On 12 December, the Food and Drug Administration (FDA) granted accelerated approval to Sarepta Therapeutics’ Vyondys 53 (golodirsen, an exon-53 skipping therapy) to treat patients with a rare disease, Duchenne muscular dystrophy (DMD). 

This decision came as a surprise because in August 2019, Vyondys 53 was met with a complete response letter from the Office of Drug Evaluation. Sarepta made a formal dispute resolution request addressing the challenges and issues that were present in the complete response letter, which was settled with the support of the Office of New Drugs (OND). The OND granted the company’s appeal and Sarepta eventually resubmitted its results, which led to the approval of Vyondys 53. 

Sarepta’s Vyondys 53 was rejected previously as the FDA was concerned over two safety issues: the risk of infection at intravenous infusion ports, and renal toxicity seen in pre-clinical studies. The latter is a common issue for this class of drugs, including Sarepta’s Exondys 51 (eteplirsen), which was approved by the FDA in September 2016. However, the doses used in pre-clinical studies were ten-fold higher than doses used in Vyondys 53’s Phase I/II study, which were used in the FDA submission. There were no signs of renal toxicity in this trial and most adverse events were consistent with what would be expected in a pediatric Duchenne population. Furthermore, in the Phase I/II study, Vyondys 53 was effective in all 39 patients enrolled, mean skipping increased from 2.59% at baseline to 18.95% at week 48, which equated to a 16-fold increase in dystrophin per patient, on average.

Following its approval, Vyondys 53 will be accessible to almost 8% of patients with DMD who have established clinical diagnosis of DMD amenable to exon 53 skipping therapy. However, approval is conditional, requiring confirmatory trials and Sarepta is currently conducting a placebo-controlled Phase III trial which will evaluate the efficacy and safety of Vyondys 53 and casimersen (an exon 45 skipping therapy) in 222 patients. 

To Sarepta’s advantage, reversing a rejection with this speed is highly unusual. The company’s previously approved exon skipping therapy, Exondys 51, also sparked controversy. Many officials were in favour of its rejection; however, a senior official overruled the decision and approved the drug, making it the first medicine approved for the treatment of DMD. Furthermore, patient advocacy groups in DMD have a strong influence on policymaking. CureDuchenne played a significant role in Exondys 51’s approval through KOLs, physicians, parents, and regulators, who gave patients a voice and informed decision-makers regarding the need for Exondys 51. Prior work from lobbyists could have influenced the FDA decision regarding the follow-on product, Vyondys 53, and thus avoided a second controversy. 

An improved approval process for follow-on exon-skipping molecules that use the same technology could allow for an expansion of their target patient population within a short period. In addition to the 12.0% of patients targeted by exon-51 and exon-53 skipping, Sarepta has five pipeline drugs and eight drugs in pre-clinical development, so the company could potentially target a large range of patients with amenable mutations for exon-skipping therapy, using the same technology as the first two approved drugs. Overall, a swift approval process is conducive to the development of additional novel therapies for DMD patients who have yet to see promising treatment options.

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Related Reports

GlobalData (2018). Duchenne Muscular Dystrophy (DMD): Competitive Landscape to 2026, January 2018, GDHC001CL

GlobalData (2019). Duchenne Muscular Dystrophy (DMD): Opportunity Analysis and Forecasts to 2029, to be published