In this week's early online edition of the Proceedings of the National Academy of Sciences, researchers from South Plainfield, N.J.-based PTC Therapeutics Inc and colleagues from the University of Alabama at Birmingham reported preclinical findings on PTC124's activity in a mouse model of cystic fibrosis.

The paper follows a publication in Nature last year showing the compound's effectiveness in a mouse model of muscular dystrophy. Nature's editors named the 2007 paper as one of their top picks for the year. (See BioWorld Today, April 24, 2007.)

Cystic fibrosis is a comparatively rare disease, and only 10 percent of cystic fibrosis cases are due to nonsense mutations. PTC124 has received orphan drug designation for the treatment of cystic fibrosis, as well as Duchenne's muscular dystrophy, from both the FDA and the European Commission; the company is in Phase II trials for both indications.

But PTC124 could find a large market because the drug is not aimed at one particular disease. Instead, "you're tweaking the translation machinery that's used to make all the proteins of the cell," PNAS paper senior author David Bedwell, professor of microbiology at the University of Alabama, told BioWorld Today.

PTC Therapeutics' CEO Stuart Peltz told BioWorld Today that "once you get [a compound] approved in one indication, you build on that," and that if PTC124 is approved for several indications the company could enter into discussions with the FDA about how it might achieve a broad label more in line with its mechanism of action. Some antibiotics do have broad labels, as do some oncology drugs.

But for now, it's one indication at a time. PTC124 is in Phase IIa trials for cystic fibrosis, and PTC Therapeutics is in the process of starting a randomized placebo-controlled Phase IIB trial to demonstrate clinical benefit in Duchenne's muscular dystrophy. Peltz said the company also is in the process of deciding on which indication to pursue next.

The compound's broad applicability stems from its mechanism of action. PTC124 interacts with the cellular translation machinery in such a way that it selectively reads through premature stop codons. Bedwell said that the consensus figure in the scientific literature is that roughly 25-30 percent of disease-causing mutations are premature stop codons. Because normal stop codons are not affected by PTC124, truncated proteins can be restored without producing chaos via a plethora of overly long cellular constituents.

There are other drugs that also can restore truncated proteins, notably the antibiotic gentamicin. But Bedwell said that the use of gentamicin is associated with kidney failure and hearing loss - a problem that becomes much more serious with long-term use: "PTC124's advantage appears to be its lack of toxicity."

In their PNAS paper, the researchers used a mouse that has a premature stop codon in the mRNA for its chloride ion channel. That channel is mutated in cystic fibrosis patients. The channel is absent throughout the body, and cystic fibrosis patients can have a wide variety of symptoms. The scientists administered PTC124 either per injection or orally, and tested the mice to look for evidence of chloride currents, which would show that the channels are working.

They found that chloride currents in intestinal cells of mutant mice treated with PTC124 were a quarter to a third of those seen in normal mice. The effects of PTC124 were similar in magnitude to those of gentamicin. Bedwell said "the real gold standard in CF is to show that you can prevent the slow decline of lung function."

It is usually the lungs that give cystic fibrosis patients the most trouble. The movement of chloride ions in airway epithelial cells is blocked by the defective channel, and so the mucus coating the lungs cannot be kept moist by normal processes. As a result, the lungs are susceptible to bacterial infections. The average life expectancy for cystic fibrosis sufferers has improved greatly over the past few decades, but remains less than 40 years.

But, Bedwell added, estimates in the scientific literature on the degree of channel restoration that's necessary to have a clinical effect range from 5 percent to 30 percent, "So we're in the right ballpark."