Phase 2 Trial of Selective Tyrosine Kinase 2 Inhibition in Psoriasis

Papp, Kim; Gordon, Kenneth B.; Thaçi, Diamant; Morita, Akimichi; Gooderham, Melinda; Foley, Peter; Girgis, Ihab; Kundu, Sudeep; Banerjee, Subhashis

doi:10.1056/nejmoa1806382

Cited by 322 publications

(361 citation statements)

References 22 publications

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“…Possible differences in clinical profiles of compounds selective for TYK2 or JAK3 vs those selective for JAK1 are evidenced in early study data, although further research in more robust settings is required. For example, BMS‑986165 has not been associated with laboratory changes such as increased lipid levels, which can occur with IL‐6 inhibition …”

Section: Discussionmentioning

confidence: 99%

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

Dowty

Lin

Jesson

et al. 2019

Pharmacology Res & Perspec

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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.

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Section: Discussionmentioning

confidence: 99%

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

Dowty

Lin

Jesson

et al. 2019

Pharmacology Res & Perspec

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“…This causes inhibition of the downstream pleiotropic effects of IL‐17RA and probably explains the potentially higher clinical efficacy obtainable by receptor blockade compared to neutralization of a single ligand . In line with the efficacy of blocking downstream cytokine signaling are the impressive Phase II data on the TYK2 inhibitor BMS‐986165, where PASI75 was obtained for 75% of patients at week 12 .…”

Section: From Disease Understanding To Biomarkers Endotypes and Tarmentioning

confidence: 99%

Personalized medicine—concepts, technologies, and applications in inflammatory skin diseases

Litman

2019

APMIS

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“…Given the success of JAK inhibition in many inflammatory disorders, then it is envisaged that specific antagonism of Tyk2 will lead to novel oral anti‐IL‐23 therapeutic strategies. Indeed, proof of concept for Tyk2 blockers has already been furnished in psoriasis . The TNF blockers and IL‐17A blockers do not signal directly via JAK/STAT pathways, yet there is emerging evidence for several JAK inhibitors in both AS and PsA.…”

Section: The Il‐23 Cytokinementioning

confidence: 99%

Interleukin‐23 pathway at the enthesis: The emerging story of enthesitis in spondyloarthropathy

Bridgewood

Sharif

Sherlock

et al. 2020

Immunological Reviews

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The inflammatory disorders collectively termed the seronegative spondyloarthropathies (SpA) include ankylosing spondylitis (AS), psoriatic arthritis (PsA), reactive arthritis, the arthritis associated with inflammatory bowel disease including Crohn's disease and ulcerative colitis, the arthritis related to anterior uveitis, and finally, somewhat controversially Behcet's disease. All of these diseases are associated with SNPs in the IL‐23R or the interleukin‐23 (IL‐23) cytokine itself and related downstream signaling JAK pathway genes and the interleukin‐17 (IL‐17) pathway. In rheumatoid arthritis, the target of the immune response is the synovium but the SpA disorders target the tendon, ligament, and joint capsule skeletal anchorage points that are termed entheses. The discovery that IL‐23R–expressing cells were ensconced in healthy murine enthesis, and other extraskeletal anchorage points including the aortic root and the ciliary body of the eye and that systemic overexpression of IL‐23 resulted in a severe experimental SpA, confirmed a fundamentally different immunobiology to rheumatoid arthritis. Recently, IL‐23R–expressing myeloid cells and various innate and adaptive T cells that produce IL‐17 family cytokines have also been described in the human enthesis. Blockade of IL‐23 pathway with either anti‐p40 or anti‐p19 subunits has resulted in some spectacular therapeutic successes in psoriasis and PsA including improvement in enthesitis in the peripheral skeleton but has failed to demonstrate efficacy in AS that is largely a spinal polyenthesitis. Herein, we discuss the known biology of IL‐23 at the human enthesis and highlight the remarkable emerging story of this unique skeletal tissue.

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Phase 2 Trial of Selective Tyrosine Kinase 2 Inhibition in Psoriasis

Cited by 322 publications

References 22 publications

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

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

Personalized medicine—concepts, technologies, and applications in inflammatory skin diseases

Interleukin‐23 pathway at the enthesis: The emerging story of enthesitis in spondyloarthropathy

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