Anacor Pharmaceuticals, Inc (PALO ALTO, California), a biopharmaceutical company developing small molecule therapeutics derived from its boron chemistry platform, announced positive results from a phase IIa clinical trial of AN2728, a boron-containing inhibitor of phosphodiesterase-4 (PDE4), in patients with psoriasis. The study met its primary and all secondary endpoints.
    
Using ultrasound, researchers measured the thickness of the inflammatory infiltrate in the psoriatic plaques and also recorded the clinical response based on an investigator global evaluation of disease severity. In 69% of patients, the area treated with AN2728 scored better at the end of therapy than the area treated with the vehicle ointment, compared with 6% of patients in whom the vehicle-treated areas were superior. These results were statistically significant (P <.001). In addition, plaques treated with AN2728 continued to improve over the 28 days of therapy. No drug-related safety issues were reported.

The randomized, double-blind, placebo-controlled trial was designed to evaluate the safety and efficacy of AN2728 ointment 5% concentration as a patient-administered application. The study took advantage of the bilateral characteristic of psoriasis, in which 35 patients were treated twice a day for 4 weeks on one area of psoriasis with AN2728 ointment and on a matching area with vehicle. Anacor intends to start a third phase Ib microplaque trial to assess safety and clinical potency of a cream formulation in 2008, and is planning additional preclinical toxicity studies to assess dermal and systemic safety and tolerability.

Two phase Ib dose-ranging trials have investigated the effects of concentration and formulation on drug efficacy. These earlier trials demonstrated significant activity even at a 0.5% concentration of AN2728, the lowest concentration tested. In 2007, Anacor completed a phase Ib microplaque clinical trial in Germany for AN2728 in patients with psoriasis. The 12-day study enrolled 12 patients who each had their psoriatic lesions divided into 6 test areas to which one of the following was applied: AN2728 ointment 5%, AN2728 cream 5%, commercially-available psoriasis therapies betamethasone (Betnesol-V) and tacrolimus (Protopic), vehicle cream and vehicle ointment. Evaluations of the sections were made at days 1, 8, and 12. The primary endpoint of the study was the change in thickness of the psoriatic lesion as measured by sonography; the secondary endpoint was improvement based on clinical score as evaluated by a physician. The study demonstrated that AN2728 caused a significant reduction in the thickness of psoriatic lesions compared with vehicle (P = .025). The mean percentage reduction in infiltrate thickness for AN2728 was 54%, compared with 48% for Protopic ointment and 72% for Betnesol-V cream. Secondary endpoint results of the clinical assessments paralleled primary endpoint results of the sonographic assessments.

In December 2007, Anacor completed a second phase Ib clinical trial for AN2728 in psoriasis  patients. That study differed from the first in that it was a dose-ranging study designed to compare AN2728 ointment with the vehicle ointment. While the final study report is not yet available, top line results are. Based on the primary endpoint, which was the change in the thickness of the inflammatory infiltrate, all 3 concentrations were significantly better than the ointment vehicle (P <.003). The mean percentage reductions for 0.5%, 2%, and 5% AN2728 ointment were 36%, 35%, and 26% respectively. The percentage reductions for the positive controls were 59% and 34% for betamethasone and Protopic, respectively. The final study report will be available in the first half of 2008. No treatment-related adverse events were observed in either trial.

In the first half of 2008, Anacor intends to start a third phase Ib microplaque trial to assess safety and clinical potency of a cream formulation, and is planning additional preclinical toxicity studies to assess dermal and systemic safety and tolerability.

PDE4 is critical to the production of TNF-α and other pro-inflammatory cytokines, and AN2728 inhibits the release of TNF- α, IL-12 and -23. If approved, AN2728 would be the first topical nonsteroidal treatment that inhibits TNF- α release.