Data from a recent phase 3 trial of deramiocel is encouraging, but not encouraging enough to garner a positive recommendation from an FDA advisory committee.
An investigational treatment for Duchenne muscular dystrophy has been shown to slow disease progression in a phase 3 trial, but an FDA advisory committee isn’t yet convinced of its efficacy and safety.
The American trial, which involved more than 100 boys and adolescent males with advanced DMD, found that quarterly deramiocel infusions outperformed placebo in preserving upper limb function after 12 months while maintaining a similar safety profile.
DMD is an X-linked genetic disorder that affects skeletal and cardiac muscle, leading to loss of mobility, progressive myopathy/cardiomyopathy, and eventual, premature death. Boys and young men affected by DMD have a median life expectancy less than 30 years.
Deramiocel is a cellular suspension made from human allogenic cardiosphere-derived cells (CDCs). The treatment was initially developed to treat cardiomyopathy, but preclinical studies would later show the CDCs also improved skeletal muscle in various models of DMD.
“The HOPE-2 trial of deramiocel in advanced DMD – the first to use intravenous cell delivery and repeat sequential dosing of a cell therapy to treat a genetic disease – showed stabilisation of upper limb function and improved heart function relative to placebo without restriction by genotype, meeting the primary endpoint with 71% slowing of decline in mid-level [upper limb function],” researchers wrote in The Lancet.
“In parallel, deramiocel improved [left ventricular ejection fraction] and left ventricular volumes versus placebo. A follow-up open label extension study (HOPE-2 OLE) revealed sustained benefits in upper limb and cardiac function over three years relative to external natural history control groups with no serious safety concerns over three years.
“Our aim was to assess the efficacy and safety of deramiocel in boys and young men with advanced DMD and support the findings of HOPE-2.”
Researchers recruited 106 males aged ≥10 years (median age 15.0 years) with genetically confirmed DMD from 20 sites across the US as part of the phase 3 trial. All patients had a Performance of Upper Limb 2.0 (PUL2.0, a validated functional scale for quantifying skeletal muscle impairment) entry item score between 2 and 6 and a total PUL2.0 score ≤40 (a PUL2.0 score of 42 – the highest possible score – suggests normal upper limb function). Patients with an LVEF ≤35%, forced vital capacity percentage predicted <30%, and severe elbow contractures (30º) were excluded.
Fifty-four participants were randomised to receive deramiocel, while the remaining 52 received placebo. The two groups had similar levels of upper limb dysfunction (median PUL2.0 scores at baseline of 27.6 for deramiocel, 26.5 for placebo, and 27.1 across all participants). Patients received deramiocel (1.5 x 108 CDCs) or placebo via intravenous infusion on day one and then every three months for three years.
The primary outcome – mean percentage change in PUL2.0 total score between baseline and 12 months – favoured the active treatment. Patients who received deramiocel had a between-group least-squares mean difference of 8.1% more than placebo between the two time points (95% confidence interval 2.1-14.1). This corresponds to a 1.0-point absolute between-groups difference on the PUL2.0 scale, reflecting a 65% slowing of DMD progression relative to placebo.
“The… difference seen in the total PUL2.0 score at 12 months, in the context of a highly heterogenous disease in which [the] PUL score might continuously decline over one to two decades, indicates a clinically relevant delay in disease progression,” wrote the researchers.
“A 54% reduction in mean skeletal muscle disease progression over 12 months, if sustained, would be equivalent to delaying approximately one year of untreated progression over two years.”
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deramiocel on the trial’s key secondary outcome, the change in LVEF between baseline and 12 months.
“Although CDCs are heart-derived, their benefits are not heart-restricted; they recruit general mechanisms pertinent to skeletal muscle as well,” the researchers said.
“In the context of DMD, deramiocel does not address the underlying dystrophin deficiency, but, by modulating maladaptive inflammatory and fibrotic pathways in DMD, disease progression is attenuated. It is particularly encouraging that deramiocel shows efficacy even in advanced DMD, in which tissue damage is already extensive.”
There were 594 treatment-emergent adverse events reported in the first 12 months of treatment, occurring in a similar proportion of patients in the deramiocel and placebo groups (94.3% versus 82.7%). Almost all adverse events (98%) were mild or moderate in severity, with 23% of events related to hypersensitivity. Hypersensitivity reactions were reported by a greater proportion of patients in the deramiocel group compared to the placebo group (41.5% versus 15.4%).
The most commonly reported adverse events across all cases were headaches (32.5%), cough (15.2%), pyrexia (14.3%), nausea (12.4%), and tachycardia (12.4%).
“These findings reinforce deramiocel as a safe, effective, and promising therapy for individuals living with DMD. Longer follow-up is needed to establish durability, long-term safety, and effects on clinically important cardiac outcomes,” the researchers concluded.
Elsewhere, an advisory committee for the US Food and Drug Administration voted 9-3 against approving deramiocel for the treatment of cardiomyopathy in patients with DMD.
A statement released by Capricor Therapeutics, the developer of deramiocal, said the FDA’s Cellular, Tissue and Gene Therapies Advisory Committee felt the evidence did not support deramiocel as an effective therapy for cardiomyopathy in DMD. However, the committee was more positive about its effect on upper limb function.
“We remain committed to deramiocel and to the patients who could benefit from it,” said Capricor Therapeutics CEO Linda Marbán, PhD. “The Advisory Committee gave us an important opportunity to present the clinical evidence, and we were encouraged by the Committee’s discussion of deramiocel’s impact on skeletal muscle.”
“We remain confident in the strength of the HOPE-3 data. In a moving open public hearing, patients, families, and clinicians shared their experience with the therapy, underscoring the unmet need within the Duchenne community.”
The FDA often, but does not always, follow the recommendations made by its various advisory committees.
Deramiocel is considered an “orphan drug” for the treatment of DMD by both the FDA and the European Medicines Agency.
