TARGETED THERAPY FOR RA?

Syk Kinase Inhibitor Rapidly Reduces Disease Activity in RA

NEW YORK (Reuters Health) Oct 28 - A new class of oral drugs for treatment of rheumatoid arthritis -- Syk kinase inhibitors -- produces a rapid reduction in disease activity, according to results of a phase II trial presented Monday at the American College of Rheumatology Annual Scientific Meeting in San Francisco.

"Clinical effect was noted as early as week 1" in patients with active disease while taking methotrexate, the investigators report, and up to half of patients treated at the highest dose were in remission after 3 months of treatment.

"Syk kinase, an intracellular protein that functions as a key mediator of Fc-gamma and B cell signaling, is thought to be an essential player in activation of immune cells," presenter Dr. Michael E. Weinblatt told Reuters Health. "It has been detected in rheumatoid synovial lining cells, and in an animal model of inflammatory arthritis, an inhibitor of Syk kinase suppressed arthritis activity."

The Treatment of Arthritis with Syk Kinase Inhibition (TASKI-1) trial included 189 patients randomly assigned to the investigational drug R788 (Rigel Pharmaceuticals) at doses of 50, 100, or 150 mg, all twice daily, or placebo.

The two highest doses were associated with significantly superior response compared to placebo, reported Dr. Weinblatt, who is with Brigham and Women's Hospital in Boston. The ACR 20 response rates at 12 weeks in the 100 mg bid and the 150 mg bid groups were 65% and 72%, respectively, compared with 32% in the 50 mg bid group and 38% with placebo.

Corresponding rates of ACR 70 response were 33%, 40%, 2% and 4%, respectively.

Furthermore, one third of patients on 100 mg twice daily and half of those taking 150 mg twice daily achieved remission, whereas no more than one in five in the other two groups did so.

The major adverse effects were dose-related and reversible and included diarrhea and neutropenia.

"The rapid onset of effect, the improvement in arthritis parameters and serum biomarkers show that inhibition of Syk kinase is a viable new target for the treatment of rheumatoid arthritis," the investigators conclude in their abstract.

"Larger phase 2 studies are now in progress to help define the best dose and the longer term response rate and tolerability profile," Dr. Weinblatt added.