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Muscular Dystrophy Drug Drisapersen on Path to Accelerated Approval

FDA outlines confirmatory trials

The FDA has outlined an accelerated approval pathway for drisapersen, a targeted RNA therapy, for the potential treatment of patients with Duchenne muscular dystrophy (DMD).

Following this positive feedback, the product’s developer (Prosensa Holding N.V.) has confirmed that it will pursue a new drug application (NDA) filing for drisapersen with the FDA under an accelerated approval pathway based on existing data. The company plans to submit a file later this year and will commit to the initiation of two confirmatory post-approval studies.

The FDA has outlined suggested approaches for the confirmatory trials. In its guidance letter, the agency stated: “A historically controlled trial might be acceptable to confirm clinical benefit following accelerated approval. We note that a historically controlled study is likely to provide interpretable evidence of efficacy only if the beneficial effect of drisapersen is large, by clearly showing that performance is better in drisapersen-treated subjects than could be reasonably expected, based on knowledge of the natural history of the disease. The effect size would have to be sufficient to overcome the uncertainty inherent in historically controlled trials, and motivational factors that can affect the results.”

The agency also said: “A randomized, placebo-controlled trial of another exon-skipping drug with a similar mechanism of action, directed at a different exon (e.g., PRO044 or PRO045), with demonstration of a correlation between dystrophin protein production and definitive clinical benefit on 6-minute walk or another measure, could provide confirmatory evidence of drisapersen’s clinical benefit if approval were based on a surrogate endpoint.”

In the third quarter of 2014, in conjunction with the start of confirmatory post-approval studies of drisapersen, Prosensa will re-dose an initial cohort of boys who had previously participated in clinical trials of the drug. Based on the FDA's guidance, one option is to enroll previously treated patients in these confirmatory studies. Moreover, an onging natural history study by Prosensa, which has enrolled 250 patients, may serve as an historical control.

Drisapersen (previously known as GSK2402968/PRO051) is a targeted RNA therapy based on exon-skipping technology. It is designed for patients with dystrophin gene mutations that are amenable to an exon 51 skip (up to 13% of boys with DMD).

Drisapersen has “orphan drug” status in the U.S. In June 2013, the drug was also granted a “breakthrough therapy” designation, based on results from a phase II trial (DEMAND II) conducted in 2013.

The clinical program for drisapersen comprises three double-blind, placebo-controlled studies (DEMAND II, DEMAND III, and DEMAND IV) and two long-term open-label extension trials (DMD114673 and DEMAND IV).

DMD is a severely debilitating childhood neuromuscular disease that affects up to 1 in 3,500 live male births. The rare disease is caused by mutations in the dystrophin gene, resulting in the absence of or a defect in the dystrophin protein. Patients experience progressive loss of muscle function, often making them wheelchair bound before the age of 12. Respiratory and cardiac muscles can also be affected by the disease. Few patients survive to the age of 30.

Source: Prosensa; June 3, 2014.

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