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Comment by Chad Studebaker on September 2, 2011 at 6:29am

http://www.clinicaltrials.gov/ct2/show/NCT01247207?term=ataluren&am...

Comment by Melanie Sunny on April 20, 2010 at 12:43pm

AAN: Details of Failed MD Drug Trial Disclosed

TORONTO -- An academic researcher said here that an investigational drug for muscular dystrophy actually did better in a placebo-controlled phase IIb trial than its manufacturer suggested in a press release last month.

Patients treated with low-dose ataluren (PTC124), an oral small-molecule agent, had a mean improvement of 29 meters in their six-minute walk distance relative to placebo-treated patients, just short of the 30 meters that was the study's primary efficacy endpoint, according to Brenda L.Y. Wong, MD, of Cincinnati Children's Medical Center, one of the site investigators in the trial.

Speaking at the the American Academy of Neurology's annual meeting, Wong also said the difference from placebo was statistically significant by ranked analysis of covariance, though not with the simple analysis of covariance test that had been prespecified.

When ataluren's manufacturer, PTC Therapeutics, announced trial results last month, it said simply that "the primary endpoint of change in six-minute walk distance did not reach statistical significance within the 48-week duration of the study," giving no other details.

Ataluren forces proper translation of the gene for dystrophin when it contains a nonsense mutation. Such mutations account for about 13% of all cases of Duchenne/Becker muscular dystrophy, Wong said. Other types of mutations, such as deletions, account for the majority of cases, although the end result in all cases is lack of normal dystrophin protein.

With nonsense mutations, what normally happens during translation is that the ribosome halts when it reaches the garbled code. Ataluren causes the ribosome to skip over the mutation and continue translating the gene, ceasing as it should when it reaches the stop codon.

The trial randomized 174 patients to placebo or one of two doses of ataluren for 48 weeks. The mean baseline score in six-minute walk distance was about 360 meters.

The low dose consisted of 10 mg/kg in the morning, 10 mg/kg at midday, and 20 mg/kg in the evening. Each of these was doubled in the high-dose group.

An unexpected result was that the high-dose group was no more effective than placebo: both of these groups recorded a 42-meter reduction in six-minute walk distance over the 48-week study.

The low-dose group, however, had a reduction of only 13 meters.

The low-dose regimen was also significantly better (P<0.05) than either placebo or the high dose in the median time to 10% worsening in six-minute walk distance.

Wong said the investigators were now trying to figure out why the high dose was so much less effective than the lower dose. One possibility, she said, was that it affects ribosomal activity too strongly, so that the resulting protein ends up malformed.

Investigators collected muscle biopsies during the study to measure dystrophin levels, but the results had not been analyzed yet, she said.

PTC and its development partner, Genzyme, are also testing the drug in other genetic disorders caused by nonsense mutations, including cystic fibrosis and hemophilia A and B.

Comment by ferre on April 19, 2010 at 5:24pm

for the moment we have no result of the biopsy

best

françoise

Comment by BeritSofie on April 19, 2010 at 5:17pm

Hi
Our 10 year old boy was not in the trial, but he has a stop codon mutation.
We tried to enroll him into the trial, but unfortunately we were too late.

Yes, I saw this too !!!! 1 yard !!!! Like any other parents who has a child with this mutation, I am very suprised/angry/disapointed......They cannot give up on this drug for our boys. Heard anything about the biopsies taken during the trial ?

Comment by ferre on April 19, 2010 at 4:53pm

hi

as parent of a kid on ataluren trial, I'm very surprised to see that the difference between the target and the results on the low dose were only 1 yard on the 6MW! is it a good reason to give up? I asked the details of the sample and the calculation of the statistic level of confidence because I am afraid the real reason is a disagreement between the different partners of the company.