FDA Approves Antisense Oligonucleotide Therapy Golodirsen for Duchenne Muscular Dystrophy Subtype 

The Food and Drug Administration (FDA) granted accelerated approval to an antisense oligonucleotide (ASO) therapy, golodirsen (Vyondys 53; Sarepta Therapeutics, Cambridge, MA), for treatment of individuals with Duchenne muscular dystrophy (DMD) who have a confirmed mutation of the dystrophin gene that is amenable to exon 53 skipping. It is estimated that approximately 8% of individuals with DMD have this mutation. Golodirsen is produced on a phosphorodiamidate morpholino oligomer (PMO) platform and administered by injection. 

The accelerated approval of golodirsen is based on the surrogate endpoint of an increase in dystrophin production in the skeletal muscle observed in some participants treated with the drug. A clinical benefit of the drug, including improved motor function, has not been established. In making this decision, the FDA considered the potential risks associated with golodirsen, the life-threatening and debilitating nature of the disease and the lack of available therapy.

“The FDA recognizes the urgent need for new medical treatments for serious neurological disorders and we have a long-standing commitment to working with researchers, drug companies and participants to facilitate the development and approval of treatments for rare diseases. With the accelerated approval, participants with Duchenne have a confirmed mutation of the dystrophin gene amenable to exon 53 skipping will now have available the first treatment targeted specifically for this disease subtype,” said Billy Dunn, MD, acting director of the Office of Neuroscience in the FDA’s Center for Drug Evaluation and Research. “Use of the accelerated approval pathway will make Vyondys 53 available to participants based on initial data and we look forward to learning more about the drug’s clinical benefit from the ongoing confirmatory clinical trial.”

Hypersensitivity reactions, including rash, pyrexia, pruritis, urticaria, dermatitis, and skin exfoliation have occurred in participants who were treated with golodirsen. Renal toxicity was not seen in humans in clinical trials, but was observed in animal studies. With other ASO therapies, renal toxicity, including potentially fatal glomerulonephritis, has been observed after administration. The most common adverse reactions that occurred in at least 20% of participants treated with golodirsen and more frequently than with placebo were headache (41%), pyrexia (41%), fall (29%), abdominal pain (27%), nasopharyngitis (27%), cough (27%), vomiting (27%), and nausea (20%). 

Golodersin was evaluated in a 2-part clinical study. In the first part 8 participants received golodersin and 4 received placebo. In the second part all 12 initial participants and 13 additional participants received the ASO treatment on an open-label basis. Treatment with golodirsen resulted in increased mean dystrophin levels from 0.10% of normal at baseline to 1.02% of normal after 48 or more weeks of treatment.