VX-509 (Decernotinib), an Oral Selective JAK-3 Inhibitor, in Combination With Methotrexate in Patients With Rheumatoid Arthritis

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Abstract

To assess the efficacy and safety of decernotinib (VX-509), an oral selective inhibitor of JAK-3, in patients with rheumatoid arthritis (RA) in whom the response to methotrexate treatment was inadequate.

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Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis.

Roy Fleischmann, Joel Kremer, John M Cush … (2012)

Tofacitinib (CP-690,550) is a novel oral Janus kinase inhibitor that is being investigated as a targeted immunomodulator and disease-modifying therapy for rheumatoid arthritis. In this phase 3, double-blind, placebo-controlled, parallel-group, 6-month study, 611 patients were randomly assigned, in a 4:4:1:1 ratio, to 5 mg of tofacitinib twice daily, 10 mg of tofacitinib twice daily, placebo for 3 months followed by 5 mg of tofacitinib twice daily, or placebo for 3 months followed by 10 mg of tofacitinib twice daily. The primary end points, assessed at month 3, were the percentage of patients with at least a 20% improvement in the American College of Rheumatology scale (ACR 20), the change from baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) scores (which range from 0 to 3, with higher scores indicating greater disability), and the percentage of patients with a Disease Activity Score for 28-joint counts based on the erythrocyte sedimentation rate (DAS28-4[ESR]) of less than 2.6 (with scores ranging from 0 to 9.4 and higher scores indicating more disease activity). 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 patients with a DAS28-4(ESR) of less than 2.6 was not significantly higher with tofacitinib than with placebo (5.6% and 8.7% in the 5-mg and 10-mg tofacitinib groups, respectively, and 4.4% with placebo; P=0.62 and P=0.10 for the two comparisons). Serious infections developed in six patients who were receiving tofacitinib. Common adverse events were headache and upper respiratory tract infection. Tofacitinib treatment was associated with elevations in low-density lipoprotein cholesterol levels and reductions in neutrophil counts. In patients with active rheumatoid arthritis, tofacitinib monotherapy was associated with reductions in signs and symptoms of rheumatoid arthritis and improvement in physical function. (Funded by Pfizer; ORAL Solo ClinicalTrials.gov number, NCT00814307.).

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Remission in rheumatoid arthritis: agreement of the disease activity score (DAS28) with the ARA preliminary remission criteria.

Raymond Creemers, Klaas van Gisbergen, Gerdine A J Fransen (2004)

To determine which cut-off point in the RA disease activity score (DAS28) corresponds to fulfilment of the ARA criteria for clinical remission. The disease activity of patients included in the Nijmegen RA inception cohort was systematically assessed every 3 months. For all visits, a modification of the ARA preliminary criteria for clinical remission was applied and the DAS28 was calculated. Receiver operating characteristic analysis was used to determine the cut-off point with maximum sensitivity and specificity in DAS28 corresponding with fulfilment of the modified ARA criteria. Three hundred and seventy-eight patients contributed 4378 visits. In 6.5% of the visits four of the five items and in 1.5% all five items of the modified ARA criteria were fulfilled. The optimal cut-off point for the DAS28 that corresponds to fulfilment of the modified ARA criteria was determined to be 2.66. DAS28 <2.6 corresponds to fulfilment of the preliminary ARA criteria for clinical remission in RA.

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Phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) or adalimumab monotherapy versus placebo in patients with active rheumatoid arthritis with an inadequate response to disease-modifying antirheumatic drugs.

Roy Fleischmann, Maurizio Cutolo, Mark C Genovese … (2012)

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. 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 subcutaneously every 2 weeks (total of 6 injections) followed by oral tofacitinib at 5 mg twice a day for 12 weeks. The primary end point was the responder rate according to the American College of Rheumatology 20% improvement criteria (ACR20) at week 12. Treatment with tofacitinib at a dose of ≥3 mg twice a day resulted in a rapid response with significant efficacy when compared to placebo, as indicated by the primary end point (ACR20 response at week 12), achieved in 39.2% (3 mg; P ≤ 0.05), 59.2% (5 mg; P < 0.0001), 70.5% (10 mg; P < 0.0001), and 71.9% (15 mg; P < 0.0001) in the tofacitinib group and 35.9% of patients in the adalimumab group (P = 0.105), compared with 22.0% of patients receiving placebo. Improvements were sustained at week 24, according to the ACR20, ACR50, and ACR70 response rates as well as classifications of remission according to the 3-variable Disease Activity Score in 28 joints (DAS28) using C-reactive protein and the 4-variable DAS28 using the erythrocyte sedimentation rate. The most common treatment-emergent adverse events (AEs) in patients across all tofacitinib treatment arms (n = 272) were urinary tract infection (7.7%), diarrhea (4.8%), headache (4.8%), and bronchitis (4.8%). Tofacitinib monotherapy at ≥3 mg twice a day was efficacious in the treatment of patients with active RA over 24 weeks and demonstrated a manageable safety profile. Copyright © 2012 by the American College of Rheumatology.

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Author and article information

Journal

Title: Arthritis & Rheumatology

Abbreviated Title: Arthritis & Rheumatology

Publisher: Wiley-Blackwell

ISSN: 23265191

Publication date Created: January 2016

Publication date (Print): January 2016

Volume: 68

Issue: 1

Pages: 46-55

Article

DOI: 10.1002/art.39473

PubMed ID: 26473751

SO-VID: 7920c7ab-065a-4928-b150-62d31d9d9ae6

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http://doi.wiley.com/10.1002/tdm_license_1.1

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VX-509 (Decernotinib), an Oral Selective JAK-3 Inhibitor, in Combination With Methotrexate in Patients With Rheumatoid Arthritis : VX-509 WITH METHOTREXATE FOR RHEUMATOID ARTHRITIS

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SDG 3: Good Health and Well-Being

Most cited references 19

Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis.

Remission in rheumatoid arthritis: agreement of the disease activity score (DAS28) with the ARA preliminary remission criteria.

Phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) or adalimumab monotherapy versus placebo in patients with active rheumatoid arthritis with an inadequate response to disease-modifying antirheumatic drugs.

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