Drugs in Clinical Development for Duchenne Muscular Dystrophy: Summary and Table
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Drugs in Clinical Development for Duchenne Muscular Dystrophy: Summary and Table
Ó Springer International Publishing Switzerland 2014
Duchenne muscular dystrophy (DMD) is a rare, genetic, neuromuscular disorder for which there are currently no proven treatments. Mutation in the Duchenne gene exons leads to an absence or defect of the dystrophin protein. The result is progressive loss of muscle function in those with the disorder, beginning in early childhood and often making patients wheelchair bound by the time they reach adolescence. Other muscles, including respiratory and cardiac muscles, can also be affected by the disease and boys with DMD often die before they reach their thirtieth birthday. Currently there are a number of compounds under development to delay progression of the disease (see Table 1), with the first of these gaining conditional approval in the EU this year and another recently filed with the US Food and Drug Administration (FDA). The path to approval for these candidates has been rocky, with regulators seemingly amending their views on the benefit/risk balance for the disease to allow for more rapid drug approval. In the EU, PTC Therapeutics’ has gained conditional approval for ataluren (Translarna), a protein restoration therapy for the treatment of patients with nonsense mutation DMD, after enduring a rejection from European regulators just months earlier. Conditional approval can be granted for medicines that satisfy an unmet medical need. Approval is based on available data that, while not comprehensive, indicate a benefit to patients. The approval must be renewed yearly until such time as sufficient data exist to allow full approval to be granted. Data from ongoing phase III studies are expected in 2015.
Prosensa is developing drisapersen, an antisense oligonucleotide that induces exon skipping of exon 51 and is intended to treat approximately 13 % of all DMD patients who have gene mutations/deletions that are amendable to exon 51 skip. Exon-skipping RNA-based therapeutics correct the genetic mutation by camouflaging the affected exon. These synthetic antisense oligonucleotides skip an exon next to the deletion to correct the reading frame, allowing muscle cells to produce a smaller but functional version of the protein. US regulators have awarded drisapersen breakthrough therapy status. The breakthrough therapy designation was created for medicines deemed likely to demonstrate ‘‘substantial improvement’’ over existing drugs. The designation is distinct from FDA’s other fast-track programmes, such as accelerated approval and priority review, as it involves more intensive guidance from the agency on putting together an efficient drug development programme. Prosense has begun the FDA submission process and fast track review could see the agency give their decision as early as mid-2015. Just one step behind drisapersen is Sarepta Therapeutics’ exon-skipping compound eteplirsen, which is currently in phase III and expected to file in mid- to late-2015. The US FDA has a
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