Rheumatoid Arthritis - Small Molecules—Kinase inhibitors

Several oral agents that target inflammatory pathways have now been developed and are being tested in rheumatoid arthritis. The most recent of these agents reported target intracellular signal transducing enzymes known as kinases. These enzymes are linked to different cytokine receptors and other extracellular receptors, and are required for a series of events that lead to cellular activation and new gene transcription. We have previously reviewed the efficacy of an inhibitor of Janus kinases, JAK 1 and JAK2, presented at EULAR 2008 with results also presented at ACR 2008 as abstract 714. We have also recently reviewed the article reporting the efficacy of an inhibitor of Spleen tyrosine kinase, Syk, in our Hot News section, which was also presented as Abstract 1189 at ACR2008. At ACR2008, Phase IIB results for an inhibitor of Janus Kinase (JAK) was reported at ACR2008.

LB13: The Oral JAK Inhibitor CP-690,550 (CP) in Combination with Methotrexate is Efficacious, Safe and Well Tolerated in Patients with Active Rheumatoid Arthritis with an Inadequate Response to Methotrexate Alone

Authors:

J. Kremer, S. Cohen, B. Wilkinson, C. Conell, J. French, J. Gomez Reino, D. Gruben, K. Kanik, S. Krishnaswami, V. Pascual-Ramos, G. Wallenstein, S. Zwillich.

Purpose:

To compare the efficacy, safety and tolerability of 6 dose levels of oral CP vs placebo for the treatment of RA in patients with active RA on stable background MTX, who had an inadequate response to MTX alone; to characterize the dose-response profile of CP. CP is an oral agent that inhibits JAK3.

Methods:

This was a 6-month, double-blind, placebo-controlled Phase 2B study, in patients with active RA. Patients were randomized equally to 1, 3, 5, 10, 15 mg BID, or 20 mg QD, of CP or placebo. Patients receiving CP 1 mg, 3 mg BID, 20 mg QD, or placebo who did not achieve ≥20% reduction from baseline in swollen and tender joint counts at Week 12 were reassigned to CP 5 mg BID for the remainder of the study. The primary outcome was ACR response rate at Week-12. Efficacy and safety assessments were carried out at Weeks 2, 4, 6, 8, 12, 16, 20, and 24.

Results:

Data are presented from an interim analysis at Week12; efficacy data are through Week12 (or early termination), safety data are through Week24. 509 pts (80% women) were randomized. Mean ages across dose groups were 50.8-56.1 years (range 18-81 years). Mean disease duration ranged from 7.1-11.7 years; 69%-89% were rheumatoid factor positive. At baseline, mean tender joint counts ranged from 21.49-24.71, swollen joint counts from 14.04-16.52 and HAQ-DI from 1.20-1.57. Mean baseline DAS28-3 (CRP) scores ranged from 5.14-5.49.
The most frequently reported treatment-emergent AEs (all causality) were: nausea 2.4%; headache 2.2% and increased ALT 2.0%. Serious AEs ranged from 1-8% in the CP dose groups with none in the placebo arm. 5 serious infections were reported, with no dose-related pattern. Minor dose-related changes in hemoglobin (Hb) were seen; only 2 patients experienced Hb drops >3 g/dL below baseline (1 patient each on placebo and CP 10 mg BID) and no patients’ neutrophil count fell below 500/µL. Dose-dependent increases in LDL, HDL and total cholesterol were observed, which appeared to plateau between Weeks 6 and 12. Reversible ALT increases of >3x the ULN were seen in 5 patients receiving CP 15 mg BID and in one patient in each of CP 10 mg BID, 20 mg QD and placebo

Conclusion:

Doses of CP 3 mg BID and higher were efficacious vs placebo. Tolerability, AEs and some changes in laboratory values were dose-dependent. A range of doses appears suitable to evaluate further in Phase 3 studies.

Editorial Comment:

This study confirms the rapid efficacy seen in an earlier small study with this oral JAK inhibitor. It is notable that the results here are at 12 weeks (3 months). The results presented were last observation carried forward rather than the more stringent non-responder imputation however which may have biased for a more favorable outcome. Even with a relatively high level of placebo responses the differences between active treatments were significant for most doses. The dose-related changes in LFTs, cholesterol, and neutrophils in the short term of this study will certainly merit further evaluation over longer periods of time. This study along with the recent data on Syk kinase does suggest that targeting intracellular kinases may be effective in treating RA. But clearly the early safety signals will need to be studied especially in patients on concomitant medications and with other comorbidities.