DMD Exon Skipping Therapy Not Ready for Approval, FDA Says

BioMarin Pharmaceutical, Inc., announced that a Complete Response letter has been issued by the U.S. Food and Drug Administration (FDA) to the company’s New Drug Application (NDA) for Kyndrisa (drisapersen) for the treatment of Duchenne muscular dystrophy (DMD) amenable to exon 51 skipping.

Complete Response Letters are issued to confirm that the review cycle for an application is complete and that the application is not ready for approval in its present form. The agency has concluded that the standard applied for new drug approval, that of  substantial evidence of effectiveness, has not been met. The company will review the Complete Response letter and work with the FDA to establish appropriate further steps regarding its application, BioMarin said in a press release.

DMD is an x-linked genetic disorder affecting mainly males that gradually worsens muscle capacity, often leaving patients wheelchair dependent by ages 7 to 13. In the disease, a specific gene section called an exon is deleted, which does not allow the rest of the genes to correctly assemble. The dystrophin gene has 79 exons, which all have their specific place. When one exon doesn’t exist, those surrounding it cannot link, and the dystrophin protein fails to work.

Exon skipping is thought to have the potential to treat approximately 83 percent of the genetic errors that cause DMD by encouraging cellular machinery to ‘skip over’ an exon. Small pieces of DNA, called antisense oligonucleotides (AOs), are used to ‘mask’ or replace the exon to be ‘skipped,’ so it can be ignored during protein production. With exon 51 skipping, for instance, exons 50 and 51 are masked, so that exon 49 can join to exon 52 and continue protein production, Muscular Dystrophy UK reports. Kyndrisa is an antisense oligonucleotide designed for this particular process.

Ongoing extension studies into Kyndrisa will continue in parallel with ongoing clinical trials into other exon-skipping oligonucleotides, like BMN 053, BMN 045 and BMN 044, and patients currently enrolled in the trials will continue to receive therapy.

Kyndrisa is currently under regulatory review in the European Union and BioMarin expects that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) will release its review on the company’s Marketing Authorization Application (MAA) for Kyndrisa in the first half of 2016. The application suggests Kyndrisa is a potentially effective treatment for DMD amenable to exon 51 skipping.