Oral tyrosine kinase 2 inhibitor PF-06826647 demonstrates efficacy and an acceptable safety profile in participants with moderate-to-severe plaque psoriasis in a phase 2b, randomized, double-blind, placebo-controlled study

Tehlirian, Christopher; Singh, Ravi Shankar Prasad; Pradhan, Vivek; Roberts, Erika S; Tarabar, Sanela; Peeva, E; Vincent, Michael S.; Gale, Jeremy D.

doi:10.1016/j.jaad.2022.03.059

Cited by 31 publications

(38 citation statements)

References 43 publications

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“…Our data obtained using Tyk2-deficient mice and cells indicate that TYK2-mediated signals directly and/or indirectly contribute to these molecular events, suggesting the fundamental and functional roles of TYK2 in the appearance of psoriasis symptoms. Recently, highly selective TYK2 inhibitors, deucravacitinib (BMS-986165) and PF-06826647, have been developed and clinically tested for the treatment of psoriasis patients [52][53][54][55]. As expected, TYK2 inhibitors have a significant clinical impact with high efficacy and low risks.…”

Section: Discussionmentioning

confidence: 86%

Role of tyrosine kinase 2 signals during progression of psoriasis

2022

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Psoriasis is a skin disease characterized by scaly erythema, parakeratosis, and epidermal hyperplasia. Application of imiquimod (IMQ), a ligand for Toll-like receptor 7, produces a mouse model for psoriasis. IMQ application induces scaling, erythema, and thickness in skin lesions, and the symptoms are milder in interleukin-23 p19 (Il23p19)-deficient and Il17a-deficient mice than in wild-type mice; this suggests that the interleukin-23 (IL-23)/T helper 17 (Th17) axis and Th17 cell-secreting cytokines play essential roles in the IMQ-induced psoriasis model. It is notable that a genome-wide association study identified the human tyrosine kinase 2 (TYK2) gene within the psoriasis susceptibility locus. After IMQ application, mice lacking Tyk2, a mouse homologue of the human TYK2 gene, exhibited significantly lower symptom scores of psoriasis and diminished inflammatory cell infiltration in the skin lesions. Tyk2-deficient mice also failed to increase CD4+IL-17+ or CD4+ interferon-γ+ (IFN-γ+) T cells in the draining lymph nodes or to produce Th17 cell-related cytokines after IMQ application. Furthermore, Tyk2 deficiency led to diminished skin inflammation induced by IL-23 and IL-22 injections. These results indicate that Tyk2-mediated signals in mice contribute to multiple steps of immune and inflammatory responses during the development of psoriasis; therefore, TYK2 targeting may be a promising strategy to treat patients with psoriasis. Recent clinical trials have shown that TYK2 inhibitors have a high overall response rate with good tolerability in the management of psoriasis. This review describes the fundamental mechanisms of Tyk2 inhibition in immune/inflammatory diseases.

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Section: Discussionmentioning

confidence: 86%

Role of tyrosine kinase 2 signals during progression of psoriasis

2022

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“…Ropsacitinib, a selective TYK2 inhibitor, was compared to placebo in a phase IIb clinical trial to evaluate efficacy and safety in adult patients with moderate-to-severe plaque psoriasis. 78 A significantly greater proportion of patients treated with oral ropsacitinib 200 mg or 400 mg QD achieved PASI90 versus placebo at week 16 (Table 4). 78 Significant improvements were seen in all secondary efficacy endpoints (PASI50/75/90/100; PGA responses) at week 40 with both doses of ropsacitinib compared with placebo.…”

Section: Clinical Trial Data For Deucravacitinib and Other Tyk2 Inhib...mentioning

confidence: 99%

Clinical Implications of Targeting the JAK-STAT Pathway in Psoriatic Disease: Emphasis on the TYK2 Pathway

et al. 2022

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Cytokines in the interleukin (IL)−23/IL-17 axis are central to psoriasis pathogenesis. Janus kinase (JAK) signal transducer and activator of transcription (STAT) regulates intracellular signalling of several cytokines (including IL-12, 23, 22, 6, 17, and interferon (IFN)-γ) in the IL-23/IL-17 axis, and, as a result, has become a therapeutic target for psoriasis treatment. Although several JAK1-3 inhibitors, with varying degrees of selectivity, have been developed for immune-mediated inflammatory diseases, use in psoriasis is limited by a low therapeutic index as anticipated by signals from other disease indications. More selective inhibition of the JAK family is an area of interest. Specifically, selective tyrosine kinase (TYK)2 inhibition suppresses IL-23/IL-17 axis signalling, and at therapeutic doses, has a favorable safety profile compared to therapeutic doses of JAK1-3 inhibitors. Phase III efficacy and safety data for the selective allosteric TYK2-inhibitor, deucravacitinib, in adult patients with moderate-to-severe plaque psoriasis is promising. Furthermore, phase II clinical trials for ropsacitinib (PF-06826647), a selective TYK2 inhibitor, and brepocitinib (PF-06700841), a JAK1/TYK2 inhibitor, have also demonstrated efficacy and an acceptable safety profile in adult patients with moderate-to-severe plaque psoriasis. Other novel TYK2 allosteric inhibitors, NDI-034858 and ESK-001, are currently being investigated in adult patients with plaque psoriasis. This article reviews the details of the JAK-STAT pathway in psoriasis pathophysiology, the rationale for selective targeting of JAKs in the treatment of psoriasis, and provides clinical perspective on clinical trial data for JAK and TYK2 inhibitors.

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“…A Physician’s Global Assessment (PGA) response, defined as a PGA score of 0/1 (clear/almost clear) with a decrease from baseline ≥ 2 points, was achieved by a numerically greater proportion of patients across all treatment groups compared with placebo from weeks 6 to 16. The most common treatment-emergent AEs in patients treated with ropsacitinib up to week 16 were nasopharyngitis, URTI, and increased blood pressure (Table 1 ) [ 69 ]. AEs due to hematology, chemistry, and lipid laboratory abnormalities were observed in a dose-dependent manner.…”

Section: Clinical Profile Of Tyk2 Inhibitors In Psomentioning

confidence: 99%

“…Ropsacitinib was well tolerated and efficacious in reducing disease activity at 28 days, as measured by PASI 75, target plaque severity score, and body surface area [ 33 ]. In the phase 2b, double-blind, placebo-controlled trial, 179 patients were randomized 1:1:2:2:2 to ropsacitinib (50 mg, 100 mg, 200 mg, or 400 mg) or placebo QD for 16 weeks, after which patients on the 200 mg or 400 mg dose continued this dose and patients randomized to other doses were rerandomized to 200 mg or 400 mg QD (NCT03895372) [ 69 ]. At week 16, a significantly greater proportion of patients achieved PASI 90, the primary endpoint, with ropsacitinib at a dose of 200 mg (33.0%, P = 0.0004) and 400 mg (46.5%, P < 0.0001) compared with placebo.…”

Section: Clinical Profile Of Tyk2 Inhibitors In Psomentioning

confidence: 99%

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Novel Therapies in Plaque Psoriasis: A Review of Tyrosine Kinase 2 Inhibitors

Martin¹

2023

Dermatol Ther (Heidelb)

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Plaque psoriasis is a systemic immune-mediated disease driven by interleukin-17 producing cells under the regulation of interleukin-23. Interleukin-23 signaling is mediated by the intracellular kinase tyrosine kinase 2, a Janus kinase family member. Tyrosine kinase 2 is a potential target for oral small-molecule therapies to treat psoriasis and psoriatic arthritis. A number of tyrosine kinase 2 inhibitors are in development or approved for the treatment of psoriasis or psoriatic arthritis. Deucravacitinib, an oral, selective, allosteric tyrosine kinase 2 inhibitor, is approved by the US Food and Drug Administration as a first-in-class treatment for adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy, and is approved by Pharmaceuticals and Medical Devices Agency (PDMA) in Japan for patients with plaque psoriasis, generalized pustular psoriasis, and erythrodermic psoriasis who have had an inadequate response to conventional therapies. Deucravacitinib selectively binds to the unique tyrosine kinase 2 regulatory pseudokinase domain in an allosteric fashion, preventing a conformational change in the catalytic domain required for ATP substrate binding, thus effectively locking tyrosine kinase 2 in an inactive state. Two other tyrosine kinase 2 inhibitors in later stage clinical development, brepocitinib (PF-06700841) and ropsacitinib (PF-06826647), are orthosteric inhibitors that target the highly conserved catalytic domain. This selective allosteric tyrosine kinase 2 inhibition may explain the improved safety profile of deucravacitinib versus orthosteric Janus kinase and tyrosine kinase 2 inhibitors. Two phase 3 psoriasis trials demonstrated deucravacitinib was efficacious and not associated with safety concerns characteristic of Janus kinase inhibitors, hence the new class designation (TYK2 inhibitor) by health authorities in the USA and Japan. Allosteric tyrosine kinase 2 inhibitors represent a promising new class of molecules for the treatment of psoriasis and psoriatic arthritis, and longer-term trials will establish their place in therapy. Graphical Abstract

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Oral tyrosine kinase 2 inhibitor PF-06826647 demonstrates efficacy and an acceptable safety profile in participants with moderate-to-severe plaque psoriasis in a phase 2b, randomized, double-blind, placebo-controlled study

Cited by 31 publications

References 43 publications

Role of tyrosine kinase 2 signals during progression of psoriasis

Role of tyrosine kinase 2 signals during progression of psoriasis

Clinical Implications of Targeting the JAK-STAT Pathway in Psoriatic Disease: Emphasis on the TYK2 Pathway

Novel Therapies in Plaque Psoriasis: A Review of Tyrosine Kinase 2 Inhibitors

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