Last updated Feb. 9, 2022, by Marisa Wexler, MS
Fact-checked by José Lopes, PhD
Vyondys 53 (golodirsen, SRP-4053) is an approved exon skipping therapy developed by Sarepta Therapeutics to treat people with Duchenne muscular dystrophy (DMD) whose disease is amenable to exon 53 skipping — representing about 8% of DMD patients.
The therapy is designed to address the root cause of Duchenne by allowing the body to produce a functional version of the dystrophin protein whose lack causes the disease.
Sarepta applied to the U.S. Food and Drug Administration (FDA) for the approval of Vyondys 53 in 2019. The FDA initially rejected the application, citing safety concerns, specifically a risk of infections and kidney injury linked with the therapy.
After Sarepta filed an appeal, and the two sides met, the agency reversed its decision, giving Vyondys 53 accelerated approval in December 2019. The FDA uses the accelerated approval pathway to give conditional authorization to medications that are likely to help patients based on an established biological effect (i.e., increased dystrophin production), but where the clinical benefits for those with the disease are not yet fully established. Typically, the FDA requires the therapy’s developer to conduct additional trials to establish treatment effectiveness.
How Vyondys 53 works
DMD is caused by mutations in the gene DMD, which codes for a protein called dystrophin that is important for muscle health. Like other protein-coding genes, the DMD gene is separated into sections called exons and introns: exons provide the actual protein-coding parts of the gene, while introns are non-coding regions between exons.
When the DMD gene is “read,” the entire gene, with its 79 exons, gets copied into a temporary molecule called messenger RNA. This RNA then is edited to remove the introns, and the exons are spliced together into a mature code that can be read by the cell’s protein-making machinery, called ribosomes.
Certain mutations in DMD, in exons 43 to 55, can cause a “frameshift,” where all of the downstream parts of the genetic code get moved out of alignment due to the mutation, rendering them unreadable by ribosomes. Vyondys 53 works by binding to the DMD messenger RNA and prompting a particular exon — exon 53 — to be removed from the RNA prior to it being sent to ribosomes. Removing this exon fixes the frameshift, allowing the cell to make a shorter, but still functional, version of the dystrophin protein.
Vyondys 53 in clinical trials
A Phase 1/2 clinical trial (NCT02310906), completed in 2019, assessed the safety, tolerability, efficacy, and pharmacokinetics of Vyondys 53 in 25 boys with DMD who had mutations amenable to exon 53 skipping. Of note, pharmacokinetics is a medication’s movement in, through, and out of the body.
Participants received weekly infusions of Vyondys 53, and muscle biopsies were performed before and after 48 weeks (just less than one year) of treatment. Results showed a marked increase in functional dystrophin following 30 mg per kg of bodyweight of Vyondys 53 — from less than 0.1% of normal levels prior to treatment, to just over 1% of normal after 48 weeks, on average. Sarepta’s application to the FDA to review Vyondys 53 for approval was supported by these findings.
Now, Sarepta is currently sponsoring a Phase 3 study called ESSENCE (NCT02500381) to evaluate the effectiveness of Vyondys 53 and Amondys 45 (casimersen), another exon-skipping therapy developed by Sarepta, compared with a placebo. Boys with mutations amenable to skipping exon 53 (for Vyvondys 53) or exon 45 (for Amondys 45) are taking part in a trial conducted around the world. Interim results that showed treatment with Amondys 45 could increase dystrophin levels in eligible patients served as the basis for that therapy’s accelerated approval by the FDA in 2021.
A Phase 3 extension study (NCT03532542) also is being sponsored by Sarepta to evaluate the long-term safety and tolerability of Vyondys 53 and Amondys 45 in DMD patients who have been treated previously with these exon-skipping treatments in a clinical trial setting. A total of 260 DMD boys, ages 7 to 23, will be invited to participate in this study. Boys with mutations amenable to exon 53 skipping will be included in the Vyondys 53 treatment group, while those with mutations that can benefit from exon 45 skipping will be treated with Amondys 45.
Patients will receive weekly intravenous (into-the-vein) infusions of the respective treatment for up to 144 weeks (nearly three years), and the number of serious adverse events will be assessed.
Vyondys 53 is given at a dosage of 30 mg per kg of body weight, administered once per week via an infusion into the bloodstream that usually lasts 35 to 60 minutes.
The most common side effects associated with Vyondys 53 include headache, fever, falls, abdominal pain, the common cold, cough, vomiting, and nausea.
Vyondys 53 may cause kidney toxicity, and kidney health should be assessed during treatment.
Certain people may experience an allergic reaction to Vyondys 53, with symptoms such as fever or rash. If an allergic reaction occurs, the symptoms should receive appropriate treatment, and the infusion of Vyondys 53 may be slowed or stopped.
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