Gene Therapy for Duchenne Muscular Dystrophy (DMD)

The United States Food and Drug Administration (FDA) has approved a gene therapy drug for children with Duchenne Muscular Dystrophy (DMD). The drug called Elevidys is an adeno-associated viral vector-based gene therapy. The drug will administered intra-venously to children who are 4 or 5 years old. Each injection will cost around $3.2 million.

What is Duchenne Muscular Dystrophy or DMD?

Duchenne Muscular Dystrophy (DMD) is a genetic disorder characterized by progressive muscle degeneration and weakness. It primarily affects males, typically diagnosed in early childhood.

DMD is caused by a mutation in the dystrophin gene, which results in the absence or deficiency of the dystrophin protein—a crucial component for maintaining muscle integrity. Without dystrophin, muscle fibers become fragile and easily damaged during muscle contractions.

The symptoms of DMD usually manifest in early childhood, starting with difficulties in walking and motor coordination. Over time, muscle weakness progresses, leading to the loss of ability to walk and the need for walking aids. As the disease progresses, muscle wasting, contractures (tightening of tendons and muscles), respiratory difficulties, cardiac complications, and impaired cognitive function can also occur. In fact, patients often succumb to the disease in their 20s or 30s because of heart and/or respiratory failure.

About one in every 3,300 boys are affected by this disorder. Most current treatment approaches address the symptoms of the disease, but not its underlying genetic cause.

Since a single gene is responsible for DMD, it can be efficiently targeted by gene therapy.

What is Gene Therapy

Gene therapy is a medical approach aimed at treating or preventing diseases by modifying the genetic material of an individual’s cells. It involves introducing new genetic material, such as genes or gene-editing tools, into the patient’s cells to correct or replace faulty or missing genes, alter gene expression, or provide therapeutic effects.

In the case of DMD, gene therapy will aim to modify and coorect the mutation in the dystrophin gene.

How does Elevidys work?

Elevidys is the brand name for a viral vector-based gene therapy called Delandistrogene moxeparvovec. The viral vector is designed to deliver a gene that leads to production of Elevidys micro-dystrophin that contains selected domains of the dystrophin protein present in normal muscle cells. Elevidys micro-dystrophin then can perform the function of normal dystrophin and prevent the onset of DMD.

Elevidys micro-dystrophin is a shortened form of the full dystrophin protein. While the normal full dystrophin is 427 kilo Dalton (kDa) in size, Elevidys micro-dystrophin is more than 3 times smaller than the full protein at 138 kDa.

Elevidys may cause some side effects, as reported by individuals who received Elevidys during clinical trials. They were vomiting, nausea, acute liver injury, fever and thrombocytopenia (abnormally low platelet count in the blood).

Preliminary Approval

The FDA has provided preliminary approval to the drug based on data from a randomised clinical trial that established that Elevidys increased the expression of the Elevidys micro-dystrophin protein observed in Elevidys-treated individuals aged 4 to 5 years with DMD.

The clinical trial is still ongoing. However, the FDA concluded that it already demonstrates that an increase in expression of Elevidys micro-dystrophin predicts a clinical benefit in individuals 4 to 5 years of age with DMD. Importantly, the FDA has approved this gene therapy drug to only those who do not have significant pre-existing immunity against viral vectors used in this gene therapy.

Essentially, the FDA fast-tracked the approval considering the life-threatening and debilitating nature of DMD in children. According to the FDA, any potential risks from the gene therapyare far out-weighed by the risks from the genetic disorder itself.

As a condition of approval, the FDA is requiring the company making the drug to complete the clinical trial to confirm the drug’s clinical benefit. The required study is designed to assess whether Elevidys improves physical function and mobility in ambulatory DMD patients with a confirmed mutation in the DMD gene. The FDA has also stated that it will review the data from this trial as quickly as possible to consider if further action, such as a revised indication or withdrawal of Elevidys, may be necessary.

“The approval of Elevidys is a watershed moment for the treatment of Duchenne. Elevidys is the first and only gene therapy approved for Duchenne, and this approval brings us closer to our goal of bringing forward a treatment that provides the potential to alter the trajectory of this degenerative disease,” Sarepta President and CEO Doug Ingram said in a company statement.