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Oral JAK-3 inhibitor plus methotrexate efficacious, safe in RA

Thursday, October 30 2008 | Comments

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What's This? By David MacDougall

CP-690,550, an oral inhibitor of Janus kinase 3 (JAK-3), is safe and efficacious when used in combination with methotrexate in patients with rheumatoid arthritis (RA) who have had an inadequate response to methotrexate alone, according to findings from a double-blind, Phase IIb, dose-finding study.

JAK-3 is a tyrosine kinase essential for proper signal transduction downstream of selected cytokine receptors and for robust T-cell and natural killer cell activation and function. Inhibition of JAK-3 with CP-690,550 has been shown to inhibit acute rejection in primate recipients of kidney allografts, the study authors noted.

In the trial, 509 patients with active RA and an inadequate response to methotrexate were randomized to receive CP-690,550 1 mg, 3 mg, 5 mg, 10 mg, or 15 mg twice daily; CP-690,550 20 mg once daily; or placebo in combination with methotrexate for 6 months. The patients who received twice-daily treatment with CP-690,550 1 mg or 3 mg, those who received 20 mg once daily, and those who received placebo who did not achieve >20% reduction from baseline in swollen and tender joint counts at week 12 were reassigned to treatment with CP-690,550 5 mg twice daily for the remainder of the study.

The primary outcome measure was the American College of Rheumatology (ACR) response rate at week 12. Efficacy data were assessed through week 12 and safety data were examined through week 24.

At 12 weeks, ACR20 response rates in all CP-690,550 dose groups were significantly better than the response rate in the placebo group was (P<.05 for each). The ACR50 response rates at week 12 were significantly greater in the 5 mg twice-daily (37%, P<.05), 20 mg once-daily (36%, P<.05), and 15 mg twice-daily (47%, P<.0001) groups than in the placebo group.

Additionally, the Health Assessment Questionnaire Disability Index (HAQ-DI) response rates at week 12 were significantly greater in all CP-690,550 dose groups than in the placebo group (P<.05 for each). The Disease Activity Score 28 (DAS28) response rates at week 12 were significantly greater in the 3 mg twice-daily (32%, P<.05), 10 mg twice-daily (30%, P<.05), 20 mg once-daily (25%, P<.05), and 15 mg twice-daily (38%, P<.0001) groups than in the placebo group.

The most frequently reported treatment-related adverse events were nausea (2.4%), headache (2.2%), and increased alanine aminotransferase (2.0%). Dose-dependent increases in high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and total cholesterol were observed and appeared to plateau between weeks 6 and 12.

"Doses of CP-690,355 3 mg [twice daily] and higher were efficacious versus placebo," the study authors wrote. "A range of doses appears suitable to evaluate further in Phase 3 studies." (Kremer J, et al. Late-Breaking Abstract 13.)

This information concerns a use that has not been approved by the Food and Drug Administration.

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