Duchenne muscular dystrophy (DMD) patients with a mutation in exon 53 of the dystrophin gene now have a second approved treatment option, and Xtalks spoke with Sharon Hesterlee, PhD, Muscular Dystrophy Association executive vice president and chief research officer, to learn more. Viltepso (viltolarsen), an injectable drug developed by NS Pharma, has gone through the US Food and Drug Administration’s (FDA) accelerated approval process, but the company has yet to confirm that the drug has a true clinical benefit.
Viltepso is the second drug approved to treat DMD patients amenable to exon 53 skipping, however this type of mutation affects just eight percent of all patients with the rare disease. Sarepta Therapeutics’ Vyondys 53 (golodirsen) was approved in December of 2019, and along with the company’s first DMD drug — Exondys 51 (eteplirsen) — the company maintains they can now treat up to 20 percent of individuals with DMD in the US.
As DMD is caused by a lack of functional dystrophin protein, which supports and strengthens muscle fibers, therapies designed to treat this rare genetic disorder have focused on exon skipping to avoid the area of the dystrophin gene that is mutated and produce a nearly full-length dystrophin protein. Since symptoms of DMD, including muscle deterioration and weakness, often begin to present in male children between the age of three and five, early interventions capable of increasing dystrophin levels are important to slow further muscle deterioration.
Results from a small, North American Phase II clinical trial involving just 16 patients with DMD was used to support the FDA’s accelerated approval of Viltepso. Eight of these patients were assigned to the placebo control group with the remaining eight boys receiving the recommended dose of Viltepso of 80 mg/kg/wk.
All of the patients in the treatment arm showed a rise in dystrophin levels, with an average increase of up to nearly six percent of normal amounts after 25 weeks of treatment. A second multicenter, open-label study of Viltepso involving 16 patients with DMD was conducted in Japan.
“For decades, neurologists who treat DMD have hoped for the discovery of therapies capable of significantly improving dystrophin production, and the magnitude of dystrophin increases observed with Viltepso are impressive,” study investigator Dr. Vamshi Rao, attending physician in the Neurology Department at Ann & Robert H. Lurie Children’s Hospital of Chicago, said in a statement.
Based on this surrogate endpoint, the FDA approved Viltepso on the assumption that higher dystrophin levels would convey a clinical benefit to DMD patients with an exon 53 mutation. However, NS Pharma will need to demonstrate this clinical benefit in the Phase III RACER53 clinical trial, which is currently enrolling patients.
Competitor Sarepta Therapeutics’ Vyondys 53 was given the go-ahead through the same accelerated approval pathway in 2019 after a setback in the form of a Complete Response Letter from the FDA. The regulator’s safety concerns centered on the risk of infection from intravenous infusion ports used to administer Vyondys 53 and renal toxicity that was observed in preclinical studies, which tested doses ten-fold higher than those used in clinical trials.
Like NS Pharma, Sarepta continues to run a Phase III clinical trial to confirm the clinical benefit of Vyondys 53 in the treatment of DMD.
But for the 80 percent of patients with other subtypes of DMD, no targeted treatments are currently available. In 2017, PTC Therapeutics’ corticosteroid drug Emflaza (deflazacort) was approved to treat a broad range of patients with DMD. The drug has been shown to slow the progression of disease symptoms, and is indicated for the treatment of patients as young as two years old.
“Given a clear regulatory pathway and a history of success in getting these drugs approved I do think there will be additional therapies of this type targeted to other groups of mutations in the dystrophin gene,” Dr. Hesterlee told Xtalks. “At some point, though, these drugs may be largely superseded by others like gene therapy that, in preliminary studies, produce significantly more dystrophin than the current generation of exon-skipping drugs and will be applicable to much larger groups of patients.”
When asked about the outlook for patients with DMD whose subtype makes them ineligible for these exon skipping therapies, Dr. Hesterlee pointed towards drugs currently in development that could benefit a wider patient population.
“There are a number of therapeutics in development that could be applicable to all of those with DMD—for example, gene therapy, which is in development at Sarepta, Pfizer and Solid Biosciences, is in various stages of testing and showing good results,” said Dr. Hesterlee. “In addition, small molecule drugs from Catabasis and ReveraGen are both in Phase III testing for DMD. These drugs both act on similar pathways as corticosteroids but may have less side effects.”