FDA Rejects Biomarin NDA for Kyndrisa

FDA has issued BioMarin Pharmaceutical Inc. a complete response letter on its NDA for Kyndrisa (drisapersen) for treating Duchenne muscular dystrophy (DMD) amenable to exon 51 skipping. The letter told that company that the agency has concluded that the standard of substantial evidence for the drug’s effectiveness has not been met. BioMarin says it is reviewing the letter and will work with FDA to determine the appropriate next steps for the NDA.

In November, almost all members of FDA’s Peripheral and Central Nervous System Drugs Advisory Committee said that the lack of statistical significance of efficacy in a Kyndrisa Phase 3 trial in patients with DMD weakened the already mixed findings from two earlier studies. Panel members were not asked to vote directly on whether to recommend the drug for approval, but rather on the value of the three studies. The vote on questions raised by the Phase 3 study was 15-2.

Although the primary endpoint for the Phase 3 trial was a 30-meter difference in walk test scores at 48 weeks, the company said there was only a 10-meter difference at that time, although the results were significant at 96 weeks. Some panelists noted that parents would be happy to have a 10-meter improvement and said it was possible that the drug could be beneficial to some patients.

Before the advisory committee meeting, FDA medical reviewers had expressed concerns with adverse events, including thrombocytopenia, which occurred in 10% of those taking the drug, compared with 3% on placebo, and renal toxicity in 30% of patients compared with 4% of placebo patients. The reviewers also noted that 79% of patients had significant injection site reactions.

Parents who commented often said that the side effects were manageable, especially in light of the improvement they believe the drug provides.

BioMarin says that the ongoing Kyndrisa extension studies will continue, as will the ongoing clinical trials for other exon-skipping oligonucleotides, BMN 044, BMN 045 and BMN 053, while BioMarin is exploring its next steps. Patients currently receiving Kyndrisa, BMN 044, BMN 045 and BMN 053 will remain on therapy.

Kyndrisa is an antisense oligonucleotide that induces exon skipping to provide a molecular patch for dystrophin transcripts produced by certain mutated dystrophin genes, according to the company. “Exons are the parts of a gene that contain the instructions for generating a protein,” it says. “In applicable cases, skipping an exon near the mutation allows for the production of a truncated but functional dystrophin protein.”