A lack of viable dystrophin is the cause of Duchenne muscular dystrophy (DMD). But the dystrophin gene is too large to deliver to cells using the adeno-associated virus vectors that is commonly used in gene therapy. Sarepta, Solid Biosciences and Pfizer are developing a shortened form of the gene (microdystrophin gene therapy) that stimulates a truncated form of dystrophin.
Microdystrophin was designed to resemble a protein found in patients with Becker muscular dystrophy, a milder form of the disease. However, the microdystrophin produced by delandistrogene moxeparvovec is different from what is found in patients with Becker muscular dystrophy or created with exon skipping drugs. While delandistrogene moxeparvovec has been shown to produce large amounts of microdystrophin, it is not currently known if microdystrophin has the same functional benefit as normal dystrophin in DMD patients. Limited evidence has shown a benefit compared to historical DMD data.
Sarepta announced four-year results from a four patient, Phase I/II trial (NCT03375164), where delandistrogene moxeparvovec maintained a 7-point improvement in the North Star Ambulatory Assessment (NSAA) over baseline and a 9.4-point improvement compared to a historical control group in patients with DMD.
Sarepta announced interim data from 20 patients enrolled in Part 1 of a 48-week, 41 patient, Phase II trial(NCT03769116), where delandistrogene moxeparvovec resulted in micro-dystrophin expression of 28.1% at 12-weeks. At 48 weeks, treatment with delandistrogene moxeparvovec improved the NSAA score by 1.7 points in the 20 treated patients, but the improvement was not statistically significant compared to a 0.9 point improvement in 21 placebo patients.
Sarepta announced data from 20 patients enrolled in Part 2 of a 48-week, 41 patient, Phase II trial(NCT03375164), where treatment with delandistrogene moxeparvovec improved the NSAA score by 2 points compared to a 103 patient, weighted external control group (1.3 point increase vs 0.7 point decrease).
In July 2018, the FDA placed a hold on a delandistrogene moxeparvovec trial due to the presence of a trace fragment of DNA plasmid in one lot of the drug. The hold was lifted in September 2018. A second hold was placed in August 2021 when a patient developed asthenia that required hospitalization and respiratory support after receiving delandistrogene moxeparvovec. The hold was lifted in October 2021 when additional information on risk was submitted to the FDA.
In limited patent data, the most common adverse events were vomiting, nausea, acute liver injury, fever and thrombocytopenia.
In September 2020, the FDA requested that Sarepta use a different potency assay when manufacturing delandistrogene moxeparvovec before using the drug in a Phase III trial. The Phase I ENDEAVOR trial evaluated delandistrogene moxeparvovec made by Sarepta’s commercial-scale manufacturing process. Sarepta announced one-year functional results from 20 patients enrolled in Cohort 1 of the open-label, Phase I, ENDEAVOR trial (NCT04626674), where treatment with delandistrogene moxeparvovec improved the NSAA score compared to a historical control group of patients with DMD.
An FDA review of delandistrogene moxeparvovec, in May 2023, questioned whether microdystrophin protein expression is a valid surrogate endpoint that can be used for approval, since microdystrophin has not demonstrated a pharmacologic effect on a biomarker in the pathway of the disease. The FDA failed to find a benefit for ambulatory DMD patients in a review of delandistrogene moxeparvovec trials. The FDA’s Cellular, Tissue, and Gene Therapies Advisory Committee (CTGTAC) voted 8 to 6 to recommend approval of delandistrogene moxeparvovec.
The FDA delayed the PDUFA date for delandistrogene moxeparvovec by one month in order to consider an accelerated approval for Duchenne patients ages 4-5 years old. The FDA granted an accelerated approval for delandistrogene moxeparvovec (Elevidys, Sarepta), on 6/22/2023, for the treatment of Duchenne muscular dystrophy in boys aged 4 and 5. Full approval and expansion to other age groups or withdrawal from the market will depend on the results of the Phase III EMBARK trial (NCT05096221). The EMBARK trial is forecast to report top-line results by the end of the year. Sarepta set the initial price for delandistrogene moxeparvovec at $3.2 million for the single dose gene therapy.
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