RESEARCH - Treatment of RA with a Syk kinase inhibitor

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Arthritis Rheum. 2008 Oct 30;58(11):3309-3318.

Treatment of rheumatoid arthritis with a syk kinase inhibitor: A

twelve-week, randomized, placebo-controlled trial.

Weinblatt ME, Kavanaugh A, Burgos-Vargas R, Dikranian AH,

Medrano- G, Morales- JL, FT, Musser TK, Straniero

N, Vicente- AV, Grossbard E.

Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

OBJECTIVE: Spleen tyrosine kinase (Syk) has been identified as an

important modulator of immune signaling in B cells and cells bearing

Fcgamma-activating receptors. R788, a prodrug of active metabolite

R406, has been shown to be an inhibitor of Syk kinase, active in a

variety of in vitro and in vivo models, suggesting potential activity

in the treatment of rheumatoid arthritis (RA).

METHODS: We enrolled 189 patients with active RA despite methotrexate

therapy in a 3-month, multicenter, ascending-dose, double-blind,

placebo-controlled trial. The primary end point was the American

College of Rheumatology 20% improvement criteria (ACR20) response rate

at week 12.

RESULTS: Twice-daily oral doses of 100 mg and 150 mg of R788 were

significantly superior to placebo or twice-daily oral doses of 50 mg

at week 12 (ACR20 achieved in 65% and 72% versus 38% and 32% of

patients, respectively [P < 0.01]). ACR50 (achieved in 49% and 57%

versus 19% and 17% of patients, respectively) and ACR70 (achieved in

33% and 40% versus 4% and 2% of patients, respectively) scores showed

a similar pattern. Clinical effect was noted as early as 1 week after

initiation of therapy. Reductions in serum interleukin-6 and matrix

metalloproteinase 3 levels also occurred as early as week 1 in the

groups receiving 100 mg and 150 mg R788. The major adverse effects

were gastrointestinal side effects (predominantly diarrhea) and

neutropenia (<1,500/mm(3)), both of which were dose related.

CONCLUSION: These results indicate that an inhibitor of Syk kinase

produces significant clinical benefits at 12 weeks in a population of

patients with active RA receiving methotrexate therapy. Syk kinase may

be an important new therapeutic target in RA and related autoimmune

conditions.

PMID: 18975322

http://www.ncbi.nlm.nih.gov/pubmed/18975322

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