Efficacy and Safety of ABT-494, a Selective JAK-1 Inhibitor, in a Phase IIb Study in Patients With Rheumatoid Arthritis and an Inadequate Response to Methotrexate

Abstract

Objective: To evaluate the efficacy and safety of ABT-494, a selective JAK-1 inhibitor, in patients with moderate-to-severe rheumatoid arthritis (RA) and an inadequate response to methotrexate (MTX).

Methods: Three hundred RA patients receiving stable doses of MTX were randomly assigned equally to receive immediate-release ABT-494 at 3, 6, 12, or 18 mg twice daily, 24 mg once daily, or placebo for 12 weeks. The primary efficacy end point was the proportion of patients meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at week 12, as determined using the last observation carried forward method.

Results: At week 12, the proportion of ACR20 responses was higher with ABT-494 (62%, 68%, 80%, 64%, and 76% for the 3, 6, 12, 18, and 24 mg doses, respectively) than with placebo (46%) (using nonresponder imputation) (P < 0.05 for the 6, 12, and 24 mg doses). There was a significant dose-response relationship among all ABT-494 doses (P < 0.001). The proportions of patients achieving ACR50 and ACR70 responses were significantly higher for all ABT-494 doses (except the 12 mg dose for the ACR70 response) than for placebo, as were changes in the Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP). Rapid improvement was demonstrated by significant differences in ACR20 response rates and changes in the DAS28-CRP for all doses compared with placebo at week 2 (the first postbaseline visit). The incidence of adverse events was similar across groups; most were mild, and infections were the most frequent. One serious infection (community-acquired pneumonia) occurred with ABT-494 at 12 mg. There were dose-dependent increases in high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol, but the LDL cholesterol:HDL cholesterol ratios were unchanged through week 12. Mean hemoglobin levels remained stable at lower doses, but decreases were observed at higher doses.

Conclusion: This study evaluated a broad range of doses of ABT-494 in RA patients with an inadequate response to MTX. ABT-494 demonstrated efficacy, with a safety and tolerability profile similar to that of other JAK inhibitors.

Trial registration: ClinicalTrials.gov NCT02066389.

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

Figures

Figure 1

Proportion of patients with rheumatoid arthritis meeting the American College of Rheumatology criteria for 20% improvement (ACR20), 50% improvement, and 70% improvement at week 12 of treatment with ABT‐494 (modified intent‐to‐treat population; nonresponder imputation analysis). † = The sensitivity analysis for correction of affected high‐sensitivity C‐reactive protein samples demonstrated that there was a potential shift of 1 patient from responder to nonresponder in the placebo arm for ACR50 response (from 18% down to 16%). ∗ = P < 0.05; ∗∗ = P < 0.01; ∗∗∗ = P < 0.001 versus placebo. BID = twice daily; QD = once daily.

Figure 2

A–C, Proportions of patients achieving ACR20 responses (A), ACR50 responses (B), and ACR70 responses (C) over 12 weeks (modified intent‐to‐treat [ITT] population; nonresponder imputation [NRI] analysis). D, Mean change in Disease Activity Score in 28 joints using the C‐reactive protein level (DAS28‐CRP) from baseline through 12 weeks (modified ITT population; observed patients). E and F, Proportion of patients achieving a DAS28‐CRP of ≤3.2 or <2.6 (E) or low disease activity or clinical remission based on Clinical Disease Activity Index (CDAI) criteria (CDAI score ≤10 indicates low disease activity; CDAI score ≤2.8 indicates clinical remission) (F) at week 12 of treatment with ABT‐494 (modified ITT population; NRI analysis). ∗ = P < 0.05; ∗∗ = P < 0.01; ∗∗∗ = P < 0.001 versus placebo. See Figure 1 for other definitions.

Figure 3

A, Mean hemoglobin levels over 12 weeks in all patients. B, Mean change in hemoglobin levels from baseline over 12 weeks in patients with high‐sensitivity C‐reactive protein levels of >5 mg/liter at baseline. The normal range for hemoglobin is 13.2–17.0 gm/dl in males and 11.5–15.5 gm/dl in females. Shown are observed data from the safety population. See Figure 1 for definitions.