Low-Dose Ataluren Shows Some Benefit in DMD/BMD

A new analysis of a trial of ataluren in Duchenne and Becker muscular dystrophies due to nonsense mutations shows a low dose may slow decline in walking ability

A low-dose regimen of ataluren (formerly called PTC124), an experimental drug developed by PTC Therapeutics to treat Duchenne muscular dystrophy (DMD) or Becker muscular dystrophy (BMD) caused by a certain type of genetic mutation, is superior to a high-dose regimen or a placebo.

PTC announced the findings at the 15th International Congress of the World Muscle Society, held in Kumamoto, Japan, Oct. 12-16, 2010, and in an Oct. 15 press release. (See Pivotal Data Presented at the World Muscle Society Congress Suggest Ataluren Slows the Loss of Walking Ability in Patients with Nonsense Mutation Duchenne/Becker Muscular Dystrophy.)

Those who took the lower dose of ataluren showed a slower decline in walking ability over the course of nearly a year than those in the high-dose or placebo groups.

The new announcement confirms findings released by PTC in April 2010, at a meeting of the American Academy of Neurology in Toronto.

In March 2010, a preliminary analysis of the results of this 174-person, phase 2b trial of ataluren in people with DMD or BMD with certain genetic mutations revealed only that there did not seem to be a benefit for this drug. 

About ataluren

Ataluren is designed to coax muscle fibers to "read through" (ignore) a premature stop codon, also known as a nonsense mutation, in the gene for the muscle protein known as dystrophin.

The goal of treatment with ataluren is for the fibers to produce functional dystrophin, the protein missing in people with DMD and deficient in those with BMD.

Nonsense mutations are responsible for dystrophin deficiency in some 5 percent to 15 percent of the DMD/BMD population.

PTC received $1.75 million in grant funding from MDA for development of ataluren, although MDA did not fund the Phase 2b trial. PTC is collaborating with the biopharmaceutical firm Genzyme for the development of ataluren.

About the new findings

The so-called six-minute walk test was the primary outcome measure for this 174-person, 48-week trial. At the end of the trial, all participants had lost some walking ability, as measured by the distance they could cover in six minutes.

However, after about a year, those in the low-dose ataluren group were able to walk an average of 29.7 meters (about 97 feet) further than those in the placebo group. The high-dose group, by contrast, walked on average the same distance in six minutes as the placebo group.

Participants were ambulatory males who were at least 5 years old. Thirty-seven trial sites in North America, Europe, Australia and Israel were part of this study.

The low-dose group received oral ataluren at 10 milligrams per kilogram of body weight each morning and at midday and 20 milligrams per kilogram in the evening. The high-dose group received 20 milligrams per kilogram in the morning and at midday and 40 milligrams per kilogram in the evening. The placebo group received a look-alike, inert substance.

The six-minute walk test was the primary outcome measure, but other outcomes were also assessed, including safety, muscle function and strength, and muscle dystrophin levels.

Ataluren was generally well tolerated, and adverse events were similar across all treatment groups. Serious adverse events were infrequent, and none were considered related to the drug.

The trial results suggested "positive trends" in muscle function, as measured by timed function tests, in those receiving the low-dose regimen of ataluren compared to those receiving a placebo, PTC said.

PTC said dystrophin protein expression could not be properly assessed, in part because of technical limitations. The company said no relationship could be established between dystrophin levels and distance covered in the six-minute walk test.

Meaning for people with DMD

The guardedly positive results from this phase 2b trial of ataluren make it more likely than it first appeared that PTC and Genzyme will continue to develop this drug for those with nonsense-mutated-related DMD or BMD.

MDA will continue to monitor ataluren's progression through the regulatory process.