New Muscle In The Fight Against DMD

Last week’s biotech headlines lit up with the FDA’s unexpected approval of Sarepta Therapeutics’ (Cambridge, MA) newest Duchenne muscular dystrophy (DMD) drug, Vyondys 53. The FDA changed course after rejecting the product in August because of safety concerns, which the company has now addressed.

DMD is a genetic disorder that causes progressive muscle degeneration and weakness. It arises from a mutation in the gene that codes for a critical muscular protein. This ultimately leads to serious medical problems, including heart and lung problems. Typical life expectancy for a child with DMD is 25 years. It afflicts one in approximately 3,500 newborn baby boys worldwide.

Today’s WEEKLY examines the science behind DMD and explains the mechanism of Sarepta’s drug.

Muscle Glue

DMD patients produce no functional dystrophin. This protein forms part of a complex of proteins that strengthen muscle fibers and protect them from injury during contraction and relaxation. Dystrophin connects the proteins that make up muscle cells’ structural framework with the network of proteins that surrounds each cell. Physiologists and others sometimes refer to dystrophin as the glue that holds muscle cells together. Dystrophin also likely plays a role in transmitting chemical signals within muscle cells.

Faulty dystrophin leads to damaged and progressively weaker muscles. Almost from the start, kids with DMD exhibit developmental delays. Over time, standing and walking become impossible. Patients in their late teens and twenties often develop cardiomyopathy or fatal respiratory problems because the muscles that support breathing deteriorate so profoundly.

When It’s Best To Be A Girl

DMD occurs almost exclusively in boys. This is because the gene for dystrophin sits on the X-chromosome. Females are born with two X chromosomes; males with one X and one Y. Therefore, baby girls end up with two copies of the dystrophin gene. As long as one produces working dystrophin, a child will have healthy muscles. Down the road, though, a girl with one faulty dystrophin gene may “gift” a son with a copy of it. This form of inheritance is called X-linked.

About two-thirds of DMD cases result from inherited mutations; the rest arise from spontaneous genetic changes. (Article continues below)

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Vyondys 53 is an exon-skipping therapy. Exons are one part of a gene’s structure. Recall that genes provide the recipe to a cell for making a protein. When cellular enzymes first read a gene, they produce pre-messenger RNA (pre mRNA). This RNA contains segments that aren’t involved in making the final protein. These segments are introns. The remaining bits of RNA are the exons. Once spliced together, exons form the final mRNA that the cell converts to protein.

Vyondys 53: How It Works

Vyondys 53 is an antisense therapy. This approach consists of administering short, synthetic RNA analogues with sequences that complement the target RNA. In this case, the target is exon 53 of the dystrophin pre-mRNA. When Vyondys 53 enters cells, it binds to exon 53. This combination causes the enzymes that convert pre-mRNA into mRNA to skip over exon 53. The resulting mRNA then produces a truncated version of the normal dystrophin protein. In 2016, Sarepta won approval for Exondys 51, another exon-skipping treatment that targets Exon 51 to treat DMD.

Both drugs target specific mutations so they won’t help everyone with DMD. Roughly eight percent of DMD patients have a mutation in exon 53 and should respond to Vyondys 53. About 13 percent are likely to respond to Exondys 51.

Easily Confused: Surrogate Endpoints Versus Clinical Endpoints

In clinical trials, an endpoint consists of an event or outcome that researchers can measure objectively to determine whether an intervention helps. There are two types: clinical endpoints and surrogate endpoints.

A clinical endpoint indicates that a drug provides a direct clinical benefit to the patient. In DMD, an example of a clinical endpoint would be a confirmed increase in muscle activity as a result of the treatment.

In some cases, companies can use a surrogate endpoint to assess a treatment’s value instead of a clinical endpoint. For Exondys 51 and Vyondys 53, Sarepta relied on the surrogate endpoint of increased dystrophin production. Surrogate endpoints allow the FDA to approve new drugs for serious or life-threatening diseases faster. If a drug is approved via a surrogate endpoint, the FDA requires the manufacturer to conduct follow-up studies to confirm that the product results in a measurable clinical benefit. Sarepta is now running these studies for both Exondys 51 and Vyondys 53.

The Biotech Primer WEEKLY will be taking a break for the next two weeks in honor of the season. Happy Holidays to all of our readers!

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