PNP inhibitors in trials for T-cell-related diseases

San Diego, Calif. — Studies are under way evaluating purine nucleoside phosphorylase (PNP) inhibitors as a novel treatment for T-cell related skin diseases.

The PNP inhibitors are being developed by BioCryst Pharmaceuticals, Birmingham, Ala., and are small molecules that cause selective killing of activated T-cells.

"Some of our CTCL patients began to clear immediately while receiving the first course of treatment in the hospital, and so far the drug has been nontoxic. Therefore, forodesine HCl has shown promise in these very early studies. However, only further investigations will allow us to characterize the true clinical value of the PNP inhibitors," she says.

Further development Since forodesine has good oral bioavailability, it has been developed into an oral formulation that is now being evaluated in a phase 1 study enrolling patients with IB or greater-stage CTCL.

A second-generation compound known as BCX-4208 is even more potent and is being developed as an oral treatment for psoriasis and other T-cell mediated autoimmune diseases. It entered a phase 1 pharmacokinetic and safety study in healthy volunteers in November. Pending the results, the company plans to next undertake a multidose phase 1 trial in healthy subjects, and if the outcomes continue to be favorable, it will conduct a phase 2 open-label study in psoriasis patients.

"We are very excited about this class of drugs, which, because of their unique mechanism of action, may offer a safe and effective alternative for the treatment of CTCL (and) psoriasis, as well as a number of other diseases," says J. Claude Bennett, M.D., president, chief operating officer and medical director, BioCryst. "However, the potential for these compounds to provide an oral therapeutic option is one of their most exciting features considering that oral therapies are highly desirable for patients with CTCL whose skin is often very fragile, painful, and prone to infections, while recent breakthroughs in biologicals for psoriasis must be given via a parenteral route," he says.

Novel mechanism The experiment of nature referred to by Dr. Duvic was the discovery about 25 years ago of an inherited PNP deficiency in some children who had a profound, selective impairment of T-cell function or selective depletion of T-cells.

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