Despite targeting an indication with a very small population, PTC Therapeutics has fully enrolled a pivotal trial for ataluren (PTC124), its potential disease-modifying therapy for Duchenne muscular dystrophy, and expects to produce top-line data early next year, with regulatory filings in the U.S. and EU following closely if the data are promising.

Privately held PTC discovered ataluren, a small molecule, orally available new molecular entity, while searching for a drug to suppress the nonsense mutation of numerous genetic disorders. In doing so, ataluren could become the first FDA-approved therapy for DMD (¹ Also see "PTC Advances Cystic Fibrosis Candidate On Encouraging Data" - Pink Sheet, 12 June, 2008.).

The South Plainfield, N.J., firm also is investigating the molecule in cystic fibrosis, but believes ataluren could prove applicable to nonsense mutation versions of approximately 2,400 genetic disorders, CEO Stuart Peltz said in an interview. One of the major challenges in advancing the candidate in DMD, however, was determining a primary endpoint to demonstrate efficacy.

"What we needed to do was work with the advocacy groups, the clinical investigators, to coalesce around an endpoint such as the six-minute walk," he explained. "People were doing very good work using many different endpoints, but [we had] to get people to think about how do you get a drug approved, which is [based upon] how a patient functions, feels and survives ... not just from a scientific perspective but a regulatory perspective."

The 6MWT was validated as an endpoint for DMD through work done by researchers at the University of California-Davis (² Also see "Faster Pace For Duchenne MD Research" - Pink Sheet, 2 October, 2008.). Previously, this test has been used to investigate therapies for pulmonary and cardiovascular diseases.

DMD has a very small patient base, including about 1,700 Americans, and has been granted orphan disease status in the U.S. and Europe. PTC has managed to enroll about 8 percent of DMD patients worldwide with the disorder in its trial, which is studying two doses of ataluren versus placebo over a 12-month period. The company says this is the highest proportion of a patient base ever studied in an orphan drug clinical trial.

A second full-year, open-label study in which placebo group patients will switch over to the study drug will follow the initial trial, Peltz said.

Trial involves helping patients get to sites

Including the U.S., the trial is being conducted in 11 countries on four continents, in eight languages, at 38 different sites. In order to enroll patients, PTC has helped some participants move closer to trial sites, and in one case, the firm flies a patient from Argentina to Ohio every six weeks for the two-day treatment cycle.

PTC opted for a full-year treatment duration, rather than six months, to ensure the most robust data set possible, Peltz said. In addition to the 6MWT, patients will be evaluated for several additional endpoints, including step-activity monitoring, heart-rate monitoring during the 6MWT, timed function testing and muscle strength testing.

"It's sort of a quintessential example of personalized medicine - you need to know not only what the disease is, but what the genotype is, the mutation that led to the disease, and only if you have the nonsense mutation is the drug then applicable to you," Peltz said.

Although this is PTC's first pivotal trial, it anticipates bringing ataluren to market for DMD by late 2010 or early 2011, with approval in CF expected to follow by about one year. Peltz said the company plans to initiate the pivotal CF trial "in the upcoming months."

Further indications PTC will seek for the drug likely will include hemophilia and a host of enzyme disorders, he added.

PTC signed a co-development and commercialization deal with orphan-disease focused Genzyme last summer, in which PTC retains U.S. and Canadian rights while Genzyme will market ataluren in the rest of the world. Under the agreement, PTC could realize milestone payments of up to $337 million, plus double-digit royalties on sales in Cambridge, Mass.-based Genzyme's markets (³ Also see "PTC Taps Genzyme’s Global Reach, Pocketbook In Ultra-orphan Licensing Deal" - Pink Sheet, 17 July, 2008.).

The company expects to be able to handle North American commercialization with a relatively small sales force, Peltz explained. The drug has an early advantage in DMD because so many of the opinion leaders already are participating in the trial, he said.

-Joseph Haas (j.haas@elsevier.com)

PTC Fully Enrolls Duchenne MD Trial; Expects Top-Line Data In Early 2010

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