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 diseasemodifying 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.

Network pharmacology of JAK inhibitors

“…2B). This overlap is consistent with reported efficacy in early RA trials for both JAK1i and a reported JAK3i-biased inhibitor (8,29,30). There were, however, quantitative differences between signatures of isoform-specific JAKi (e.g., JAK1i remains more effective than JAK3i at inhibiting ISGs), and the comparative effect of JAK1i and JAK3i on the IL-2 response varies with dosage.…”

Efficacy of VX-509 (decernotinib) in combination with a disease-modifying antirheumatic drug in patients with rheumatoid arthritis: clinical and MRI findings

“…Patients treated with VX-509 experienced mild but consistent dose-dependent increases in alanine aminotransferase, aspartate aminotransferase and creatine kinase. The increases in cholesterol and liver enzymes in patients receiving VX-509 in this study were similar to those observed in prior studies 10 11…”

“…Dose-dependent responses were observed for DAS28-CRP and DAS28-ESR scores, ACR response and RAMRIS scores for synovitis and osteitis. No new safety concerns developed, and treatment was generally well tolerated, with an AE profile similar to that previously seen for this agent 10 11. These findings complement those of phase II studies that demonstrated the efficacy and safety of VX-509 as monotherapy10 and in combination with methotrexate in patients with RA 11…”

“…A 12-week, placebo-controlled, phase IIa study previously demonstrated that twice-daily VX-509 50, 100 or 150 mg as monotherapy improved signs and symptoms of RA in patients with insufficient response to disease-modifying antirheumatic drugs (DMARDs). Safety signals included infections and increased liver transaminase and lipid levels 10. In a second, 24-week, placebo-controlled, phase IIb study,11 VX-509 (100, 150 or 200 mg per day or 100 mg twice daily) administered in combination with methotrexate alleviated the signs and symptoms of RA in patients who had an inadequate response to methotrexate.…”

Janus kinase inhibitors in autoimmune diseases

“…32 Moreover, a reportedly selective Jak1 inhibitor, GLPG0634, also met its primary endpoint in a phase IIa RA trial with no anaemia and no lipid abnormalities observed. 33 CEP-33779, a selective Jak2 inhibitor, showed efficacy in two preclinical arthritis models.…”