Encouraging Preliminary Results With Oral JAK Inhibitor in Rheumatoid Arthritis

Alice Goodman

October 22, 2009

October 22, 2009 (Philadelphia, Pennsylvania) — An investigational oral Janus kinase (JAK) inhibitor achieved significant responses in patients with active rheumatoid arthritis (RA) when used alone or in combination with methotrexate, according to preliminary clinical trials reported here at American College of Rheumatology (ACR) 2009.

Based on these positive results, the drug will be moved forward to phase 3 trials, researchers announced. Both studies were sponsored by Pfizer.

Molecule CP 690,550 "is truly unique as a biologic agent targeted to a specific molecule — the JAK — which activates the cell nucleus to produce multiple cytokines and proinflammatory factors implicated in inflammation and in RA. It is also an oral targeted agent," said Joel M. Kremer, MD, Pfaff Family Professor of Medicine at Albany Medical College in New York, and lead author of 1 of 2 phase 2b trials presented at the meeting. The anti-tumor necrosis factor drugs currently on the market for the treatment of RA are injectable.

The first study, a 24-week double-blind placebo-controlled trial, was an evaluation of 384 patients with active RA who failed on background methotrexate and had longstanding disease. Results were reported by R.M. Fleischmann, MD, from the Metroplex Clinical Research Center in Dallas, Texas.

Patients were randomized to 1 of 5 different doses of CP 690,550 (1 mg, 3 mg, 5 mg, 10 mg, or 15 mg twice daily) or placebo. Methotrexate therapy was discontinued during this 24-week study.

Patients who received a 5, 10, or 15 mg twice-daily dose of the JAK inhibitor without background methotrexate experienced significant improvements in ACR response rates and Disease Activity Score (DAS) 28 remission rates at week 24, compared with the placebo group.

At 24 weeks, the percentage of patients who achieved at least a 20% improvement according to the ACR definition (ACR20) with JAK inhibitor monotherapy were 51% (P ≤ .05), 65.6% (≤ .0001), and 66.7% (≤ .0001) for a 5, 10, or 15 mg twice-daily dose, respectively, compared with 25.4% for the placebo group.

The percentage of patients with at least a 50% improvement (ACR50) was 34.7% (≤ .05), 44.3% (≤ .0001), and 54.4% (≤ .0001), respectively, compared with 10.2% for the placebo group.

The percentage of those who achieved at least a 70% improvement ( ACR70) was 20.4% (≤ .05), 37.7% (≤ .0001), and 33.3% (≤ .01) for a 5, 10, or 15 mg twice-daily dose, respectively, compared with 6.8% for the placebo group.

Remission, as measured by DAS28, was observed in 14.6% of those receiving the 5 mg twice-daily dose (≤ .05), 21.3% of those receiving the 10 mg twice-daily dose (≤ .01), and 21.1% of those receiving the 15 mg twice-daily dose (≤ .01), compared with 1.8% for the placebo group.

A second 24-week double-blind placebo-controlled study of CP 690,550 involved 507 patients with active RA despite ongoing treatment with methotrexate. In this study, patients remained on stable background methotrexate therapy, and the JAK inhibitor was added in 1 of 6 doses (1, 3, 5, 10, or 20 mg once daily; or 15 mg twice a day) or placebo.

Clinical responses occurred for all 6 doses of the JAK inhibitor, but the 5, 10, and 20 mg once-daily doses and the 15 mg twice-daily dose achieved significant ACR response rates and DAS28 remission rates compared with placebo; results were consistent with those in the monotherapy study.

"This is a promising treatment for patients with RA. Like all new agents in development, we will need to determine the longer-term safety and efficacy, as well as the dose that might eventually be used in the clinic," Dr. Kremer said. Pfizer plans to go forward with 5 and 10 mg twice-daily doses in its phase 3 investigation.

In both studies, the most common treatment-emergent adverse events were urinary tract infection, headache, and diarrhea. Most adverse events were mild or moderate in severity. Serious adverse events leading to discontinuation were infrequent. Adverse effects for CP 690,550 were consistent with those reported in other studies of RA patients, and included dose-dependent decreases in mean neutrophil counts and increases in serum cholesterol levels. For patients receiving background methotrexate, increased transaminase levels were consistent with those in previous RA studies.

Based on these studies, Dr. Kremer thinks that the 5 and 10 mg twice-daily doses will be moving forward in the phase 3 development program. He said that the 15 mg twice-daily dose is associated with elevated transaminase levels and the 20 mg once-daily dose is not as effective as the 5 or 10 mg twice-daily doses.

Exciting Approach

"This new JAK inhibitor should be considered a major advance in the treatment of RA," said Eric Matteson, MD, chair of rheumatology at the Mayo Clinic in Rochester, Minnesota.

"JAK is 1 piece of the puzzle of this polygenic and polymorphic disease process," he explained,

Dr. Matteson said that having an oral targeted agent for the treatment of RA would be a practical advantage for patients and physicians, but he cautioned that a drug targeted to a specific disease mechanism can result in unwanted effects on the immune response. Further study is needed to characterize the dosing and the safety of this new drug.

"This is a potentially exciting approach. We hope it will provide additional efficacy along with convenience of administration. It will probably be used in combination with other drugs," he said.

The studies were sponsored by Pfizer. Dr. Fleischmann reports financial ties with Abbott, Amgen, Wyeth, Celgene, Centocor, Roche, Genentech, Pfizer, Lilly, UCB, Regeneron, Array, Lexicon, and GlaxoSmithKline. Dr. Kremer reports financial ties with Abbott, Amgen, BMS, Centocor, Genentech, Pfizer, and UCB. Dr. Matteson reports financial ties with Amgen, Wyeth, Centocor, UCB, Genentech, and Pfizer, but reports no JAK-specific disclosures.

American College of Rheumatology (ACR) 2009: Abstracts 1924 and 1925. Presented October 20, 2009.


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