A Phase IIb Study of ABT-494, a Selective JAK-1 Inhibitor, in Patients With Rheumatoid Arthritis and an Inadequate Response to Anti-Tumor Necrosis Factor Therapy

Joel M Kremer, Paul Emery, Heidi S Camp, Alan Friedman, Li Wang, Ahmed A Othman, Nasser Khan, Aileen L Pangan, Steven Jungerwirth, Edward C Keystone, Joel M Kremer, Paul Emery, Heidi S Camp, Alan Friedman, Li Wang, Ahmed A Othman, Nasser Khan, Aileen L Pangan, Steven Jungerwirth, Edward C Keystone

Abstract

Objective: To compare the efficacy and safety of ABT-494, a novel selective JAK-1 inhibitor, with placebo in patients with moderate-to-severe rheumatoid arthritis (RA) and an inadequate response or intolerance to at least 1 anti-tumor necrosis factor (anti-TNF) agent.

Methods: In this 12-week, double-blind, placebo-controlled, dose-ranging study, 276 RA patients receiving a stable dose of methotrexate (MTX) who had previously received treatment with at least 1 anti-TNF agent were randomized equally to receive immediate-release ABT-494 at 3, 6, 12, or 18 mg twice daily or matching placebo twice daily. The primary end point was the proportion of patients meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at week 12.

Results: At week 12, significantly more patients receiving ABT-494 (53-71%) than those receiving placebo (34%) achieved an ACR20 response (by nonresponder imputation analysis) (P < 0.05), with a dose-response relationship among all ABT-494 doses (P < 0.001). ACR50 and ACR70 response rates were significantly higher in those receiving ABT-494 (36-42% and 22-26%, respectively) than in those receiving placebo (16% and 4%, respectively). Changes from baseline in the Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP) were significantly greater for all doses of ABT-494 than for placebo (P ≤ 0.01). Onset of action of ABT-494 was rapid, with significant differences from placebo at week 2 both in ACR20 response rate (for 12 and 18 mg) and in change in the DAS28-CRP (P < 0.001 for 6-18 mg). The most frequent adverse events (AEs) were headache, nausea, upper respiratory tract infection, and urinary tract infection. Infection rates were higher at higher doses of ABT-494, but no infections were serious. No deaths were reported among those receiving ABT-494.

Conclusion: In patients with an inadequate response or intolerance to anti-TNF agents, ABT-494 added to MTX showed rapid, dose-dependent improvements in RA signs and symptoms, with safety and tolerability similar to those of other drugs of this class. No new AEs were identified.

Trial registration: ClinicalTrials.gov NCT01960855.

© 2016 The Authors. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of the American College of Rheumatology.

Figures

Figure 1
Figure 1
A, Percentages of patients with rheumatoid arthritis achieving a response to ABT‐494 at 3, 6, 12, or 18 mg twice daily (BID) or to matching placebo twice daily according to the American College of Rheumatology criteria for 20% improvement (ACR20), 50% improvement, and 70% improvement at week 12 (nonresponder imputation [NRI] analysis). † = the sensitivity analyses for correction of affected high‐sensitivity C‐reactive protein samples predicted a potential shift of 1 subject from responder to nonresponder in the placebo arm for an ACR20 response (from 34% to 32%). ∗ = P < 0.05; ∗∗ = P < 0.01; ∗∗∗ = P < 0.001 versus placebo. B, ACR20 responses at week 12 by number of previously received anti–tumor necrosis factor (anti‐TNF) agents (NRI analysis). P values were not calculated for ACR20 responses based on number of previously received anti‐TNF agents. Results in both panels are shown for the modified intent‐to‐treat population.
Figure 2
Figure 2
Responses of patients with rheumatoid arthritis to ABT‐494 or placebo. A, ACR20 responses over time (NRI analysis). B, ACR50 responses over time (NRI analysis). C, ACR70 responses over time (NRI analysis). D, Mean change from baseline in Disease Activity Score in 28 joints using the C‐reactive protein level (DAS28‐CRP) (last observation carried forward analysis). E and F, Patients achieving a DAS28‐CRP of ≤3.2 or <2.6 (NRI analysis) (E) and low disease activity (score ≤10) or clinical remission (score ≤2.8) according to Clinical Disease Activity Index (CDAI) criteria (NRI analysis) (F) with ABT‐494 treatment or placebo at week 12. Results in all panels are shown for the modified intent‐to‐treat population. † = the sensitivity analyses for correction of affected high‐sensitivity CRP samples predicted a potential shift of 1 subject from responder to nonresponder in the 12 mg treatment arm for a DAS28‐CRP of ≤3.2 (from 49% to 47%). ∗ = P < 0.05; ∗∗ = P < 0.01; ∗∗∗ = P < 0.001 versus placebo. See Figure 1 for other definitions.
Figure 3
Figure 3
Mean hemoglobin levels over time in patients with rheumatoid arthritis receiving ABT‐494 at 3, 6, 12, or 18 mg twice daily (BID) or matching placebo twice daily. Normal ranges for hemoglobin are 11.5–15.5 gm/dl in women and 13.2–17.0 gm/dl in men. Safety population with observed data.

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Source: PubMed

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