Repeated intravenous cardiosphere-derived cell therapy in late-stage Duchenne muscular dystrophy (HOPE-2): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial

Abstract

Background: Cardiosphere-derived cells (CDCs) ameliorate skeletal and cardiac muscle deterioration in experimental models of Duchenne muscular dystrophy. The HOPE-2 trial examined the safety and efficacy of sequential intravenous infusions of human allogeneic CDCs in late-stage Duchenne muscular dystrophy.

Methods: In this multicentre, randomised, double-blind, placebo-controlled, phase 2 trial, patients with Duchenne muscular dystrophy, aged 10 years or older with moderate upper limb impairment, were enrolled at seven centres in the USA. Patients were randomly assigned (1:1) using stratified permuted blocks to receive CAP-1002 (1·5 × 108 CDCs) or placebo intravenously every 3 months for a total of four infusions. Clinicians, caregivers, patients, and clinical operations personnel were fully masked to treatment groups. The primary outcome was the change in mid-level elbow Performance of Upper Limb version 1.2 (PUL 1.2) score at 12 months, assessed in the intention-to-treat population. Safety was assessed in all individuals who received an investigational product. This trial is registered with ClinicalTrials.gov, NCT03406780.

Findings: Between March 1, 2018, and March 31, 2020, 26 male patients with Duchenne muscular dystrophy were enrolled, of whom eight were randomly assigned to the CAP-1002 group and 12 to the placebo group (six were not randomised due to screening failure). In patients who had a post-treatment PUL 1.2 assessment (eight in the CAP-1002 group and 11 in the placebo group), the mean 12-month change from baseline in mid-level elbow PUL1.2 favoured CAP-1002 over placebo (percentile difference 36·2, 95% CI 12·7-59·7; difference of 2·6 points; p=0·014). Infusion-related hypersensitivity reactions without long-term sequelae were observed in three patients, with one patient discontinuing therapy due to a severe allergic reaction. No other major adverse reactions were noted, and no deaths occurred.

Interpretation: CAP-1002 cell therapy appears to be safe and effective in reducing deterioration of upper limb function in patients with late-stage Duchenne muscular dystrophy. Various measures of cardiac function and structure were also improved in the CAP-1002 group compared with the placebo group. Longer-term extension studies are needed to confirm the therapeutic durability and safety of CAP-1002 beyond 12 months for the treatment of skeletal myopathy and cardiomyopathy in Duchenne muscular dystrophy.

Funding: Capricor Therapeutics.

Conflict of interest statement

Declaration of interests CMM has acted as a consultant on clinical trials of Duchenne muscular dystrophy for Astellas, Avidity Biosciences, Capricor Therapeutics, Catabasis, Edgewise Therapeutics, Entrada Therapeutics, Epirium Bio (formerly Cardero Therapeutics), FibroGen, Italfarmaco, Pfizer, PTC Therapeutics, Roche, Santhera Pharmaceuticals, and Sarepta Therapeutics; he reports honoraria for presentations from PTC Therapeutics, Sarepta Therapeutics, Solid Biosciences, Santhera Pharmaceuticals, Capricor Therapeutics, and Catabasis; he has received compensation for participation in advisory boards from PTC Therapeutics, Sarepta Therapeutics, Avidity Biosciences, Edgewise Therapeutics, and Santhera Pharmaceuticals; he has received research support for clinical trials from Capricor Therapeutics, Catabasis, Italfarmaco, Pfizer, PTC Therapeutics, Santhera Pharmaceuticals, and Sarepta Therapeutics; and reports grants from the US Department of Defense, US National Institutes of Health (NIH), Parent Project Muscular Dystrophy, and the National Institute on Disability, Independent Living and Rehabilitation Research. EM owns founder's equity in Capricor Therapeutics. SH received payments to her employer (Pentara Corporation) for consulting services from Capricor Therapeutics and Fulcrum Therapeutics. NH received payments to his employer (Pentara Corporation) for consulting services. SH and NH received support for the current study, including payments to their employer (Pentara Corporation), for special expertise and knowledge in the field of clinical trial analysis services (including study design, statistical analysis plan creation, data management and case report form design, SDTM/ADaM conversion, TLF, and statistical reporting), as well as statistical consulting and SAS programing. ME is a paid employee of Atom International, and has served as a consultant for Solid Biosciences, Sarepta Therapeutics, Santhera Pharmaceuticals, Roche, PTC Therapeutics, Pfizer, NS Pharma, Genethon, Fibrogen, Catabasis, and Capricor Tharapeutics. RSF has participated (2016–21) as an investigator in clinical trials sponsored by AveXis/Novartis Gene Therapies, Biogen, Catabasis, Cytokinetics, Ionis, Muscular Dystrophy Association, NIH, Lilly, ReveraGen, Roche, Sarepta, Scholar Rock, and Summit; he has received honoraria for participating in symposia and on advisory boards for these same pharmaceutical companies; he serves without compensation as an adviser to the n-Lorem and EveryLife Foundations; his institution receives funding from Biogen for the coordination of a US registry for spinal muscular atrophy, iSMAC; and he receives licensing fees from the Children's Hospital of Philadelphia and publishing royalty fees from Elsevier. CT has participated as an investigator in clinical trials and clinical studies sponsored by AveXis/Novartis Gene Therapies, Bristol Myers Squibb, Catabasis, Capricor Therapeutics, Fibrogen, Muscular Dystrophy Association, NIH, Pfizer, PTC Therapeutics, Roche, Sarepta, Santhera Pharmaceuticals, and Summit. MMH has received research funding for participating in clinical trials from Capricor Therapeutics, Sarepta Therapeutics, PTC Therapeutics, Mallinckrodt Pharmaceuticals, and Wave Life Sciences; he has received a non-restricted educational grant from Sarepta Therapeutics, infrastructure clinical grants from the Muscular Dystrophy Association and Parent Project Muscular Dystrophy, and research grants from CureSMA; he has received honorarium for advisory boards and consulting from Biogen, Avexis/Novartis Gene Therapies, Sarepta Therapeutics, and PTC Therapeutics; he actively consults for Emerging Therapy Solutions; and he serves without compensation on DuchenneXchange and as a board member for Three Gaits and as an adviser for Hopeful Together. KNH has served as a consultant for QRAL Group, Stealth Biotech, Vertex Pharmaceuticals, and PTC Therapeutics, and serves on a PTC Therapeutics advisory board. OHM has acted as a consultant on clinical trials of Duchenne muscular dystrophy for Capricor Therapeutics, Catabasis, FibroGen, and Santhera Pharmaceuticals; he has received research support for clinical trials from Santhera Pharmaceuticals; and he has received compensation for participation in symposia sponsored by Santhera Pharmaceuticals. EKH has served as a consultant for Capricor, Cardero Therapeutics, and Genzyme, and has served on advisory boards for Sarepta, Santhera Pharmaceuticals, GlaxoSmithKline, Pfizer, PTC Therapeutics, Mallinkrodt Pharmaceuticals, and Bristol Myers Squibb; and he has served on advisory boards for the Muscular Dystrophy Association and Parent Project Muscular Dystrophy. PF has served as a consultant to Capricor Therapeutics. DDA, SR, PW, RRS, and LM were paid employees of Capricor Therapeutics during the conduct of the study. All other authors declare no competing interests.

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