On Dec. 12, the US Food and Drug Administration (FDA) granted accelerated approval to golodirsen (Vyondys 53) for the treatment of Duchenne muscular dystrophy (DMD) in patients amenable to skipping exon 53. It is the second exon-skipping, disease-modifying drug to treat DMD, the most common childhood form of muscular dystrophy. The drug is administered by intravenous infusion. Vyondys 53 will be made available in the United States and marketed by Sarepta Therapeutics.
In September 2016, the approval of eteplirsen (marketed by Sarepta as Exondys 51) marked a watershed moment for treating neuromuscular diseases with gene-targeting therapies such as exon skipping. Approval of Vyondys 53, another exon-skipping drug designed to treat a different subset of DMD individuals than those who qualify for Exondys 51, is another significant step forward in the development of therapies for DMD — and all neuromuscular diseases — that target the root cause of the disease.
“The approval of Vyondys 53 is another breakthrough toward treating Duchenne, a disease that, up until a few years ago, had no approved therapies,” says MDA’s Executive Vice President and Chief Research Officer Sharon Hesterlee, PhD. “It’s another milestone for the field of DMD research and drug development, and it represents the fulfillment of the promise of effective genetic medicines for DMD patients and their families.”
DMD is caused by mutations in the dystrophin gene (DMD) on the X chromosome that result in little or no production of dystrophin, a protein essential to keeping muscle cells intact. Vyondys 53 is called an “exon-skipping” drug in that it is designed to target and promote skipping over a section of genetic code in order to avoid the gene mutation and produce more of the dystrophin protein. It is estimated that up to 8% of patients with DMD have mutations amenable to treatment with Vyondys 53. Although treatment with Vyondys 53 will not cure DMD, it could slow progression of the disease, which, in turn, could extend the length of time individuals with DMD could walk, eat independently, and breathe without assistance.
Clinical trials support approval of Vyondys 53
The FDA based its decision to grant accelerated approval to Vyondys 53 on the positive results of a pivotal (phase 1/2) clinical trial conducted in Europe to assess the safety, tolerability, pharmacokinetics (how the drug is absorbed, distributed, and metabolized in the body), and efficacy (dystrophin expression) of Vyondys 53 in 25 boys with DMD with confirmed deletions of the dystrophin gene amenable to exon 53 skipping. Preliminary results reported in late 2017 showed that treatment with Vyondys 53 for approximately one year was associated with a significant boost in dystrophin protein production. Muscle biopsies confirmed that all participants responded to the drug, with increased levels of exon 53 skipping compared to measurements taken at baseline (prior to beginning treatment). A 10.7-fold increase in levels of dystrophin protein was seen, equating to a rise from an initial average among patients of 0.095 percent of normal protein levels to a mean of 1.019 percent.
The 25 boys with DMD who participated in the phase 1/2 clinical trial were evaluated for a total of 144 weeks. Positive results were seen across all endpoints, including proper exon skipping, increased dystrophin production, and increased dystrophin intensity. The approval was based on an observed statistically significant increase in dystrophin production in skeletal muscle of patients treated with Vyondys 53, which is reasonably likely to predict clinical benefit for those patients. The continued approval of Vyondys 53 may be contingent on confirmation of a clinical benefit in a post-marketing confirmatory trial (ESSENCE), which is currently enrolling and expected to conclude by 2024.
Hypersensitivity reactions, including rash, fever, itchy skin, hives, dermatitis, and skin exfoliation, have occurred in patients who were treated with Vyondys 53. Renal toxicity was observed in animal studies. The most common adverse reactions that occurred in at least 20% of treated patients and more frequently than in placebo-group patients were headache (41%), fever (41%), fall (29%), abdominal pain (27%), nasopharyngitis (27%), cough (27%), vomiting (27%), and nausea (20%).
SareptAssist is a patient support program designed to provide patients with information to help navigate the process of starting and staying on therapy. Sarepta’s dedicated team will provide information on insurance benefits, financial assistance options, treatment logistics, options for drug delivery, and ongoing education and support.
MDA’s Resource Center provides support, guidance, and resources for patients and families, including information about the approval of Vyondys 53, open clinical trials, and other services. Contact the MDA Resource Center at 1-833-ASK-MDA1 or ResourceCenter@mdausa.org.
About Vyondys 53
Vyondys 53 uses Sarepta Therapeutics’ exon-skipping technology to target exon 53 of the DMD gene. Exon skipping is a treatment strategy in which sections of genetic code are “skipped” (spliced out, or left out) during the protein manufacturing process, allowing cells to create shortened but partially functional dystrophin protein, the muscle protein missing in DMD. Exon skipping is not a cure for DMD but potentially could lessen the severe muscle weakness and atrophy that is the hallmark of the disease.
Just as individuals with DMD caused by a mutation that would be amenable to skipping exon 51 could benefit from treatment with Exondys 51, those with DMD caused by a mutation that would be impacted by skipping exon 53 potentially could benefit from treatment with Vyondys 53.
The FDA’s decision to approve Vyondys 53 highlights the importance of years of commitment to supporting and funding breakthrough research by MDA and others into gene identification and unlocking the cause of DMD. MDA-supported research has been central to the development of the exon-skipping approach behind both Exondys 51 and Vyondys 53 from the beginning, having funded foundational work upon which the strategy was built as well as extensive research into the strategy since that time. Laboratory development of exon-skipping therapies began in the 1990s, including notably with MDA-funded work by Steve Wilton, PhD, and colleagues. Their work led to the invention of what would later become Exondys 51 and Vyondys 53.
Since its inception, MDA has committed more than $218 million to DMD and Becker muscular dystrophy research and more than $1 billion across the spectrum of neuromuscular diseases.