The Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of a TYK2/JAK1 Inhibitor (PF‐06700841) in Healthy Subjects and Patients With Plaque Psoriasis

Banfield, Christopher; Scaramozza, Matthew; Zhang, Weidong; Kieras, Elizabeth; Page, Karen; Fensome, Andrew; Vincent, Michael S.; Dowty, Martin E.; Goteti, Kosalaram; Winkle, Peter; Peeva, Elena

doi:10.1002/jcph.1046

Cited by 82 publications

(98 citation statements)

References 32 publications

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“…BMS‐986165 is a selective TYK2 inhibitor being studied in SLE, psoriasis, psoriatic arthritis, and IBD. PF‐06700841 is a TYK2/JAK1 inhibitor being tested in psoriasis, IBD, and alopecia areata. Additional TYK2 inhibitors are also being developed …”

Section: Next‐generation Selective Jakinibsmentioning

confidence: 99%

Translational and clinical advances in JAK-STAT biology: The present and future of jakinibs

Gadina

Johnson

Schwartz

et al. 2018

Journal of Leukocyte Biology

128

100

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In this era, it is axiomatic that cytokines have critical roles in cellular development and differentiation, immune homeostasis, and host defense. Equally, dysregulation of cytokines is known to contribute to diverse inflammatory and immune-mediated disorders. In fact, the past 20 years have witnessed the rapid translation of basic discoveries in cytokine biology to multiple successful biological agents (mAbs and recombinant fusion proteins) that target cytokines. These targeted therapies have not only fundamentally changed the face of multiple immune-mediated diseases but have also unequivocally established the role of specific cytokines in human disease; cytokine biologists have many times over provided remarkable basic advances with direct clinical benefit. Numerous cytokines rely on the JAK-STAT pathway for signaling, and new, safe, and effective small molecule inhibitors have been developed for a range of disorders. In this review, we will briefly summarize basic discoveries in cytokine signaling and briefly comment on some major unresolved issues. We will review clinical data pertaining to the first generation of JAK inhibitors and their clinical indications, discuss additional opportunities for targeting this pathway, and lay out some of the challenges that lie ahead.

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Section: Next‐generation Selective Jakinibsmentioning

confidence: 99%

Translational and clinical advances in JAK-STAT biology: The present and future of jakinibs

Gadina

Johnson

Schwartz

et al. 2018

Journal of Leukocyte Biology

128

100

View full text Add to dashboard Cite

show abstract

“…To avoid JAK2 inhibition mediated side effects, dual JAK1/TYK2 inhibition without influence on JAK2 signaling could be interesting. PF-06700841 is a new selective JAK inhibitor also mainly targeting TYK2 but also JAK1 76,77 .…”

Section: New Jak Related Molecules In Deveopment In CDmentioning

confidence: 99%

Efficacy of JAK inhibitors in Crohn’s Disease

Rogler

2019

Journal of Crohn's and Colitis

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Inhibition of Janus kinases in Crohn’s disease (CD) patients has shown conflicting results in clinical trials. Tofacitinib, a pan-JAK inhibitor showed efficacy in ulcerative colitis (UC) and has been approved for the treatment of patients with moderate to severe UC. In contrast, studies in patients suffering from CD were disappointing and the primary endpoint of clinical remission could not be met in the respective phase II induction and maintenance trials. Subsequently, the clinical development of tofacitinib was discontinued in CD. In contrast, efficacy of filgotinib, a selective JAK1 inhibitor, in CD patients was demonstrated in the randomized, double-blinded, placebo-controlled phase II FITZROY study. Upadacitinib also showed promising results in a phase II trial in moderate to severe CD. Subsequently phase III programs in CD have been initiated for both substances, which are still ongoing. Several newer molecules of this class of orally administrated immunosuppressants are tested in clinical programs. The concern of side effects of systemic JAK inhibition is addressed by either exclusively intestinal action or higher selectivity (Tyk2 inhibitors). In general, JAK inhibitors constitute a new promising class of drugs for the treatment of CD.

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“…The pharmacological inhibition of TYK2 (TYK2inibs) is a recognized approach to the treatment of chronic inflammatory and autoimmune diseases and is under consideration for cancer treatment. Several TYK2inibs are in clinical trials [108,[251][252][253]. A CTLA-4-TYK2-STAT3 axis has been reported in B cell lymphoma cells and tumor-associated B cells [254] and will be relevant to immune checkpoint therapy.…”

Section: Discussionmentioning

confidence: 99%

TYK2 in Tumor Immunosurveillance

Karjalainen¹,

Shoebridge²,

Krunic³

et al. 2020

Cancers

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We review the history of the tyrosine kinase 2 (TYK2) as the founding member of the Janus kinase (JAK) family and outline its structure-function relation. Gene-targeted mice and hereditary defects of TYK2 in men have established the biological and pathological functions of TYK2 in innate and adaptive immune responses to infection and cancer and in (auto-)inflammation. We describe the architecture of the main cytokine receptor families associated with TYK2, which activate signal transducers and activators of transcription (STATs). We summarize the cytokine receptor activities with well characterized dependency on TYK2, the types of cells that respond to cytokines and TYK2 signaling-induced cytokine production. TYK2 may drive beneficial or detrimental activities, which we explain based on the concepts of tumor immunoediting and the cancer-immunity cycle in the tumor microenvironment. Finally, we summarize current knowledge of TYK2 functions in mouse models of tumor surveillance. The biology and biochemistry of JAKs, TYK2-dependent cytokines and cytokine signaling in tumor surveillance are well covered in recent reviews and the oncogenic properties of TYK2 are reviewed in the recent Special Issue ‘Targeting STAT3 and STAT5 in Cancer’ of Cancers.

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The Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of a TYK2/JAK1 Inhibitor (PF‐06700841) in Healthy Subjects and Patients With Plaque Psoriasis

Cited by 82 publications

References 32 publications

Translational and clinical advances in JAK-STAT biology: The present and future of jakinibs

Translational and clinical advances in JAK-STAT biology: The present and future of jakinibs

Efficacy of JAK inhibitors in Crohn’s Disease

TYK2 in Tumor Immunosurveillance

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