Background ABT-494 is a novel selective JAK1 inhibitor.
Objectives The safety and efficacy of ABT-494 was characterized vs placebo (PBO) in patients (pts) with moderate to severe RA and an inadequate response to stable background methotrexate therapy (MTX-IR).
Methods In a phase 2b, 12-week, randomized, double-blind PBO-controlled study, MTX-IR pts with active RA on stable background MTX were randomized 1:1:1:1:1:1 to ABT-494 3, 6, 12, and 18 mg twice daily (BID), 24 mg once daily (QD), or matching PBO. The primary efficacy endpoint was ACR20 response at week 12.
Results Baseline demographics and characteristics of the 299 randomized, treated pts were similar across groups. ACR20 response rates were significantly higher with ABT-494 at 6 mg BID (68%), 12 mg BID (80%), and 24 mg QD (76%) vs PBO (46%; non-responder imputation; Table 1). ACR50 and ACR70 response rates and change from baseline in DAS28(CRP) were also statistically significantly better for all ABT-494 doses (except ACR70 in 12 mg BID) vs PBO. Clinical remission by DAS28(CRP) was achieved by significantly more pts on ABT-494 (except 24 mg QD) vs PBO. Onset of action was rapid for ACR20, ACR50, and ACR70 responses, with significant (P≤0.027) differences in ACR20 observed at week 2 for all dose groups vs PBO. DAS28(CRP) ≤3.2 and CDAI ≤10 were achieved by significantly more pts on ABT-494 (except 24 mg QD for CDAI) vs PBO.
AE incidence was numerically higher with ABT-494, with a trend of dose dependence (Table 2). The incidence of infections was similar across groups. One serious infection (community acquired pneumonia) occurred with ABT-494 12 mg BID. One pt receiving ABT-494 3 mg BID and 2 pts receiving 24 mg QD had non-serious zoster infections (single dermatomes). A pt in the 6-mg BID dose group, aged 79 y and smoking 40 y, was diagnosed with lung cancer 8 days after study completion and died 3 months later. No deaths occurred during the study. ABT-494 treatment resulted in dose-dependent increases in LDL and HDL cholesterol. Liver function test elevations were sporadic, with no clear dose dependence. Mean hemoglobin values remained stable or increased at lower doses, most notably in pts with elevated CRP at baseline. Dose-dependent decreases in hemoglobin were seen at higher doses, without clinical impact.
Conclusions This phase 2b study evaluated a broad dose range to understand the boundaries of JAK1 selectivity and demonstrated the efficacy of ABT-494 vs PBO in MTX-IR pts with active RA on stable background MTX. ABT-494 had an acceptable safety and tolerability profile.
Acknowledgement The design, study conduct, analysis, and financial support of the clinical trial (NCT02066389) were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the content. All authors had access to all relevant data. Mariana Ovnic, PhD, Katherine Groschwitz, PhD, and Michael J. Theisen, PhD of Complete Publication Solutions, LLC, provided medical writing support. This presentation contains information on the investigational product ABT-494.
Disclosure of Interest M. Genovese Grant/research support from: AbbVie, Consultant for: AbbVie, J. Smolen Grant/research support from: AbbVie, Consultant for: AbbVie, M. Weinblatt Consultant for: AbbVie, Eli Lilly, and Pfizer, S. Meerwein Shareholder of: AbbVie, Employee of: AbbVie, H. Camp Shareholder of: AbbVie, Employee of: AbbVie, L. Wang Shareholder of: AbbVie, Employee of: AbbVie, A. Othman Shareholder of: AbbVie, Employee of: AbbVie, N. Khan Shareholder of: AbbVie, Employee of: AbbVie, S. Jungerwirth Shareholder of: AbbVie, Employee of: AbbVie