Efficacy and safety of the Janus kinase 1 inhibitor PF-04965842 in patients with moderate-to-severe psoriasis: phase II, randomized, double-blind, placebo-controlled study

Schmieder, George J.; Draelos, Zoe Diana; Pariser, David M.; Banfield, Christopher; Cox, Lori Ann; Hodge, Martin R.; Kieras, Elizabeth; Parsons‐Rich, Dana; Menon, Sandeep; Salganik, M.P.; Page, Karen; Peeva, E

doi:10.1111/bjd.16004

Cited by 76 publications

(73 citation statements)

References 20 publications

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“…A clinical study with JAK1/2 inhibitor baricitinib, however, revealed significantly improved SLE symptoms, supporting a critical role of JAK/STAT signaling in the pathogenesis of SLE (48). As activated JAK1 elicits signals from a wide range of cytokine receptors [such as interleukin (IL)-2-, IL-4-, and IL-10-receptor families besides type I and type II IFN], specific JAK1 inhibitors are under investigation in further inflammatory skin conditions, including atopic dermatitis (AD) (49) and psoriasis (PSO) (50), which demonstrated significant beneficial effects in clinical trials, as well as hidradenitis suppurativa (NCT03569371).…”

Section: Discussionmentioning

confidence: 99%

Selective Janus Kinase 1 Inhibition Is a Promising Therapeutic Approach for Lupus Erythematosus Skin Lesions

et al. 2020

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Background: Cutaneous lupus erythematosus (CLE) is an interferon (IFN)-driven autoimmune skin disease characterized by an extensive cytotoxic lesional inflammation with activation of different innate immune pathways. Aim of our study was to investigate the specific role of Janus kinase 1 (JAK1) activation in this disease and the potential benefit of selective JAK1 inhibitors as targeted therapy in a preclinical CLE model. Methods: Lesional skin of patients with different CLE subtypes and healthy controls (N = 31) were investigated on JAK1 activation and expression of IFN-associated mediators via immunohistochemistry and gene expression analyses. The functional role of JAK1 and efficacy of inhibition was evaluated in vitro using cultured keratinocytes stimulated with endogenous nucleic acids. Results were confirmed in vivo using an established lupus-prone mouse model. Results: Proinflammatory immune pathways, including JAK/STAT signaling, are significantly upregulated within inflamed CLE skin. Here, lesional keratinocytes and dermal immune cells strongly express activated phospho-JAK1. Selective pharmacological JAK1 inhibition significantly reduces the expression of typical proinflammatory mediators such as CXCL chemokines, BLyS, TRAIL, and AIM2 in CLE in vitro models and also improves skin lesions in lupus-prone TREX1 −/−-mice markedly. Conclusion: IFN-associated JAK/STAT activation plays a crucial role in the pathophysiology of CLE. Selective inhibition of JAK1 leads to a decrease of cytokine expression, reduced immune activation, and decline of keratinocyte cell death. Topical treatment with a JAK1-specific inhibitor significantly improves CLE-like skin lesions in a lupus-prone TREX1 −/−-mouse model and appears to be a promising therapeutic approach for CLE patients.

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Section: Discussionmentioning

confidence: 99%

Selective Janus Kinase 1 Inhibition Is a Promising Therapeutic Approach for Lupus Erythematosus Skin Lesions

et al. 2020

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“…A clinical trial, designed to compare upadacitinib with adalimumab and placebo is ongoing (NCT02629159); all told, at least 20 clinical trials are ongoing in arthritis, IBD, and dermatological diseases (Table ). Itacitinib is also a selective JAK1 inhibitor being studied in phase 3 trials in GVHD (NCT03139604, NCT03320642) and malignancies (hematologic and solid tumor), and PF‐ 04965842 is a JAK1 inhibitor being investigated for treatment of psoriasis and atopic dermatitis . GSK2586184 is a selective JAK1 inhibitor studied in IBD, SLE, and psoriasis but a clinical trial is reported to be terminated because of drug interactions with statins (NCT02000453).…”

Section: Next‐generation Selective Jakinibsmentioning

confidence: 99%

“…inhibitor being studied in phase 3 trials in GVHD (NCT03139604, NCT03320642) and malignancies (hematologic and solid tumor), and PF-04965842 is a JAK1 inhibitor being investigated for treatment of psoriasis and atopic dermatitis. 174,175 GSK2586184 is a selective JAK1 inhibitor studied in IBD, SLE, and psoriasis but a clinical trial is reported to be terminated because of drug interactions with statins (NCT02000453).…”

Section: Jak1 Inhibitorsmentioning

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

129

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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“…A JAK1 inhibitor, PF-04965842, is also in clinical trials in atopic dermatis and severe psoriasis 112 . Both topical tofacitinib and ruxolitinib are tested for alopecia and vitiligo.…”

Section: Jak Inhibitor Therapiesmentioning

confidence: 99%

JAK inhibitors for the treatment of myeloproliferative neoplasms and other disorders

et al. 2018

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JAK inhibitors have been developed following the discovery of the JAK2V617F in 2005 as the driver mutation of the majority of non- BCR-ABL1 myeloproliferative neoplasms (MPNs). Subsequently, the search for JAK2 inhibitors continued with the discovery that the other driver mutations ( CALR and MPL) also exhibited persistent JAK2 activation. Several type I ATP-competitive JAK inhibitors with different specificities were assessed in clinical trials and exhibited minimal hematologic toxicity. Interestingly, these JAK inhibitors display potent anti-inflammatory activity. Thus, JAK inhibitors targeting preferentially JAK1 and JAK3 have been developed to treat inflammation, autoimmune diseases, and graft-versus-host disease. Ten years after the beginning of clinical trials, only two drugs have been approved by the US Food and Drug Administration: one JAK2/JAK1 inhibitor (ruxolitinib) in intermediate-2 and high-risk myelofibrosis and hydroxyurea-resistant or -intolerant polycythemia vera and one JAK1/JAK3 inhibitor (tofacitinib) in methotrexate-resistant rheumatoid arthritis. The non-approved compounds exhibited many off-target effects leading to neurological and gastrointestinal toxicities, as seen in clinical trials for MPNs. Ruxolitinib is a well-tolerated drug with mostly anti-inflammatory properties. Despite a weak effect on the cause of the disease itself in MPNs, it improves the clinical state of patients and increases survival in myelofibrosis. This limited effect is related to the fact that ruxolitinib, like the other type I JAK2 inhibitors, inhibits equally mutated and wild-type JAK2 (JAK2WT) and also the JAK2 oncogenic activation. Thus, other approaches need to be developed and could be based on either (1) the development of new inhibitors specifically targeting JAK2V617F or (2) the combination of the actual JAK2 inhibitors with other therapies, in particular with molecules targeting pathways downstream of JAK2 activation or the stability of JAK2 molecule. In contrast, the strong anti-inflammatory effects of the JAK inhibitors appear as a very promising therapeutic approach for many inflammatory and auto-immune diseases.

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Efficacy and safety of the Janus kinase 1 inhibitor PF-04965842 in patients with moderate-to-severe psoriasis: phase II, randomized, double-blind, placebo-controlled study

Abstract: These results suggest that treatment with PF-04965842 improves symptoms and is well tolerated in patients with moderate-to-severe psoriasis.

Cited by 76 publications

References 20 publications

Selective Janus Kinase 1 Inhibition Is a Promising Therapeutic Approach for Lupus Erythematosus Skin Lesions

Selective Janus Kinase 1 Inhibition Is a Promising Therapeutic Approach for Lupus Erythematosus Skin Lesions

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

JAK inhibitors for the treatment of myeloproliferative neoplasms and other disorders

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