The US Food and Drug Administration (FDA) has approved the gene therapy, delandistrogene moxeparvovec (Elevidys), to treat patients ages 4 through 5 years with Duchenne muscular dystrophy (DMD) with a confirmed mutation in the DMD gene.

DMD is a severe progressive X-linked recessive disease of muscle due to mutations in the DMD gene that uncode for dystrophin. The major symptom of DMD is progressive muscle weakness that eventually leads to respiratory failure and death. Symptoms begin to appear in young boys and most are wheelchair bound by the time they are teenagers. Glucocorticoids can improve muscle function and is a mainstay of treatment for these children but it does not stop the disease progression. Antisense oligonucleotides, such as eteplirsen, golodirsen, and casimersen are exon skipping therapies, are approved to treat portions of the DMD populations that are amenable to exon 51, 52, and 45 skipping, respectively.

The new gene therapy is approved for patients with any mutation on the DMD gene. One caveat is that is currently only approved for patients aged 4 to 5 years of age.

The gene therapy was approved through the Accelerated Approval Pathway and largely based on data submitted to the FDA via the sponsor (Sarepta Therapeutics). A summary of the FDA assessment of that data is available at  https://www.fda.gov/vaccines-blood-biologics/elevidys

According to the FDA, the data submitted for review, including a 48-week, randomized, double-blind, placebo-controlled study, showed that delandistrogene moxeparvovec increased the expression of the delandistrogene moxeparvovec micro-dystrophin protein observed in delandistrogene moxeparvovec-treated individuals aged 4 to 5 years with DMD. The FDA concluded that surrogate endpoint reasonably likely to predict clinical benefit in individuals 4 to 5 years of age with DMD who do not have significant pre-existing antibody titers against the AAV rh74 vector or have other contraindications based on the inclusion criteria of the clinical trials.

A clinical benefit of this gene therapy, including improved motor function, has not been established, according to the FDA. As a condition of approval, a clinical study to confirm the gene therapy’s ability to improve physical function and mobility in ambulatory DMD patients must be provided. That study is ongoing and fully enrolled.

The approval may spark some controversy. Last month, THE FDA’s Cellular, Tissue and Gene Therapies Advisory Committee (CTGTAC) recommended approval but only by a slim margin (8 vs 6). In a report by Peter Marks, MD, PhD, Director, Center for Biologics Evaluation and Research (CBER), Dr. Marks noted:

 “The clinical efficacy outcome using the North Star Ambulatory Assessment (NSAA) among 4- and 5-year-olds showed an average 4.3-point increase in the least square mean change from baseline in the SRP-9001 group compared to a 1.9-point increase in the placebo group and in the subset of these individuals for which data are available, this outcome correlated with the level of ELEVIDYS micro-dystrophin protein expression. I therefore find that the data contained in BLA 125781, including from Study 102, provide substantial evidence of effectiveness of ELEVIDYS by demonstrating an effect on the surrogate endpoint of expression of ELEVIDYS micro-dystrophin protein that is reasonably likely to predict clinical benefit in the specific population of individuals ages 4 through 5 years.”

The most common side effects were vomiting, nausea, acute liver injury, pyrexia (fever) and thrombocytopenia. Patients’ liver function should be monitored before treatment with delandistrogene moxeparvovec, and weekly for the first three months after treatment. Patients given delandistrogene moxeparvovec may also be at risk for severe immune-mediated myositis. Additionally, myocarditis and elevations of troponin-I have been observed following use of delandistrogene moxeparvovec in clinical trials. Troponin-I levels should be monitored before administration of delandistrogene moxeparvovec and weekly for the first month after treatment.

To stay up to date on the latest FDA approvals, go to https://checkrare.com/drug-development/