Kremer, J. M. et al. The safety and efficacy of a JAK inhibitor in patients with active rheumatoid arthritis: Results of a double-blind, placebo-controlled phase IIa trial of three dosage levels of CP-690,550 versus placebo. Arthritis Rheum. 60, 1895–1905 (2009).

The role of cytokines in the pathogenesis of rheumatoid arthritis (RA) is well established and clearly demonstrated by the efficacy of tumor necrosis factor (TNF) inhibitors in some patients with this disease. Research performed over the past two decades means we now more fully understand cytokine signaling pathways at the molecular level, and so can directly target downstream molecules such as Janus kinases (JAKs), two of which—JAK1 and JAK3—are essential for signal transduction by common-γ-chain-containing cytokine receptors. What effect does 'hitting' JAKs have in established RA?

The results of a double-blind, placebo-controlled phase IIa trial of the JAK inhibitor CP-690,550 in patients with active RA who had failed to respond to previous therapies—including TNF inhibitors—have now been published in Arthritis & Rheumatism. Patients enrolled in this trial were randomized to receive placebo or 5 mg, 15 mg, or 30 mg of CP-690,550 orally, twice-daily for 6 weeks. The primary efficacy end point (the American College of Rheumatology criteria for 20% improvement [ACR20] at 6 weeks) was achieved by 70.5%, 81.2% and 76.8% of patients in the 5 mg, 15 mg and 30 mg CP-690,550 groups, respectively, compared with 29.2% in the placebo group. After 1 week of treatment, improvements in disease activity (ACR20) were seen in all CP-690,550 groups in comparison with the placebo group; improvements in ACR50 and ACR70 responses were seen by week 4 in all treatment groups. No benefit of the 30 mg dose over the 15 mg dose was seen in regard to efficacy.

After 6 weeks of treatment, safety analyses showed a similar incidence of adverse events in the placebo and 5 mg groups (59% and 58.5% experiencing ≥1 adverse event, respectively); however, patients receiving the higher doses reported more treatment-emergent adverse events (≥1 adverse event reported by 75.4% and 76.8% in the 15 mg and 30 mg groups, respectively); headache and nausea were the most common adverse events reported. The incidence of anemia, leukopenia, neutropenia, lymphopenia and thrombocytopenia was higher in recipients of 30 mg CP-690,550 than in the other treatment groups, but these were generally described as being mild to moderate in severity. Rates of infection were the same in the 15 mg and 30 mg groups (30.4%, compared with 26.2% in the placebo group).

When asked about the safety signals seen in this study, the senior author Samuel Zwillich (from Pfizer, the company who are developing CP-690,550) stated that “decreases in both hemoglobin and neutrophils were observed, but infrequently required intervention and responded promptly to drug withdrawal. Unexpected safety observations included increases in total cholesterol, HDL and LDL cholesterol, and small increases in mean serum creatinine at all dose levels. We are currently conducting additional investigations to understand these findings.”

Longer trials of this agent are ongoing. “This 'proof-of-concept' study was followed by two dose-ranging phase IIb studies of 24 weeks' duration: one in patients with active RA on a stable background of methotrexate, and the second in patients who had washed off all DMARDs,” explained Zwillich. “We have also initiated a phase III program in RA and are actively studying CP-690,550 for prevention of renal allograft rejection and treatment of psoriasis, ulcerative colitis, Crohn's disease and dry eye disease.”

John O'Shea, Scientific Director of the National Institute of Arthritis and Musculoskeletal and Skin Disease (who cloned JAK3 back in 1994 and has a patent with the NIH on targeting this pathway, as well as a Cooperative Research and Development Agreement with Pfizer) thinks there is a place for JAK inhibitors in our armamentarium against RA. “These results are interesting as this agent has apparent efficacy in a setting where other DMARDs have failed, and the adverse events don't seem to be too severe,” says O'Shea.

An area of intrigue to O'Shea is how these agents work and which cells and cytokines are being blocked. As he says, however, “knowing the mechanisms behind the activity of this agent would be interesting, but not knowing them does not stop the drug from working. Just think about methotrexate; even now we do not really know how this agent works, and it is associated with toxicity, but over time we have found doses that are safe and efficacious.”

As O'Shea concludes, “basic research has led us here. 10 years ago it was the elucidation of the JAK signaling pathways that was exciting—now we have drugs that target these pathways. This is real and is in the clinic, and soon we will really know what it means clinically to target JAKs!”