World’s First Approved Gene Therapy For Duchenne Muscular Dystrophy

 In mid-June of 2023, the U.S. Food and Drug Administration (FDA) approved the very first gene therapy for Duchenne Muscular Dystrophy (DMD), Elevidys. This breakthrough addressed the dire, unmet medical needs for patients with DMD. Here’s an insight into the trajectory of this genetic disorder and its approved treatment for pediatric patients.

A Look Into Genetics

Duchenne Muscular Dystrophy (DMD) is a rare and fatal genetic condition that results in progressive muscle damage and weakness. This disease occurs due to a mutation of the DMD gene identified on the X chromosome. The mutated DMD gene fails to produce dystrophin, a protein that helps strengthen muscle fibers and keep muscles intact. Due to this mutation, affected individuals have muscular problems and symptoms such as trouble walking or running, difficulty moving, frequent falls, learning disabilities, impaired cardiac and respiratory function, as well as failure to thrive. DMD typically begins in early childhood and primarily affects males, accounting for 1 in 3300 male births globally. The disease only rarely occurs in females. DMD has a high fatality rate due to cardiac and respiratory complications that occur. Although there are high fatality rates with Duchennes, disease severity and life expectancy vary from individual to individual. Previous targeted treatments include corticosteroids such as deflazocort and antisense oligonucleotides (ASOs), which target mRNA and facilitate protein expression. These medications only target symptoms of the disorder, and do not address the underlying genetic mutation. Additionally, they carry extensive side effects which contribute to the high mortality rates in these patients. 

New Treatment: Benefits and Risks

US FDA approved Elevidys is a new gene therapy aimed to alleviate symptoms of DMD and treat the underlying cause of the disease by altering patients' genes. This new gene therapy is produced via genetic engineering. Elevidys works by administering a gene in the body that triggers the growth of a shortened form of the dystrophin protein, about one-third the size of the original dystrophin. This micro-dystrophin works similarly to normal dystrophin, albeit at a smaller size. Thus, the goal of Elevidys is to replenish the dystrophin protein in DMD patients, addressing the underlying cause of muscle dysfunction (lack of dystrophin). 

Figure 1. Mechanism of Elevidys in DMD muscle cell. Image source here. 

A formal and complete clinical study is currently being conducted to confirm the drug's effectiveness. The treatment is to be administered in pediatric patients aged 4-5 in a single-dose intravenous infusion. The clinical study that is currently ongoing will assess how patients are functioning alongside the initial administration of this treatment. Additionally, the clinical trial will measure disease morbidity through reported side effects and changes in the overall mortality rate of DMD.

So far, the most common adverse side effects in individuals on Elevidys were vomiting (61%), prolonged nausea (40%), acute liver damage (37%), a low platelet count (12%), and fever (24%).  Complications of the infusion include acute liver injury, muscle inflammation (myositis), and heart muscle inflammation (myocarditis). Thus, patients receiving this treatment must have liver function and cardiac enzyme levels tracked to monitor for liver and heart issues. 

Accelerated Approval Pathway (AAP)

Through the Accelerated Approval Pathway, the FDA may approve drugs for fatal diseases where urgent and required medical intervention is necessary. The FDA has stated that through this approved pathway, the administered drug will provide patients with easier access to new drugs while companies conduct trials to confirm efficacy.

After AAP approval, the last step in approving the medication Elevidys was to conduct a randomized drug trial. In this study, patients were either given Elevidys or a placebo (substance with no therapeutic effect) over a 48-week period. In the later part of this trial, individuals who were given the placebo were given Elevidys, and those who were given Elevidys were given the placebo. The randomized clinical trial successfully established that Elevidys did, in fact, increase the expression of dystrophin protein in treated individuals in the age range of 4-5 years old. The FDA is hopeful of finding similar treatments for a larger age range of DMD-affected youth in the near future. 

Written by Sarosh Momin, B.S.

Edited by Siler Monk

References

1. Kempler C. FDA Approves First Gene Therapy for Treatment of Certain Patients with Duchenne Muscular Dystrophy. FDA. Published June 23, 2023. https://www.fda.gov/news-events/press-announcements/fda-approves-first-gene-therapy-treatment-certain-patients-duchenne-muscular-dystrophy 
2. Muscular Dystrophy Association. Duchenne Muscular Dystrophy (DMD). Muscular Dystrophy Association. Published 2018. https://www.mda.org/disease/duchenne-muscular-dystrophy 
3. Sarepta Therapeutics Announces FDA Approval of ELEVIDYS, the First Gene Therapy to Treat Duchenne Muscular Dystrophy | Sarepta Therapeutics, Inc. Sarepta Therapeutics, Inc. Published 2023. Accessed February 28, 2024. https://investorrelations.sarepta.com/news-releases/news-release-details/sarepta-therapeutics-announces-fda-approval-elevidys-first-gene#:~:text=ELEVIDYS%20addresses%20the%20root%20genetic%20cause%20of%20Duchenne 
4. PharmD BP. Elevidys, a Gene Therapy for Duchenne Muscular Dystrophy, Gets FDA Approval. MPR. Published June 23, 2023. Accessed February 28, 2024. https://www.empr.com/home/news/elevidys-a-gene-therapy-for-duchenne-muscular-dystrophy-gets-fda-approval/ 
5. Elevidys is the first gene therapy approved for the treatment of certain patients with Duchenne muscular dystrophy (DMD). Prime Therapeutics LLC. Published August 28, 2023. https://www.primetherapeutics.com/news/elevidys-is-the-first-gene-therapy-approved-for-the-treatment-of-certain-patients-with-duchenne-muscular-dystrophy-dmd/ 

6. Gene therapy for Duchenne muscular dystrophy. Muscular Dystrophy News Today. Accessed April 1, 2024. https://musculardystrophynews.com/gene-therapy-for-duchenne-muscular-dystrophy/