstract

ObjectiveTo assess the feasibility, safety, and efficacy of intracoronary allogeneic cardiosphere-derived cells (CAP-1002) in patients with Duchenne muscular dystrophy (DMD).MethodsThe Halt Cardiomyopathy Progression (HOPE)-Duchenne trial is a phase I/II, randomized, controlled, open-label trial (NCT02485938). Patients with DMD >12 years old, with substantial myocardial fibrosis, were randomized (1:1) to usual care (control) or global intracoronary infusion of CAP-1002 (75 million cells). Participants were enrolled at 3 US medical centers between January and August 2016 and followed for 12 months. An independent Data and Safety Monitoring Board provided safety oversight. Cardiac function and structure were assessed by MRI, and analyzed by a blinded core laboratory. Skeletal muscle function was assessed by performance of the upper limb (PUL).ResultsTwenty-five eligible patients (mean age 17.8 years; 68% wheelchair-dependent) were randomized to CAP-1002 (n = 13) or control (n = 12). Incidence of treatment-emergent adverse events was similar between groups. Compared to baseline, MRI at 12 months revealed significant scar size reduction and improvement in inferior wall systolic thickening in CAP-1002 but not control patients. Mid-distal PUL improved at 12 months in 8 of 9 lower functioning CAP-1002 patients, and no controls (p = 0.007).ConclusionsIntracoronary CAP-1002 in DMD appears safe and demonstrates signals of efficacy on both cardiac and upper limb function for up to 12 months. Thus, future clinical research on CAP-1002 treatment of DMD cardiac and skeletal myopathies is warranted.Classification of evidenceThis phase I/II study provides Class II evidence that for patients with DMD, intracoronary CAP-1002 is feasible and appears safe and potentially effective.

Disease-modifying bioactivity of intravenous cardiosphere-derived cells and exosomes in mdx mice

“…Given the preclinical insights reported here, CDCs are now being administered systemically in a placebo-controlled trial in DMD patients (HOPE-2; ClinicalTrials.gov Identifier: NCT03406780), thereby avoiding the need for cardiac catheterization as performed in the previous HOPE-Duchenne trial (31). In addition to CDCs themselves, EXOs derived from CDCs are a promising next-generation therapeutic candidate.…”

Allogeneic cardiosphere-derived cells (CAP-1002) in critically ill COVID-19 patients: compassionate-use case series

“…Due to small sample sizes, statistical tests for comparison were not performed. Categorical data presented as total count and percentage (%), and continuous data are presented as mean ± standard deviation (SD) These anti-inflammatory effects have been demonstrated in animal models of myocardial ischemia, myocarditis, muscular dystrophy, aging, heart failure with preserved ejection fraction, pulmonary arterial hypertension and dilated cardiomyopathy [3,20,21,33,34,42]. Finally, based on preclinical work, a majority of IV CDCs are retained in the lungs [6].…”

Cell Therapy With Human ESC-Derived Cardiac Cells: Clinical Perspectives

“…Cardiospheres are agglomerates of several cell types, predominantly MSC, harvested from the right ventricle by an endomyocardial biopsy (Smith et al, 2007) with a subsequent intracoronary delivery while c-kit + CSC are grown from a right appendage biopsy taken during a coronary artery bypass operation before being also reinjected into the coronary arteries. However, the first have failed to show benefits in an ischemic cardiomyopathy phase II trial which was prematurely interrupted in April, 2017 for futility; however, the use of these cells in Duchenne muscular dystrophy has yielded an encouraging efficacy signal (Taylor et al, 2019) which needs to be confirmed by the ongoing HOPE-II study, planned to randomize 84 non-ambulatory and ambulatory patients with Duchenne muscular dystrophy to intravenous infusions of either 150 million cardiosphere-derived cells every 3 months for a total of 4 doses or placebo. The use of c-kit + CSC has been largely based on preclinical data now considered to be in part fraudulent 1 and there is some consensus that these cells are rather endowed with an angiogenic potential (van Berlo et al, 2014).…”