Efficacy and Safety of PF‐06651600 (Ritlecitinib), a Novel JAK3/TEC Inhibitor, in Patients With Moderate‐to‐Severe Rheumatoid Arthritis and an Inadequate Response to Methotrexate

Abstract

Objective. To evaluate the efficacy and safety of PF-06651600 (ritlecitinib), an irreversible inhibitor of JAK3 and the tyrosine kinase expressed in hepatocellular carcinoma (TEC) kinase family, in comparison with placebo in patients with rheumatoid arthritis (RA). Methods. An 8-week, phase II, double-blind, parallel-group study was conducted. Seventy patients who were seropositive for anti-citrullinated protein antibodies and/or rheumatoid factor were randomized 3:2 to receive oral PF-06651600 (200 mg once daily) or placebo for 8 weeks. Eligible patients had an inadequate response to methotrexate, and the study design allowed up to 50% of patients to have previously received 1 tumor necrosis factor inhibitor that was inadequately effective and/or not tolerated. The primary end point was change from baseline in the Simplified Disease Activity Index (SDAI) score at week 8, assessed by Bayesian analysis using an informative prior distribution for placebo response. Results. Mean change from baseline in the SDAI score at week 8 was greater in the PF-06651600 group (−26.1 [95% credible interval −29.7, −22.4]) than in the placebo group (−16.8 [95% credible interval −20.9, −12.7]; P < 0.001). Most adverse events (AEs) were mild in severity, and no treatment-related serious AEs, severe AEs, or deaths were reported. The most common classes of AE were infections and infestations as well as skin and subcutaneous tissue disorders; there was 1 mild case of herpes simplex in the PF-06651600 group that was considered to be treatment related, which resolved within 3 days without study treatment discontinuation or antiviral therapy. Conclusion. Treatment with the oral JAK3/TEC inhibitor PF-06651600 (200 mg once daily) was associated with significant improvements in RA disease activity and was generally well-tolerated in this small 8-week study. ClinicalTrials.gov identifier: NCT02969044.

Small Molecule Inhibitors in the Treatment of Rheumatoid Arthritis and Beyond: Latest Updates and Potential Strategy for Fighting COVID-19

“…The safety, tolerability and efficacy of itacitinib was evaluated in phase II study (NCT01626573) in RA patients, but results have not been posted. Ritlecitinib (PF-06651600) is an irreversible inhibitor of JAK3 and the tyrosine kinase expressed in hepatocellular carcinoma (TEC) kinase family [ 66 ]. The efficacy and safety of ritlecitinib were evaluated in RA patients, who are seropositive for ACPA and/or RF with inadequate response to MTX.…”

“…The efficacy and safety of ritlecitinib were evaluated in RA patients, who are seropositive for ACPA and/or RF with inadequate response to MTX. Ritlecitinib was generally well-tolerated and its treatment was associated with significant improvements in RA disease activity [ 66 ]. Decernotinib (VX-509) is a potent inhibitor of JAK3 developed by Vertex Pharmaceuticals.…”

“…Most JAKi are likely to induce cytopenias, decreased neutrophil counts and anemia because of their more or less specific inhibition of JAK2 and erythropoietin together with other hematopoietic growth factors as IL-6 and IL-11 signaling [ 38 , 43 , 45 , 51 , 63 , 83 , 86 , 89 ]. However, ritlecitinib, a covalent JAK3 inhibitor with high selectivity over the other JAK isoforms JAK1 and JAK2, does not inhibit JAK2 [ 66 ]. The fact that ritlecitinib spares inhibition of JAK2 cytokine signaling, connected with some hematologic AE, has made this selective inhibitor an attractive therapeutic intervention.…”

JAK inhibitors: Ten years after

“…Thus, while ritlecitinib inhibits a narrow spectrum of Type I/II cytokine receptors, inhibition of TEC family kinases impacts signaling by the T‐cell antigen receptor, B‐cell antigen receptor, and chemokine receptors [20]. Ritlecitinib has been studied in RA and found to be superior to placebo [21]. It is also currently being studied in IBD, AA, and vitiligo (NCT03395184, NCT02958865, NCT02974868, NCT03732807, NCT04006457, NCT03715829).…”

Computational Study on Novel Natural Inhibitors Targeting Janus Kinase 3

“…JAKs phosphorylate sites on the cytokine receptor cytoplasmic tails, which create docking sites for signaling effectors, principally the signal transducers and activators of transcription (STATs). The STATs are then phosphorylated, resulting in nuclear translocation and regulating the expression of thousands of proteins [7]. Also, it has been shown that the activation of STAT3 can drive tumor metastasis, and JAK1 and JAK3 function at upstream of STAT3, which could be an necessary cascade reaction for activation of STAT3 [8].…”