Repeated Intravenous Cardiosphere-Derived Cell Therapy in Late-Stage Duchenne Muscular Dystrophy (HOPE-2): A Multicentre, Randomised, Double-Blind, Placebo-Controlled, Phase 2 Trial

Major Points and Findings:

HOPE-2 was the first double-blind, placebo-controlled trial of any cell therapy in Duchenne muscular dystrophy (DMD). The cells, CAP-1002 (now called deramiocel), are cardiosphere-derived cells grown from donor hearts. They are not mesenchymal stem cells. Boys who received the cells lost less arm function over a year than boys who received placebo.

The size of the trial limits this result. It was planned for 84 participants and stopped at 20, of whom only 8 received the cells. The statistical method was changed after the data did not fit the planned model. One boy had a severe allergic reaction. The manufacturer funded the trial and five authors were its employees. The result served as the signal that justified the larger HOPE-3 trial, which has since reported.

Aim:

To assess the safety and efficacy of four intravenous infusions of allogeneic cardiosphere-derived cells, three months apart, in boys and young men with late-stage DMD.

Methods:

Participants were males aged 10 or older with genetically confirmed DMD, recruited at seven US centres. They were either non-ambulatory or late ambulatory (a 10-metre walk taking more than 10 seconds). They needed a Performance of Upper Limb (PUL) entry score of 2 to 5, meaning they could no longer reach fully overhead but could still bring a hand to the mouth, and at least 12 months of glucocorticoid treatment with a stable dose for 6 months. Boys scoring 6 were left out because they decline too slowly to show a difference in a year, and boys scoring 0 or 1 because too little arm muscle remained to measure an effect.

Twenty-six were enrolled between March 2018 and March 2020. Six failed screening. Eight were randomised to CAP-1002 and 12 to placebo. Mean age was 14. Eighteen of the 20 were non-ambulatory.

Two donor hearts yielded 12 lots of cells, checked by surface markers (99.6% CD105-positive, 0.4% CD45-positive), viability, and viral and microbial testing. Each dose was 150 million cells in 20 mL of cryopreservation solution. Placebo was the same solution without cells.

Infusions were given at months 0, 3, 6 and 9 on an outpatient basis, with the final assessment at month 12. After one boy had a severe allergic reaction, the protocol was amended on 17 January 2019 to add pre-treatment. This consisted of a higher than usual oral glucocorticoid dose 12 to 14 hours and again 2 to 3 hours before the infusion, plus an H1 antihistamine and intravenous famotidine one hour before.

The primary outcome was the change at 12 months in the mid-level (elbow) part of the PUL 1.2 scale. Secondary outcomes were the same measure at months 3, 6 and 9, and regional heart wall thickening on cardiac MRI. Exploratory outcomes were PUL 2.0, other MRI measures, breathing tests, a patient-reported arm function scale, CK-MB and a cytokine panel.

Two things changed during the trial. First, the sponsor paused enrolment for funding reasons. After an interim futility analysis and FDA advice to move quickly to phase 3, enrolment was capped at 20. The sponsor publicly announced high-level unblinded results at that point. The authors state that clinicians, families and trial staff stayed blinded. Second, the planned statistical model failed its normality checks in this small sample, so results were re-analysed using percentile ranks. Only the primary outcome was formally tested. Every other p-value is nominal.

Results:

Arm function (primary outcome): The analysis included 8 CAP-1002 and 11 placebo participants. At 12 months the mid-level PUL 1.2 score had fallen by 0.8 points on CAP-1002 and by 3.4 points on placebo, a difference of 2.6 points (percentile difference 36.2; p = 0.014). The authors call this a 71% slowing of loss of function. Both groups still declined.

• At 6 months the difference was 1.5 points (p = 0.047).
• At 3 months (1.2 points) and 9 months (1.5 points) the differences were not statistically significant.
• Total PUL 1.2 favoured CAP-1002 by 3.2 points (p = 0.017) and total PUL 2.0 by 1.8 points (p = 0.040).
• Shoulder-level and hand-level scores did not differ between groups.

Heart: The prespecified secondary cardiac outcome, regional wall thickening, did not favour CAP-1002. Among exploratory measures, LVEF rose by 0.1 percentage points on CAP-1002 and fell by 3.9 points on placebo, a 4.0-point difference. Indexed heart volumes and CK-MB as a share of total CK also favoured CAP-1002 (p = 0.025 for CK-MB). Heart scarring was not measured because no gadolinium contrast was given.

Breathing and patient-reported function: There were no significant differences, apart from percent-predicted peak expiratory flow.

Safety: There were 69 infusions in total. There were no deaths, no acute breathing problems after infusion and no immune sensitisation syndrome.

• Hypersensitivity reactions occurred in 3 of 8 (38%) on CAP-1002, with 5 events in total, and in none on placebo.
• One of these was an acute allergic reaction during a boy’s second infusion, before pre-treatment was introduced. He needed intramuscular adrenaline and an overnight hospital stay, and had no further infusions.
• After pre-treatment was introduced, 42 infusions produced one hypersensitivity event, which did not need adrenaline.
• Treatment-related events occurred in 3 of 8 on CAP-1002 (hypersensitivity, dizziness, altered taste, sore throat) and 2 of 12 on placebo (altered taste, flushing).
• Three placebo participants dropped out, two after two infusions and one after a single infusion.

Conclusions:

The authors conclude that CAP-1002 appears safe and effective in reducing deterioration of arm function in late-stage DMD, and that longer studies are needed to confirm durability and safety beyond 12 months. Trials in younger, ambulatory boys are still needed.

The limitations they list are the small sample, follow-up of 12 months only, the exclusion of boys with the best and worst arm function, too few participants to judge breathing outcomes, and no measure of heart scarring. They note that repeat dosing of donor cells can engage the adaptive immune system, and that larger trials were needed to establish the true risk of allergic reactions.

Background Information:

The authors attribute the effect to exosomes carrying microRNAs (miR-146a, miR-181b) and Y RNA fragments that push macrophages towards a healing state and make fibroblasts less prone to scarring. Dystrophin is not restored. In the cytokine panel, interferon-gamma and IL-5 were raised at 3 months and suppressed at 6 months.

The trial was powered on a 1-point change in mid-level PUL. A difference of one point is clinically meaningful on this scale, because one point can mean losing the ability to bring a hand to the mouth, lift an object on a table or remove a lid.

The published abstract gives the 95% confidence interval for the primary result as 12.7 to 59.7. The results section of the full text gives 7.9 to 64.5, and the discussion gives a third version. The point estimate, 36.2 percentiles or 2.6 points, is the same throughout. This summary follows the results section.