The US Food Food and Drug Administration (FDA) has issued a Complete Response letter addressing the New Drug Application (NDA) for drisapersen (Kyndrisa; BioMarin Pharmaceutical Inc) for the treatment of Duchenne muscular dystrophy (DMD), the company has announced.
The FDA issues such letters to indicate that the review cycle for an application is complete and that the application is not ready for approval in its present form. The FDA concluded that the standard of substantial evidence of effectiveness has not been met.
Kyndrisa is an antisense oligonucleotide that induces exon skipping to provide a molecular patch for dystrophin transcripts produced by certain mutated dystrophin genes. Exons are the parts of a gene that contain the instructions for generating a protein. In applicable cases, skipping an exon near the mutation allows for the production of a truncated but functional dystrophin protein.
No Clear Evidence
In a press release, BioMarin said it is reviewing the Complete Response Letter and will work with the FDA to determine the appropriate next steps regarding this application.
The FDA's letter follows a meeting of its Peripheral and Central Nervous System (PCNS) Drugs Advisory Committee in November 2015, at which members discussed several pitfalls with studies of drisapersen to date.
Many committee members agreed that the research doesn't clearly provide substantial evidence of the drug's effectiveness or that the drug has an acceptable risk-benefit profile. One issue is whether drisapersen increases dystrophin levels; in biomarker studies using Western blot, post-treatment dystrophin levels remained very similar to pretreatment levels — about one third of 1% or normal — according to FDA background materials provided for the meeting.
And although some biomarker studies showed a decrease in creatine kinase and lactate dehydrogenase, it's possible these effects might be due to factors unrelated to benefits to patients with DMD, such as decreased physical activity.
DMD is caused by a genetic error in messenger RNA splicing in which an exon is "skipped." Patients with DMD experience loss of muscle fibers and muscle strength and a rapidly progressive degeneration of skeletal and cardiac muscle. Respiratory or cardiac failure is the main cause of death, often before age 30 years.
DMD affects approximately 1 in every 3500 to 5000 male children, making it the most common fatal genetic disorder diagnosed in childhood. There is currently no FDA-approved therapy to treat the disorder.
According to the company, its ongoing drisapersen extension studies will continue, as will the ongoing clinical trials for other exon-skipping oligonucleotides, while it explores next steps for this application. Patients currently receiving drisapersen and the other products will remain on therapy.
BioMarin said it anticipates that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) will provide an opinion for the company's Marketing Authorization Application (MAA) for drisapersen in the first half of 2016.
If the CHMP opinion is positive, the MAA will be referred to the European Commission (EC). If the application is approved by the EC, BioMarin would receive marketing authorization for their product in all EU member states. The EC is expected to render a final decision for drisapersen in the second half of 2016.
In a statement, Muscular Dystrophy Association Vice President and Chief Medical and Scientific Officer Valerie Cwik, MD, commented on this disappointing development.
"Our families urgently need safe and effective treatments, and although this is not the outcome so many had hoped for, we know that the FDA exercised its due diligence in considering drisapersen," Dr Cwik writes.
"We commend the remarkable strength of our community and we are proud to have worked together to reach a point where experimental therapies like drisapersen are moving through the regulatory review process. As our community moves forward, we will continue to fund critical scientific research, facilitate clinical trial participation, and advocate for policies that help ensure that the drug development and regulatory review processes move as quickly and effectively as possible," she adds.
"With more treatments staged to begin their review process in 2016, we remain optimistic that many of those living with DMD today will have safe and effective therapy options in the very near future."
An application for another similar drug for DMD, eteplirsen (Exondys 51, Sarepta Therapeutics) goes before the FDA's PCNS advisory panel on January 22.
The FDA released its briefing document for the panel on January 15, and the tone appears to reflect similar doubts about the evidence, as was seen with drisapersen.
"Based on the data submitted by the applicant, considerable doubt remains about how much, or perhaps even whether, dystrophin levels were increased by eteplirsen," the document notes.
"The data, overall, did not provide statistical evidence to support the efficacy of eteplirsen in patients who have a confirmed mutation of the DMD gene that is amenable to exon 51 skipping."
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Cite this: FDA Declines Approval for Drisapersen in DMD - Medscape - Jan 18, 2016.