SAN FRANCISCO, California— Data from a phase II study of Rigel Pharmaceuticals' oral Syk kinase inhibitor R788 (tamatinib fosdium) initially reported in a December 2007 press release were presented at the 2008 American College of Rheumatology meeting today, and they look very promising. Michael E. Weinblatt, MD, reported for the TASKI-1 Trial investigators that the 100 mg and 150 mg dose groups both had ACR20 response rates twice those of the placebo control group.1

"Clinical effect was noted as early as week one,"—Michael E. Weinblatt, MD
“Developing new treatments for this disease offers great hope for our patients,” said Dr. Weinblatt, from the division of rheumatology at Brigham and Women's Hospital in Boston, Massachusetts. “This study has also identified a new pathway to block as we continue to look for new therapies for the treatment of RA.”

Potential new class of oral drugs for RA

R788 is a novel, oral Syk kinase inhibitor that blocks the activation of mast cells, macrophages, and B cells that promote swelling and inflammatory responses. It inhibits Syk kinase-mediated IgG Fc gamma receptor signaling. Syk kinase is a nonreceptor tyrosine kinase that mediates coupling of activated immunoreceptors to signal downstream events such as proliferation, differentiation, and phagocytosis.

This double-blind, placebo-controlled Phase II study included 189 patients with active RA on chronic methotrexate (MTX) therapy. Patients were randomized to a 3-month trial of R788 (50,100, 150 mg BID) or placebo. The primary endpoint was the ACR20 response rate at week 12.

Eighty-four percent (84%) of patients completed the study, including 122 patients (86%) in the R788 treatment groups and 36 patients (77%) in the placebo group. The most common reasons for withdrawal were adverse events in the 100 mg and 150 mg R788 groups and lack of efficacy in the placebo and R788 50 mg groups.

At week 12, ACR20 response rates were 38% with placebo, 32% with 50 mg BID R788, 65% with 100 mg BID R788, and 72% with 150 mg BID R788. Both of the higher-dose groups were significantly better than placebo at P =.0009 and P <.001, respectively.

Response Rates at Week 12
  ACR20
n(%)		 ACR50
n(%)		 ACR70
n(%)		 DAS Remission
n(%)
Placebo
n=47		 18 (38%) 9 (19%) 2 (4%) 8 (17%)
R788 50 mg BID
n=46		 15 (32%) 8 (17%) 1 (2%) 9 (20%)
R788 100 mg BID
n=49		 32 (65%)* 24 (49%)† 16 (33%)‡ 17 (35%)§
R788 150 mg BID
n=47		 34 (72%)‡ 27 (57%)‡ 19 (40%)‡ 22 (47%)‡

ACR response calculated on nonresponder computation.
*P = .008*; †P = .002; ‡P <.001,§P =.07.

Source: Weinblatt et al.1

Fast action, but some dose-related toxicity problems

“Clinical effect was noted as early as week 1,” Dr. Weinblatt reported.

Serum IL-6 and MMP-3 levels also decreased significantly from baseline (P <.002) in the two higher dose groups as compared with placebo as early as week 1. This decrease was maintained at week 12.

The major adverse effects included diarrhea (45% with the 150 mg dose) and neutropenia (<1500/mm3), which occurred overall in 15% of patients treated with R788. The company had reported earlier that 19 of 21 patients who had doses reduced from BID to once-daily based on pre-specified limits for neutrophil counts and/or liver function tests were able to complete the clinical trial.

Other adverse events included dizziness in 11% of patients in the 150 mg group and 2% of patients in the placebo group. Hypertension occurred in 5% of patients in the higher R788 dose groups but not in the placebo group.

“Inhibition of Syk signaling with a relatively selective inhibitor of Syk kinase produced significant clinical benefits in a population of RA patients with active disease on MTX therapy,” Dr. Weinblatt concluded. “We are able to define a therapeutic dose based on the efficacy and toxicity results. The 100 mg BID and the 150 mg BID doses were both effective with similar degrees of clinical response; however, there were more clinical and laboratory adverse events with the 150 mg dose. 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. Longer term studies are needed to further define the safety and efficacy profile of this drug.”

Two phase IIb studies of R788 are underway. The first trial (TASKI 2) will evaluate approximately 420 RA patients receiving 100 mg of the agent PO BID or 150 mg PO QD, compared with those receiving placebo in a multicenter, randomized, double-blind, placebo-controlled, parallel-dose study of R788 in patients who have failed to respond to MTX. Patients will continue to receive a stable dose of MTX throughout the course of the 6-month clinical trial. Primary outcome results are expected in November 2009, and the estimated study completion date is March 2010.

The second trial (TASKI 3) will evaluate a group of RA patients receiving 100 mg of R788 PO BID compared with a group receiving placebo in a multicenter, randomized, double-blind, placebo-controlled, parallel-dose study of the agent in patients who have failed at least one marketed biologic agent. Approximately 195 patients will be enrolled in the trial, each of whom will receive R788 or placebo over a 3-month treatment period. Patients may continue on their stable dose of MTX and/or other (nonbiologic) therapies. Primary outcome results are expected in August 2009, and the estimated study completion date is November 2009.

Reference

1. Weinblatt ME, Kavanaugh A, Grossbard E, et al. Treatment of rheumatoid arthritis (RA) with a Syk kinase inhibitor: a 12-week randomized placebo controlled study. Presented at: ACR 2008 meeting; October 27, 2008; San Francisco, CA. Presentation 1189.