Janus kinase inhibitors for the treatment of rheumatoid arthritis demonstrate similar profiles of in vitro cytokine receptor inhibition

Abstract

Janus kinase (JAK) inhibitors have emerged as an effective class of therapies for various inflammatory diseases such as rheumatoid arthritis (RA). JAK inhibitors function intracellularly by modulating the catalytic activity of JAKs and disrupting the receptor-mediated signaling of multiple cytokines and growth factors, including those with pro-inflammatory activity. Understanding the inhibition profiles of different JAK inhibitors, based on the associated cytokine receptors and downstream inflammatory pathways affected, is important to identify the potential mechanisms for observed differences in efficacy and safety. This study applied an integrated modeling approach, using in vitro whole blood cytokine inhibition potencies and plasma pharmacokinetics, to determine JAK-dependent cytokine receptor inhibition profiles, in the context of doses estimated to provide a similar clinical response in RA clinical trials. The calculated profiles of cytokine receptor inhibition for the JAK inhibitors tofacitinib, baricitinib, upadacitinib, and filgotinib and its metabolite, were generally similar when clinically efficacious doses for RA were considered. Only minor numerical differences in percentage cytokine receptor inhibition were observed, suggesting limited differentiation of these inhibitors based on JAK pharmacology, with each showing a differential selectivity for JAK1 heterodimer inhibition. Nevertheless, only robust clinical testing involving head-to-head studies will ultimately determine whether there are clinically meaningful differences between these JAK inhibitors. Furthermore, ongoing and future research into inhibitors with alternative JAK selectivity remains of clinical importance. Thus, all JAK inhibitors should be characterized via thorough preclinical, metabolic and pharmacological evaluation, adequate long-term clinical data, and when available, real-world experience.

Keywords: JAK‐STAT; cytokine receptors; immunopharmacology; inhibition; rheumatoid arthritis.

Figure 1

Cytokine receptor inhibitory concentrations for modeled exposures of tofacitinib 5 mg BID, baricitinib 4 mg QD, upadacitinib 15 mg QD, and filgotinib/metabolite 200 mg QD. BID, twice daily; CD, cluster of differentiation; EPO, erythropoietin; G‐CSF, granulocyte colony‐stimulating factor; GM‐CSF, granulocyte‐macrophage colony‐stimulating factor; IC_xx, proportion of JAK inhibitory concentration; IFN, interferon; IL, interleukin; JAK, Janus kinase; pSTAT, phosphorylated signal transducer and activator of transcription protein; QD, once daily; TPO, thrombopoietin; TYK, tyrosine kinase