DMD/BMD Research: Ataluren Results Disappointing

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The biopharmaceutical firm PTC Therapeutics announced March 3 that ataluren, its experimental drug for certain forms of Duchenne (DMD) and Becker (BMD) muscular dystrophy, although safe and well tolerated, failed to meet its primary end point within the 48-week duration of the phase 2b trial. That end point was an improvement in how far boys with DMD or BMD could walk in six minutes.

PTC Therapeutics, which has received $1.75 million in grant funding from MDA for development of ataluren, has partnered with Genzyme Corp. for development of this compound. The experimental drug, which showed promise in preliminary clinical and preclinical trials, was designed to treat cases of DMD and BMD that are the result of flaws called “nonsense mutations” in the dystrophin gene.

Ataluren allows muscle cells to “read through” these nonsense mutations (also called premature stop codons) and produce functional dystrophin protein, a critical component of muscle, which is lacking or reduced in individuals with DMD and BMD. PTC is continuing its analysis of the effect of ataluren on dystrophin levels in trial participants.

"We're extremely disappointed in this result," said Valerie Cwik, MDA Executive Vice President-Research and Medical Director. "But we expect to learn important information from further analysis of the data and, of course, remain steadfast in our commitment to finding effective treatments for Duchenne and Becker dystrophies."

Cwik said that one of the most important questions “is whether raising dystrophin levels in boys with DMD or BMD will restore or preserve function, and if so, how much dystrophin is needed. When all the data from this well-conducted ataluren trial are fully analyzed, we will learn a great deal, which will inform us as we develop other therapies for these diseases."

Langdon Miller, PTC's chief medical officer, echoed these sentiments, saying, "This trial does provide a wealth of valuable data about ataluren and DBMD [DMD/BMD]. Additional analyses will guide the overall clinical and regulatory path forward."

PTC is developing ataluren for cystic fibrosis and hemophilia as well, and these programs are not affected by the DMD/BMD trial result.

About ataluren (PTC124)

Ataluren is an experimental drug that causes cells, such as muscle cells, to "read through," or ignore, premature stop signals in genes, such as in the dystrophin gene. Such premature stop signals cause cells to stop protein synthesis too early, before a functional protein has been made.

Preliminary results announced in 2007 for ataluren (originally called PTC124) were encouraging. (See Oral Drug Restores Missing Protein in Boys with MD.) In early studies involving 38 boys with DMD who took PTC124 for about a month, there were indications that muscle destruction had lessened, and dystrophin production increased in at least some trial participants.

About the ataluren phase 2b trial

The recently completed phase 2b trial lasted 48 weeks and included 174 participants at 37 sites in North America, Europe, Australia and Israel. Participants, all of whom were still walking, were randomly assigned to receive either a low dose of ataluren, a high dose of ataluren, or a placebo. (See Phase 2b Study of PTC124 in Duchenne/Becker Muscular Dystrophy.)

In addition to the six-minute walk test, which was the primary outcome measure, the investigators evaluated other outcomes, such as participants' activity at home, muscle and heart function, strength, cognitive ability, muscle integrity and dystrophin levels. PTC is currently conducting additional efficacy analyses.

Meaning for people with DMD and BMD

Although the results of this large-scale trial of ataluren were not what the DMD/BMD community had hoped, the knowledge gained from this trial will aid in the design of therapies and future trials.

Development of therapies for DMD/BMD continues. These include:

• gene and cell therapy approaches to replace nonfunctional dystrophin genes with functional dystrophin genes;


• exon skipping, a technology by which cells can create dystrophin protein from a flawed dystrophin gene;


• approaches that could substitute alternate muscle proteins, such as utrophin, for dystrophin; and


• other compounds that target nonsense mutations.

In addition, two cardiac drugs already on the market are being tested in DMD for their ability to protect both heart and skeletal muscle.

Watch the MDA and PTC Therapeutics Web sites for more information as it becomes available.

To read the full PTC press release, click here. 

Editor's note 3/24/10: A study of ataluren in nonambulatory boys with nonsense-mutation DMD or BMD has now been suspended. See Study of Ataluren (PTC1214) in Nonambulatory Patients With Nonsense-Mutation-Mediated Duchenne/Becker Muscular Dystrophy. In addition, a phase 2b extension study of ataluren in boys with nonsense-mutation DMD or BMD for those who had participated in the placebo-controlled phase 2b trial has been terminated. See Phase 2b Extension Study of Ataluren (PTC124) in Ducnenne/Becker Muscular Dystrophy.