A Randomized, Double‐Blind, Placebo‐Controlled, Twelve‐Week, Dose‐Ranging Study of Decernotinib, an Oral Selective JAK‐3 Inhibitor, as Monotherapy in Patients With Active Rheumatoid Arthritis

Published on Feb 1, 2015in Arthritis & Rheumatism9.586
· DOI :10.1002/ART.38949
Roy Fleischmann81
Estimated H-index: 81
(UTSW: University of Texas Southwestern Medical Center),
Nemanja Damjanov35
Estimated H-index: 35
(University of Belgrade)
+ 3 AuthorsN. Kinnman6
Estimated H-index: 6
Sources
Abstract
Objective To assess the efficacy and safety of oral decernotinib (VX-509; Vertex Pharmaceuticals) monotherapy in a 12-week, randomized, double-blind, placebo-controlled, dose-ranging study of patients with rheumatoid arthritis (RA). Methods Two hundred four adults with active RA who had been unsuccessfully treated with ≥1 disease-modifying antirheumatic drug were administered placebo tablets or decernotinib twice a day at dosages of 25 mg, 50 mg, 100 mg, or 150 mg. Primary measures of efficacy at week 12 were the response rate according to the American College of Rheumatology 20% improvement criteria (ACR20) and mean change from baseline in the Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP). Results At week 12, the ACR20 response rates were 39.0%, 61.0%, 65.0%, and 65.9% in the 25-mg, 50-mg, 100-mg, and 150-mg groups, respectively, and were significantly higher in the 50-mg group (P = 0.007) and the 100-mg and 150-mg groups (P = 0.002) as compared to the response rates in the placebo group (29.3%). The mean change from baseline in DAS28-CRP was greater in the 50-mg, 100-mg, and 150-mg groups as compared to the placebo group (P < 0.001). Decernotinib treatment resulted in higher ACR50 and ACR70 response rates, more patients with DAS28-CRP scores <2.6, and improvements in the Health Assessment Questionnaire disability index as compared to placebo. The most common adverse events in any decernotinib group were nausea (6.1%), headache (4.3%), an increase in levels of alanine aminotransferase (4.3%), and hypercholesterolemia (3.7%). In the groups receiving decernotinib, there was an increased risk of infections and increased liver transaminase levels. Conclusion Decernotinib was efficacious in improving clinical signs and symptoms of RA at week 12 at dosages of 50–150 mg twice a day. Infections and increases in liver transaminase and lipid levels were noted as potential safety signals.
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References27
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#1John J. O'Shea (NIH: National Institutes of Health)H-Index: 137
#2Apostolos Kontzias (NIH: National Institutes of Health)H-Index: 5
Last. Arian Laurence (NIH: National Institutes of Health)H-Index: 60
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Biological therapies directed at proinflammatory cytokines have irrevocably changed the landscape of treatment of rheumatoid arthritis (RA) and other autoimmune diseases. With the advances in our knowledge in cytokine signalling, the question emerges whether targeting intracellular signalling might also be a safe and efficacious strategy. Janus kinases or Jaks are critical for a large family of cytokines and the first Jak inhibitors has been approved by the FDA. It is therefore timely to conside...
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#1Gerd R Burmester (Charité)H-Index: 95
#2Ricardo BlancoH-Index: 61
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Summary Background Rheumatoid arthritis is a heterogeneous chronic disease, and no therapeutic agent has been identified which is universally and persistently effective in all patients. We investigated the effectiveness of tofacitinib (CP-690,550), a novel oral Janus kinase inhibitor, as a targeted immunomodulator and disease-modifying therapy for rheumatoid arthritis. Methods We did a 6-month, double-blind, parallel-group phase 3 study at 82 centres in 13 countries, including North America, Eur...
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#1Vasileios C. Kyttaris (BIDMC: Beth Israel Deaconess Medical Center)H-Index: 38
The outlook for patients with rheumatoid arthritis has improved significantly over the last three decades with the use of disease-modifying antirheumatic drugs. However, despite the use of methotrexate, cytokine inhibitors, and molecules targeting T and B cells, a percentage of patients do not respond or lose their response over time. The autoimmune process in rheumatoid arthritis depends on activation of immune cells, which utilize intracellular kinases to respond to external stimuli such as cy...
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At month 3, a higher percentage of patients in the tofacitinib groups than in the placebo groups met the criteria for an ACR 20 response (59.8% in the 5-mg tofacitinib group and 65.7% in the 10-mg tofacitinib group vs. 26.7% in the combined placebo groups, P<0.001 for both comparisons). The reductions from baseline in HAQ-DI scores were greater in the 5-mg and 10-mg tofacitinib groups than in the placebo groups (−0.50 and −0.57 points, respectively, vs. −0.19 points; P<0.001). The percentage of ...
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#1Ronald F van Vollenhoven (KI: Karolinska Institutet)H-Index: 81
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Background Tofacitinib (CP-690,550) is a novel oral Janus kinase inhibitor that is being investigated for the treatment of rheumatoid arthritis. Methods In this 12-month, phase 3 trial, 717 patients who were receiving stable doses of methotrexate were randomly assigned to 5 mg of tofacitinib twice daily, 10 mg of tofacitinib twice daily, 40 mg of adalimumab once every 2 weeks, or placebo. At month 3, patients in the placebo group who did not have a 20% reduction from baseline in the number of sw...
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RA is defined by the interrelated triad of disease activity, joint damage and disability. Although disease activity and its associated disability are reversible, joint damage and its associated disability are not. Thus, an important goal of RA therapy is to maximally reduce disease activity and thereby mitigate the accumulation of irreversible joint damage. Treatment for patients with RA should be initiated early and aggressively, with frequent assessments and a goal of achieving remission as qu...
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#1Yoshiya Tanaka (University of Occupational and Environmental Health Japan)H-Index: 93
#2Y. Maeshima (University of Occupational and Environmental Health Japan)H-Index: 1
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Multiple cytokines play a pivotal role in the pathogenesis of rheumatoid arthritis (RA). The appropriate intracellular signalling pathways must be activated via cytokine receptors on the cell surface, and the tyrosine kinases transduce the first ‘outside to in’ signals to be phosphorylated after receptor binding to its ligand. Among them, members of the Janus kinase (JAK) family are essential for the signalling pathways of various cytokines and are implicated in the pathogenesis of RA. The in vi...
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#1Roy Fleischmann (UTSW: University of Texas Southwestern Medical Center)H-Index: 81
#2Maurizio Cutolo (UniGe: University of Genoa)H-Index: 101
Last. Samuel H. Zwillich (Pfizer)H-Index: 31
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Objective To compare the efficacy, safety, and tolerability of 5 doses of oral tofacitinib (CP-690,550) or adalimumab monotherapy with placebo for the treatment of active rheumatoid arthritis (RA) in patients with an inadequate response to disease-modifying antirheumatic drugs. Methods In this 24-week, double-blind, phase IIb study, patients with RA (n = 384) were randomized to receive placebo, tofacitinib at 1, 3, 5, 10, or 15 mg administered orally twice a day, or adalimumab at 40 mg injected ...
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Objectives To review the evidence for the efficacy and safety of biological agents in patients with rheumatoid arthritis (RA) to provide data to develop treatment recommendations by the European League Against Rheumatism (EULAR) Task Force. Methods Medline, Embase and Cochrane databases were searched for relevant articles on infliximab (IFX), etanercept (ETN), adalimumab (ADA), certolizumab-pegol (CZP), golimumab (GLM), anakinra (ANA), abatacept (ABT), rituximab (RTX) and tocilizumab (TCZ) publi...
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Objective To determine the efficacy, safety, and tolerability of 3 different dosages of CP-690,550, a potent, orally active JAK inhibitor, in patients with active rheumatoid arthritis (RA) in whom methotrexate, etanercept, infliximab, or adalimumab caused an inadequate or toxic response. Methods Patients (n = 264) were randomized equally to receive placebo, 5 mg of CP-690,550, 15 mg of CP-690,550, or 30 mg of CP-690,550 twice daily for 6 weeks, and were followed up for an additional 6 weeks afte...
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