BioCryst Pharmaceuticals, Inc (BIRMINGHAM, Alabama), an integrated biopharmaceutical company using crystallography and structure-based drug design to develop therapeutics, announced results from the completed phase IIa trial of BCX-4208, an orally available small molecule inhibitor of purine nucleoside phosphorylase (PNP), in patients with moderate-to-severe plaque psoriasis. Consistent with interim findings reported in May 2008, the study of BCX-4208 met its primary objectives of safety and tolerability but it failed to demonstrate evidence of clinical efficacy, a secondary objective. BCX-4208 is a potent, rationally-designed, inhibitor of PNP—a purine salvage pathway enzyme that is essential for the proliferation of activated T-cells.

The trial was randomized, double-blind, placebo-controlled, dose-ranging and enrolled 66 patients with moderate-to-severe plaque psoriasis. The agent was administered once a day for 6 weeks at 20 mg or 120 mg. Patients were monitored for at least 4 weeks following treatment.

BCX-4208 was generally safe and well tolerated at doses up to 120 mg daily. Most adverse events reported were considered mild or moderate, and low in frequency; no opportunistic infections were observed. Detailed laboratory and clinical monitoring did not indicate any patterns suggestive of off-target adverse findings, and the agent displayed dose-dependent reductions in peripheral blood lymphocyte counts, including subsets measuring B-cells (CD20), total T-cells (CD3), T-helper cells (CD4), and T-suppressor/cytotoxic cells (CD8). Plasma levels of BCX-4208 increased with dose and plasma uric acid levels showed dose-related reductions. No evidence of clinical efficacy was observed in psoriasis patients with the doses and duration of administration tested. In a phase I multiple ascending-dose study, BCX-4208 showed a dose-response effect on reducing lymphocyte counts at doses up to 1040 mg administered once daily for 7 days. According to BioCryst, the pharmacokinetic and pharmacodynamic results suggest that the agent may have utility in diseases dependent on T-cells, B-cells, or uric acid.

Earlier this year, following review of the planned interim analysis of the phase IIa trial, Roche terminated its license agreement for the development of BCX-4208 for autoimmune diseases and transplant. As a result, BioCryst regained worldwide rights to BCX-4208. Roche Pharmaceuticals and BioCryst agreed to complete the phase IIa trial.