| Reference | 1. Arthritis Rheumatol. 2016 Dec;68(12):2857-2866. doi: 10.1002/art.39808. <br />
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. <br />
Genovese MC(1), Smolen JS(2), Weinblatt ME(3), Burmester GR(4), Meerwein S(5),
Camp HS(6), Wang L(6), Othman AA(6), Khan N(6), Pangan AL(6), Jungerwirth S(6). <br />
Author information: <br />
(1)Stanford University School of Medicine, Palo Alto, California.
(2)Medical University of Vienna and Hietzing Hospital, Vienna, Austria.
(3)Brigham and Women/’s Hospital, Boston, Massachusetts.
(4)Charité-Universitätsmedizin Berlin, Berlin, Germany.
(5)AbbVie Deutschland, Ludwigshafen, Germany.
(6)AbbVie, North Chicago, Illinois. <br />
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).<br />
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.<br />
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. <br />
2. Arthritis Rheumatol. 2016 Dec;68(12):2867-2877. doi: 10.1002/art.39801. <br />
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. <br />
Kremer JM(1), Emery P(2), Camp HS(3), Friedman A(3), Wang L(3), Othman AA(3),
Khan N(3), Pangan AL(3), Jungerwirth S(3), Keystone EC(4). <br />
Author information: <br />
(1)Albany Medical College, Albany, New York.
(2)University of Leeds and Leeds Teaching Hospitals NHS Trust, Leeds, UK.
(3)AbbVie, North Chicago, Illinois.
(4)Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada. <br />
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.<br />
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.<br />
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. <br />
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