The American Academy of Neurology's Guidelines Subcommittee has systematically reviewed the current evidence on the efficacy and adverse effects of delandistrogene moxeparvovec in patients with Duchenne muscular dystrophy, revealing important limitations in the treatment's demonstrated clinical benefit despite receiving U.S. Food and Drug Administration approval.
In the Evidence in Focus report, investigators identified 6 clinical trials focused on delandistrogene moxeparvovec, 4 of which had peer-reviewed published data available. From these studies (2 Class I and 2 Class III), exposure data were available on 134 boys, 128 of whom were ambulatory and between 4 and 8 years of age, but not yet 8 years.
Notably, "Both Class I studies failed to meet the primary functional motor outcome as assessed by change in the North Star Ambulatory Assessment [NSAA] score," the study authors reported. "Several secondary functional motor outcomes demonstrated improvement in the treatment group with small effect sizes, not meeting statistical significance from hierarchical analysis," they added.
One significant confounding factor identified was that: "Corticosteroid dose exposure was higher in the treatment group in the first 12 weeks after infusion, potentially contributing to measured differences between groups."
The team, led by Maryam Oskoui, MD, of McGill University, conducted a systematic literature search across PubMed, Cochrane, Clinicaltrials.gov, and the World Health Organization's International Clinical Trials Registry Platform, evaluating studies according to the 2017 American Academy of Neurology therapeutic classification of evidence scheme.
Safety outcomes were consistent across studies, with the investigators documenting "multiple treatment-related adverse events, including peri-infusion effects, immune myositis and myocarditis, thrombocytopenia, and liver toxicity." The investigators also noted that: "One death has been reported in an individual who was treated with delandistrogene moxeparvovec outside of a trial."
Despite the treatment not demonstrating efficacy in its primary outcome, the U.S. Food and Drug Administration (FDA) granted approval for delandistrogene moxeparvovec. "This decision was supported by the relative safety of the product and secondary outcome measures data in the phase III clinical trial," the study authors explained.
The FDA's decision process involved internal disagreement. "The Clinical, Clinical Pharmacology, and Statistics review teams and supervisors had concluded that there was insufficient evidence to support the use of expression of microdystrophin as a surrogate endpoint that is reasonably likely to predict clinical benefit for accelerated approval and recommended complete response," the study authors noted.
However, "The Review Committee's decision was overridden by the Center for Biologics Evaluation and Research director based on the subgroup of participants in study [ClinicalTrials.gov identifier NCT03769116] who showed improvement in the NSAA score at 1 year compared with placebo," the study authors noted.
On June 20, 2024, "the FDA granted full approval for ambulatory patients aged 4 years and older and accelerated approval for nonambulatory patients aged 4 years and older based on additional data received from the sponsor for [EMBARK] study (NCT05096221) and [ENDEAVOR] study (NCT04626674)," the study authors added.
Clinical Implications and Recommendations
The investigators emphasized that providers should "be aware of the limitations of the treatment and the need to monitor for immune-related side effects including myocarditis, liver injury, and thrombocytopenia, which may require expanded clinical infrastructure."
According to the review, "Based on biological plausibility and on the existing clinical trial data, AAV-microdystrophin gene therapies are not curative. The FDA's broad approval of the first-in-class delandistrogene moxeparvovec for Duchenne muscular dystrophy is met with both hope and uncertainty by the medical and patient communities."
The investigators concluded: "Additional clinical trials and careful collection of real-world evidence from treated patients will be essential to establish short-term and long-term effectiveness and inform understanding of benefits and risks of delandistrogene moxeparvovec across the lifespan."
Disclosures can be viewed at aan.com
Source: Neurology