It's been widely accepted that the mechanism by which the experimental drug ataluren appears to benefit walking ability in Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) is that it causes "read-through" of premature stop codons — genetic instructions that cause cells to stop making a protein before the process is complete.
When these premature stop codons — also called nonsense mutations — occur in the dystrophin gene, they cause short, nonfunctional dystrophin protein molecules to be made in muscle fibers, ultimately leading to the muscle degeneration associated with DMD and BMD. Nonsense mutations are believed to cause DMD/BMD in about 13 percent of patients with these disorders. (The remainder of cases are caused by other types of dystrophin gene mutations.)
Ataluren (formerly called PTC124), in development by PTC Therapeutics with early support from MDA, was designed to coax muscle cells to read through (ignore) premature stop codons in the dystrophin gene and to lead to production of functional dystrophin protein.
Now, the authors of a paper in PLoS Biology (published free online) say they have evidence that the mechanism by which ataluren appears to slow the decline of walking ability in DMD or BMD is not stop codon read-through.
The authors do not dispute the results of a phase 2b trial of the drug that showed boys and young men who received it at a particular dose for almost a year did better on a six-minute walk test than those who received a different dose or a placebo.
But Stuart McElroy from the University of Dundee in Scotland, and colleagues, who published their findings online June 25, 2013, in PLoS Biology, say the PTC investigators misinterpreted laboratory tests that show ataluren caused stop codon read-through in the dystrophin gene.
McElroy and colleagues tested the ability of ataluren to read through premature stop codons in a variety of tests in cells. They found that in one test — one widely used to support the drug's efficacy in cells — ataluren caused an increase in the activity of the gene for luciferase, as others have reported, but that it did not do so by stop codon read-through.
These investigators say that when they used ataluren to treat cells containing a normal (without a premature stop codon) luciferase gene, they saw the same increase in luciferase protein levels as they did when a premature stop codon was present. They interpreted this to mean that ataluren may have stabilized the luciferase protein rather than causing read-through of a stop codon in the luciferase gene.
Elizabeth Devitt, writing in the biomedical blog Spoonful of Medicine June 25, 2013, reported on the PLoS Biology paper's findings, but she also noted that, in contrast to the PLoS paper, other independent scientists have "confirmed the efficacy of the drug in read-through experiments."
Jane Larkindale, vice president of research at MDA, said that she is among those who believe the evidence showing that ataluren treatment results in increased dystrophin levels. (Several years ago, MDA sponsored research that demonstrated ataluren's ability to increase dystrophin levels in mice with a premature stop codon in the dystrophin gene and a DMD-like disorder.)
Larkindale added that, while it may be ideal to know exactly how a drug works, the U.S. Food and Drug Administration and other regulatory agencies are more interested in whether the drug works and whether it's safe.
"Prednisone is the current standard of care drug for Duchenne muscular dystrophy and we don't actually know how that works," Larkindale noted.
So far, ataluren has shown safety and some efficacy in a phase 2 trial and is now in a confirmatory phase 3 trial that is open to new participants who meet study criteria.
PTC has defended ataluren's mechanism of action, recently stating, "Numerous independent laboratories have provided confirmation of our results, demonstrating ataluren's read-through activity in studies using reporters as well as multiple animal and cell-based nonsense mutation disease models."