EULAR 2009: Novel Oral JAK-3 Inhibitor Shows Promising Safety and Efficacy in Active Rheumatoid Arthritis

Alice Goodman

June 17, 2009

June 17, 2009 (Copenhagen, Denmark) — The investigational oral JAK-3 inhibitor CP-690550 achieved encouraging responses in patients with active rheumatoid arthritis, according to an interim analysis of a randomized double-blind phase 2b dose-ranging study presented here at EULAR 2009: The Annual European Congress of Rheumatology.

"The study showed dose-dependent increases in efficacy with this novel agent. Tolerability was also dose-dependent," said Roy Fleischmann, MD, clinical professor of medicine at the University of Texas in Dallas and principal investigator for the Pfizer-supported study. Dr. Fleischmann said that Pfizer is moving on the phase 3 trials of the drug.

"If phase 3 data show equivalent or near-equivalent efficacy and safety, this JAK-3 inhibitor will be poised to be a major player in rheumatoid arthritis. It is oral and much easier to produce than TNF [tumor necrosis factor]-alpha inhibitors, so it should be more convenient to use and cheaper," Dr. Fleischmann stated during a press conference at EULAR.

The study enrolled 384 patients (84% women) with active rheumatoid arthritis (defined as at least 6 tender joints and at least 6 swollen joints). Patients were randomized to 1 of 5 doses of oral CP-690550 — 1, 3, 5, 10, or 15 mg twice a day — or to adalimumab 40 mg subcutaneously every other week for the first 12 weeks, followed by CP-690550 5 mg or placebo twice a day for 6 months. At baseline, age ranged from 52 to 55 years, disease duration ranged from 7.7 to 11 years, Health Assessment Questionnaire-Disability Index (HAQ-DI) score ranged from 1.4 to 1.6, Disease Activity Score (DAS) 28 (C-reactive protein) ranged from 5.4 to 5.6, and 10% to 83% of participants were rheumatoid-factor positive.

At a 12-week preplanned interim analysis, the 5, 10, and 15 mg doses of CP-690550 were superior to placebo for nearly all clinical outcomes on 3 common measures used to assess treatment of rheumatoid arthritis: a 20% improvement in American College of Rheumatology (ACR20) assessment of tender/swollen joints and other criteria; HAQ-DI; and DAS28. Dr. Fleischmann said that all these patients previously had an inadequate response to another disease-modifying antirheumatic drug.

At 12 weeks, patients who took CP-690550 15 mg twice a day had an ACR20 of 75.4% and DAS28 remission of 40.4%. This compares favorably to patients treated with adalimumab monotherapy, who had an ACR20 of 47.2% and a DAS28 of 4.4%. For the placebo group, ACR20 was 28.8% and DAS28 was 6.7%.

Dose-dependent decreases in mean neutrophil counts, and increases in low-density-lipoprotein cholesterol, high-density-lipoprotein cholesterol, total cholesterol, and mean serum creatinine levels were seen at week 12 in patients treated with CP-690550. The most frequent treatment-related adverse events were urinary tract infection (4.4%), diarrhea (4%), bronchitis (3.7%), and headache (3.7%). With adalimumab, the most frequent treatment-related adverse events were bronchitis and pruritus (5.7% each), and blood creatinine increase, dizziness, headache, influenza, nausea, rash, and swelling (3.8% each).

Cautious Appraisal

EULAR president Ferdinand Breedveld, MD, from Leiden University in the Netherlands, was cautious about endorsing CP-690550 on the basis of these data. "Results of the ACR20, ACR50, and ACR70 in this trial suggest that the new drug works better than placebo, with responses in the same ballpark as the biologic agents. However, in this trial, adalimumab was the comparator, and we all know that adalimumab should be used in combination with methotrexate to obtain optimal response. I would take these results with a grain of salt," he said.

"If this new drug is superior to TNF-alpha inhibitors, or even if it is equal or not quite as good, Pfizer will probably be in business with this oral drug," he said. Dr. Breedveld cautioned that there was a safety signal in the phase 2b trial with measurements of neutrophils, lipids, and liver-enzyme elevations. "Even if these effects occur in 1 in 1000 patients, that could be trouble," he said.

Dr. Fleischmann reports receiving funding for the trial from Pfizer. Dr. Breedveld reports serving as a consultant for several companies, but not for Pfizer in relation to the CP-690550.

EULAR 2009: The Annual European Congress of Rheumatology: Abstract OP-0159. Presented June 11, 2009.

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