Phase IIb study enrolled patients who had failed biologic treatment.

Rigel Pharmaceuticals’ Phase IIb trial in rheumatoid arthritis (RA) failed to demonstrate a response that was higher than placebo by a statistically significant margin in the primary and secondary endpoints. The firm’s stock dropped about 19.55% to open trading today at $11.56.

The study, called TASKi3, was a three-month, multicenter, randomized, double-blind, placebo-controlled, parallel-dose trial involving 219 RA patients in the U.S. who had failed to respond to at least one biologic treatment such as TNF inhibitors. Patients either received a 100 mg, twice-daily dose of R788 or placebo. Throughout the trial patients continued to receive their stable dose of methotrexate.

Efficacy endpoints were based on the American College of Rheumatology (ACR) criteria. The primary endpoint was the number of patients achieving at least a 20% improvement (ACR 20). Secondary efficacy endpoints included ACR 50 and ACR 70 scores and a comparison of response rates as determined by MRI using the modified RAMRIS (rheumatoid arthritis MRI scoring) system of wrists and hands.

Although the ACR scores for the R788 group were within the expected range in this patient population, the reported placebo response rates were considerably higher than seen in any other previous study of RA patients who had failed biologic treatment. It rose unaccountably between week six  and month three, Rigel explains.

The trial did show a statistically significant difference in the objective components of ACR scores, according to Rigel. Objective components were blood measurements of C-reactive protein and erythrocyte sedimentation rate. The subjective reported response rate components, however, did not show a difference as compared to placebo.

TASKi3 evaluated anatomical changes in patients’ wrist and hands using MRI and scored with the RAMRIS system. Those results showed improvements in the treated group versus the placebo group in the synovitis and osteitis scores. The erosion scores, known to be the slowest to change, showed no significant effect by the third month.

Considering the unexplained increase in ACR scores in the placebo group and the success seen in the objective components of these scores plus the MRI results, Simos Simeonidis, Ph.D., director and senior biotechnology analyst at Rodman & Renshaw, believes this trial is inconclusive and “definitely leaves the door open for the drug to show efficacy in TNF-alpha failures in the Phase III setting.

“It is worth noting that Pfizer’s CP-690,550, R788’s closest competitor, hasn’t been tested in a separate trial in this patient population,” Dr. Simeonidis points out, “and this is thus an issue that both compounds will have to address.”

Rigel’s R788 is an orally available syk kinase inhibitor designed to interrupt the cellular signaling at the trigger point of inflammation, thereby stopping the progression of the disease. In July, Rigel reported results from its Phase IIb study showing significant improvement in RA patients treated with R788 who had failed to respond to methotrexate treatment.

“Our objective with R788 in RA is to position the product after methotrexate and before biological therapies are used,” according to James M. Gower, chairman and CEO of Rigel. “We have shown excellent results in that patient population in our earlier TASKi1 and TASKi2 studies, and we believe that patient population represents the large market opportunity for this product.”

Rigel is also studying R788 in B-cell lymphoma and idiopathic thrombocytopenic purpura in Phase II trials.

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