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.

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.

• Authors: Roy M Fleischmann, Nemanja S Damjanov, Alan J Kivitz, Anna Legedza, Thomas Hoock, Nils Kinnman
• Journal: Arthritis & rheumatology (Hoboken, N.J.) (Arthritis Rheumatol) Vol. 67 Issue 2 Pg. 334-43 (Feb 2015) ISSN: 2326-5205 [Electronic] United States
• PMID: 25385260 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 by the American College of Rheumatology.

Chemical References

• 2-((2-(1H-pyrrolo(2,3-b)pyridin-3-yl)pyrimidin-4-yl)amino)-2-methyl-N-(2,2,2-trifluoroethyl)butanamide
• Antirheumatic Agents
• Enzyme Inhibitors
• Heterocyclic Compounds, 2-Ring
• Alanine Transaminase
• Janus Kinase 3
• Valine

Topics

• Administration, Oral
• Adult
• Aged
• Alanine Transaminase (metabolism)
• Antirheumatic Agents (administration & dosage, adverse effects, therapeutic use)
• Arthritis, Rheumatoid (drug therapy, metabolism)
• Disability Evaluation
• Dose-Response Relationship, Drug
• Double-Blind Method
• Enzyme Inhibitors (administration & dosage, adverse effects, therapeutic use)
• Female
• Heterocyclic Compounds, 2-Ring (therapeutic use)
• Humans
• Janus Kinase 3 (antagonists & inhibitors)
• Liver (enzymology)
• Longitudinal Studies
• Male
• Middle Aged
• Outcome Assessment, Health Care
• Surveys and Questionnaires
• Treatment Outcome
• Valine (analogs & derivatives, therapeutic use)