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Duchenne muscular dystrophy drugs at the crossroads, as newer agents advance

Nature Biotechnology volume 34, pages 675–676 (2016)Cite this article

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A Correction to this article was published on 08 November 2016

This article has been updated

As Nature Biotechnology went to press, the FDA had yet to update the deadline for its verdict on eteplirsen, having delayed a decision originally due on May 26. In the meantime, it sought additional biopsy data from an ongoing phase 3 trial, suggesting that its deliberations have extended beyond the evidence aired during a recent hearing of the FDA's Peripheral and Central Nervous System Drugs Advisory Committee, which voted against eteplirsen's approval. Whatever the outcome, Sarepta and other early movers have at least managed to establish the ground rules for tackling the root cause of DMD, an X-linked condition caused by mutations in the large muscle protein dystrophin (Table 1). The problem at this stage in the field's development is that companies' claims made in support of their drugs are ambiguous. “The efficacy is marginal. They're just not potent enough,” says Matthew Wood, professor of neuroscience at Oxford University, UK. The same applies to PTC Therapeutics, of South Plainfield, New Jersey, whose drug Translarna (ataluren) acts through a different though related mechanism—it promotes translational read-through of premature stop codons in dystrophin mRNA. The FDA refused to review its application, whereas the drug obtained conditional approval in Europe following an appeal (Nat. Biotechnol. 32, 706, 2014).

Table 1 Disease-modifying therapies for Duchenne muscular dystrophy
Full size table

Although the current generation of disease-modifying drugs in DMD has polarized observers, the prospect of an effective therapy in DMD is becoming more realistic, as next-generation approaches, including newer exon-skipping drugs and gene therapy start to reach the clinic. The focus is on boosting—or, in the case of Summit Therapeutics, bypassing—dystrophin, a large, rod-shaped protein, which plays an important role in skeletal muscle contraction. It acts as a mechanical link between the cytoskeleton and the extracellular matrix: its C terminus binds the dystrophin-associated protein complex at the muscle cell membrane or sarcolemma; its N terminus binds the cytoskeleton through actin filaments (Nat. Rev. Mol. Cell Biol. 7, 762–773, 2006). In DMD, dytrophin's absence leads to progressive muscle weakening and wasting. Most patients lose the ability to walk by about 12 years, and they also experience respiratory difficulties, curvature of the spine and cardiomyopathy. Respiratory support, steroids and cardiovascular drugs have improved average life expectancy, but it is still less than 30 years. Death usually results from cardiac or respiratory failure.

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  • 13 September 2016

    In the version of this article initially published, on page 676, the top of column 3, the article states that Wave Life Sciences hopes to file its first two IND filings this year; it should have said that the application in Huntington's will be filed this year and the one for DMD in 2017. The error has been corrected in the HTML and PDF versions of the article.

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    Cormac Sheridan

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Sheridan, C. Duchenne muscular dystrophy drugs at the crossroads, as newer agents advance. Nat Biotechnol 34, 675–676 (2016). https://doi.org/10.1038/nbt0716-675

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