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Oral Syk Kinase Inhibitor Improves Response Rates in RA Patients on Methotrexate: Presented at ACR/ARHP

By Liz Meszaros

PHILADELPHIA -- October 21, 2009 -- When added to methotrexate, R788, an investigational agent, produces significant clinical benefits and an acceptable safety profile in the treatment of patients with active rheumatoid arthritis (RA), according to results from a study presented here at the 2009 Annual Scientific Meeting of the American College of Rheumatology/Association of Rheumatology Health Professionals (ACR/AHRP).

R788 is an oral, relatively selective inhibitor of Syk kinase, which is an important modulator of immune signalling.

"Syk is an intracellular protein tyrosine kinase that serves as a key mediator of Fc and B-cell receptor signalling of inflammatory cells, including mast cells, B cells, macrophages, and neutrophils. Inhibition of Syk reduces expression of IL-6 and MMP-3 genes," lead author Michael Weinblatt, MD, Brigham & Women's Hospital, Boston, Massachusetts, said in his presentation October 20. "Inhibition of the Syk pathways is an attractive target for the treatment of RA. Phase 3 studies are now being planned for this agent."

For this 6-month, randomised, placebo-controlled phase 2b study, 457 patients with active RA (defined as >=6 painful and swollen joints) treated with methotrexate for at least 3 months were randomised to receive a 100-mg BID dose of R788, a 150-mg QD dose, or placebo.

At month 6, ACR20, ACR50, and ACR70 response rates to R788 were significantly superior to placebo, as were DAS remission rates. ACR20 response rates were 66% in the 100-mg BID group and 57% in the 150-mg QD group, compared with 35% in the placebo group. ACR50 response rates were, respectively, 43% and 32%, compared with 19% in the placebo group. ACR70 response rates were 28% and 14%, compared with 10% in placebo. DAS remission rates (DAS <2.6) were 31% in the 100-mg BID group and 21% in the 150-mg QD group, compared with 7% in the placebo group.

Significant improvements were also seen in HAQ-DI, FACIT-fatigue, and SF-36 physical domain scores of both groups receiving R788.

"A full 30% of the 100-mg BID group compared to 18% of the placebo group lowered their HAQ scores below 0.5," noted Dr. Weinblatt.

Diarrhoea was the most common adverse event, and was seen in 19% of the 100-mg BID group versus 3% in placebo. ALT elevations of >3 ULN were seen in 4% of both R788 groups, compared with 2% in the placebo group. Systolic blood pressure at month 6 rose by 0.2 mm and 0.6 mm in the 150-mg QD and 100-mg BID groups, respectively, compared with a drop of 1.8 mm in the placebo group. Increases in blood pressure were most frequently seen in patients with a history of hypertension at baseline.

The onset of clinical effect was rapid, and maximum improvements were achieved by week 6 and maintained throughout the trial, said Dr. Weinblatt.

"A rapid effect of R788 was observed in this trial, and it confirms our observations from 1 year ago that this drug begins to work as early as 1 week after administration. At week 1, 34.7% of patients in the 100-mg BID group, 23% of those in the 150-mg QD dose, and 14% of those in the placebo group achieved an ACR20," he said. "The drug worked quickly, and the vast majority of patients who responded at week 24 were already identified as responders at 6 to 8 weeks."

This study was funded by Rigel Pharmaceuticals.

[Presentation title: Treatment of Rheumatoid Arthritis (RA) With an Oral Syk Kinase Inhibitor: A 6-Month Randomized, Placebo-Controlled Phase 2B Study in Patients With Active RA on Chronic Methotrexate. Abstract LB2]

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