JAMA Dermatology

<jats:sec><jats:title>Importance</jats:title><jats:p>New, effective, and well-tolerated oral therapies are needed for treating psoriasis. Zasocitinib, a highly selective allosteric tyrosine kinase 2 (TYK2) inhibitor, is a potential new oral treatment for this disease.</jats:p></jats:sec><jats:sec><jats:title>Objective</jats:title><jats:p>To assess the efficacy, safety, and tolerability of zasocitinib in patients with moderate to severe plaque psoriasis.</jats:p></jats:sec><jats:sec><jats:title>Design, Setting, and Participants</jats:title><jats:p>This phase 2b, randomized, double-blind, placebo-controlled, multiple-dose randomized clinical trial was conducted from August 11, 2021, to September 12, 2022, at 47 centers in the US and 8 in Canada. The study included a 12-week treatment period and a 4-week follow-up period. Key eligibility criteria for participants included age 18 to 70 years; a Psoriasis Area and Severity Index (PASI) score of 12 or greater; a Physician’s Global Assessment score of 3 or greater; and a body surface area covered by plaque psoriasis of 10% or greater. Of 287 patients randomized, 259 (90.2%) received at least 1 dose of study treatment.</jats:p></jats:sec><jats:sec><jats:title>Intervention</jats:title><jats:p>Patients were randomly assigned (1:1:1:1:1) to receive zasocitinib at 2, 5, 15, or 30 mg or placebo orally, once daily, for 12 weeks.</jats:p></jats:sec><jats:sec><jats:title>Main Outcomes and Measures</jats:title><jats:p>The primary efficacy end point was the proportion of patients achieving 75% or greater improvement in PASI score (PASI 75) at week 12. Secondary efficacy end points included PASI 90 and 100 responses. Safety was also assessed.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>In total, 259 patients were randomized and received treatment (mean [SD] age, 47 [13] years; 82 women [32%]). At week 12, PASI 75 was achieved for 9 (18%), 23 (44%), 36 (68%), and 35 (67%) patients receiving zasocitinib at 2, 5, 15, and 30 mg, respectively, and 3 patients (6%) receiving placebo. PASI 90 responses were consistent with PASI 75. PASI 100 demonstrated a dose response at all doses, with 17 patients (33%) achieving PASI 100 with zasocitinib, 30 mg. Treatment-emergent adverse events occurred for 23 patients (44%) receiving placebo and 28 (53%) to 31 (62%) patients receiving the 4 different doses of zasocitinib, with no dose dependency and no clinically meaningful longitudinal differences in laboratory parameters.</jats:p></jats:sec><jats:sec><jats:title>Conclusions and Relevance</jats:title><jats:p>This randomized clinical trial found that potent and selective inhibition of TYK2 with zasocitinib at oral doses of 5 mg or more once daily resulted in greater skin clearance than placebo over 12 weeks.</jats:p></jats:sec><jats:sec><jats:title>Trial Registration</jats:title><jats:p>ClinicalTrials.gov Identifier: <jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="https://clinicaltrials.gov/study/NCT04999839?locStr=United%20States&amp;amp;amp;country=United%20States&amp;amp;amp;cond=Plaque%20Psoriasis&amp;amp;amp;intr=placebo&amp;amp;amp;term=NCT04999839&amp;amp;amp;rank=1">NCT04999839</jats:ext-link></jats:p></jats:sec>

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Dermatol Ther (Heidelb)

Quality of life and work productivity impairment among psoriasis patients: findings from the National Psoriasis Foundation survey data 2003-2011.

PLoS One

Psoriasis prevalence and severity by expert elicitation.

Psoriasis pathogenesis and the development of novel targeted immune therapies.

J Allergy Clin Immunol

Systemic pharmacological treatments for chronic plaque psoriasis: a network meta-analysis.

Cochrane Database Syst Rev

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Sci Transl Med

The psoriasis-protective TYK2 I684S variant impairs IL-12 stimulated pSTAT4 response in skin-homing CD4+ and CD8+ memory T-cells.

Sci Rep

Identification of 15 new psoriasis susceptibility loci highlights the role of innate immunity.

Nat Genet

TYK2 protein-coding variants protect against rheumatoid arthritis and autoimmunity, with no evidence of major pleiotropic effects on non-autoimmune complex traits.

Association of TYK2 rs34536443 polymorphism with susceptibility to systemic lupus erythematous in the Iranian population.

Rheumatology Research

Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease.

Nature

Tofacitinib, an oral Janus kinase inhibitor, for the treatment of chronic plaque psoriasis: results from two randomized, placebo-controlled, phase III trials.

Br J Dermatol

Oral Janus kinase inhibitors in the treatment of atopic dermatitis: a systematic review and meta-analysis.

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JAMA Netw Open

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Rheumatology (Oxford)

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Deucravacitinib versus placebo and apremilast in moderate to severe plaque psoriasis: efficacy and safety results from the 52-week, randomized, double-blinded, phase 3 program for evaluation of TYK2 inhibitor psoriasis second trial.

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33226 Analysis of histologic and molecular improvement in moderate-to-severe psoriasis: results from a phase 1b trial of the novel allosteric TYK2 inhibitor NTX-973.

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Dermatologica

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Clin Exp Dermatol

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Dermatology

Total skin clearance results in improvements in health-related quality of life and reduced symptom severity among patients with moderate to severe psoriasis.

J Dermatolog Treat

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Lancet

Secukinumab induction and maintenance therapy in moderate-to-severe plaque psoriasis: a randomized, double-blind, placebo-controlled, phase II regimen-finding study.

317 Characterization of pharmacokinetics, pharmacodynamics, tolerability and clinical activity in phase I studies of the novel allosteric tyrosine kinase 2 (TYK2) inhibitor NDI-034858.

J Invest Dermatol

New, effective, and well-tolerated oral therapies are needed for treating psoriasis. Zasocitinib, a highly selective allosteric tyrosine kinase 2 (TYK2) inhibitor, is a potential new oral treatment for this disease.
To assess the efficacy, safety, and tolerability of zasocitinib in patients with moderate to severe plaque psoriasis.
This phase 2b, randomized, double-blind, placebo-controlled, multiple-dose randomized clinical trial was conducted from August 11, 2021, to September 12, 2022, at 47 centers in the US and 8 in Canada. The study included a 12-week treatment period and a 4-week follow-up period. Key eligibility criteria for participants included age 18 to 70 years; a Psoriasis Area and Severity Index (PASI) score of 12 or greater; a Physician's Global Assessment score of 3 or greater; and a body surface area covered by plaque psoriasis of 10% or greater. Of 287 patients randomized, 259 (90.2%) received at least 1 dose of study treatment.
Patients were randomly assigned (1:1:1:1:1) to receive zasocitinib at 2, 5, 15, or 30 mg or placebo orally, once daily, for 12 weeks.
The primary efficacy end point was the proportion of patients achieving 75% or greater improvement in PASI score (PASI 75) at week 12. Secondary efficacy end points included PASI 90 and 100 responses. Safety was also assessed.
In total, 259 patients were randomized and received treatment (mean [SD] age, 47 [13] years; 82 women [32%]). At week 12, PASI 75 was achieved for 9 (18%), 23 (44%), 36 (68%), and 35 (67%) patients receiving zasocitinib at 2, 5, 15, and 30 mg, respectively, and 3 patients (6%) receiving placebo. PASI 90 responses were consistent with PASI 75. PASI 100 demonstrated a dose response at all doses, with 17 patients (33%) achieving PASI 100 with zasocitinib, 30 mg. Treatment-emergent adverse events occurred for 23 patients (44%) receiving placebo and 28 (53%) to 31 (62%) patients receiving the 4 different doses of zasocitinib, with no dose dependency and no clinically meaningful longitudinal differences in laboratory parameters.
This randomized clinical trial found that potent and selective inhibition of TYK2 with zasocitinib at oral doses of 5 mg or more once daily resulted in greater skin clearance than placebo over 12 weeks.
ClinicalTrials.gov Identifier: NCT04999839.

Tyrosine Kinase 2 Inhibition With Zasocitinib (TAK-279) in Psoriasis: A Randomized Clinical Trial.

Tyrosine Kinase 2 Inhibition With Zasocitinib (TAK-279) in Psoriasis

<jats:sec><jats:title>Importance</jats:title><jats:p>Evolving evidence suggests that patients receiving Janus kinase–signal transducer and activator of transcription inhibitors (JAK-STATi) may be at higher risk of major adverse cardiovascular events (MACE) and venous thromboembolism (VTE). Most existing literature has focused on indications that may confer a higher MACE and VTE risk than that  among patients with isolated dermatological indications.</jats:p></jats:sec><jats:sec><jats:title>Objective</jats:title><jats:p>To evaluate risk of MACE, VTE, serious adverse events (SAEs), and tolerability of systemic JAK-STATi compared with placebo, in those with a dermatologic indication.</jats:p></jats:sec><jats:sec><jats:title>Data Sources</jats:title><jats:p>A systematic review of the literature was carried out to June 2023, using databases Embase, MEDLINE, SCOPUS, Cochrane Library of Registered Trials, and registered Clinical Trials. The analysis was reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (<jats:ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="https://www.equator-network.org/reporting-guidelines/prisma/">PRISMA</jats:ext-link>) reporting guidelines. The analysis itself took place in June 2023.</jats:p></jats:sec><jats:sec><jats:title>Study Selection</jats:title><jats:p>Placebo-controlled randomized clinical trials that compared systemic JAK-STATi with placebo, and investigated the safety in patients with alopecia areata, psoriasis, vitiligo, atopic dermatitis, lichen planus or hidradenitis suppurativa.</jats:p></jats:sec><jats:sec><jats:title>Data Extraction and Synthesis</jats:title><jats:p>Study selection and data extraction by 2 authors working independently using a standardized template. Crude numbers for MACE, VTE, SAEs, and study discontinuation due to treatment emergent adverse events (TEAEs) were pooled and underwent meta-analysis.</jats:p></jats:sec><jats:sec><jats:title>Main Outcomes and Measures</jats:title><jats:p>Incidence of MACE, VTE, SAE, and study discontinuation due to TEAEs. Analysis of these values against person exposure years to determine the incidence rate (IR). Risk ratios (RRs) compared incidence rates among treatment and placebo comparator arms.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Forty-five randomized clinical trials were eligible for inclusion, with 12 996 patients receiving active JAK-STATi therapy and 4925 allocated to placebo treatment. Meta-analysis found no significant increase in MACE (<jats:italic>I</jats:italic><jats:sup>2</jats:sup> = 0.00%; RR, 0.47; 95% CI, 0.28-0.80) or VTE (<jats:italic>I</jats:italic><jats:sup>2</jats:sup> = 0.00%; RR, 0.46; 95% CI, 0.26-0.80) between placebo and JAK-STATi comparator arms. There was also no significant difference in SAEs (<jats:italic>I</jats:italic><jats:sup>2</jats:sup> = 12.38%; RR, 0.92; 95% CI, 0.72-1.20) and discontinuations between JAK-STATi and placebo (<jats:italic>I</jats:italic><jats:sup>2</jats:sup> = 23.55%; RR, 0.94; 95% CI, 0.76-1.19).</jats:p></jats:sec><jats:sec><jats:title>Conclusions and Relevance</jats:title><jats:p>This meta-analysis did not identify a significant increase in the risk of MACE and VTE in dermatology patients receiving JAK-STATi for median duration of 16 weeks. The results of this review suggest there is insufficient evidence that JAK-STATi confer an increased risk of cardiovascular complications in dermatological patients, especially when used for short time frames.</jats:p></jats:sec>

Emerging topical and systemic JAK inhibitors in dermatology.

Janus kinase-targeting therapies in rheumatology: a mechanisms-based approach.

Nat Rev Rheumatol

Cardiovascular and cancer risk with tofacitinib in rheumatoid arthritis.

Major adverse cardiovascular event definitions used in observational analysis of administrative databases: a systematic review.

BMC Med Res Methodol

RoB 2: a revised tool for assessing risk of bias in randomised trials.

Janus kinase 1 inhibitor INCB054707 for patients with moderate-to-severe hidradenitis suppurativa: results from two phase II studies.

Deucravacitinib versus placebo and apremilast in moderate to severe plaque psoriasis: Efficacy and safety results from the 52-week, randomized, double-blinded, placebo-controlled phase 3 POETYK PSO-1 trial.

Tofacitinib versus etanercept or placebo in moderate-to-severe chronic plaque psoriasis: a phase 3 randomised non-inferiority trial.

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Efficacy and safety of oral janus kinase 1 inhibitor abrocitinib for patients with atopic dermatitis: a phase 2 randomized clinical trial.

JAMA Dermatol

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A phase 2a randomized, placebo-controlled study to evaluate the efficacy and safety of the oral Janus kinase inhibitors ritlecitinib and brepocitinib in alopecia areata: 24-week results.

Integrated safety analysis of baricitinib in adults with severe alopecia areata from two randomized clinical trials.

Phase 2 randomized, dose-ranging trial of CTP-543, a selective Janus Kinase inhibitor, in moderate-to-severe alopecia areata.

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A randomized phase 2b trial of baricitinib, an oral Janus kinase (JAK) 1/JAK2 inhibitor, in patients with moderate-to-severe psoriasis.

Phase 2 Trial of Selective Tyrosine Kinase 2 Inhibition in Psoriasis.

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Safety and efficacy of upadacitinib in combination with topical corticosteroids in adolescents and adults with moderate-to-severe atopic dermatitis (AD Up): results from a randomised, double-blind, placebo-controlled, phase 3 trial.

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Lancet Rheumatol

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J Dermatol Sci

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Am J Clin Dermatol

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Int J Mol Sci

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Blood

Psoriasis and major adverse cardiovascular events: a systematic review and meta-analysis of observational studies.

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J Thromb Haemost

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J Clin Aesthet Dermatol

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J Eur Acad Dermatol Venereol

Integrated safety analysis of abrocitinib for the treatment of moderate-to-severe atopic dermatitis from the phase II and phase III clinical trial program.

Pooled safety analysis of baricitinib in adult patients with atopic dermatitis from 8 randomized clinical trials.

Tofacitinib in patients with moderate-to-severe chronic plaque psoriasis: long-term safety and efficacy in an open-label extension study.

Efficacy and safety of upadacitinib in patients with moderate to severe atopic dermatitis: analysis of follow-up data from the measure up 1 and measure up 2 randomized clinical trials.

Evolving evidence suggests that patients receiving Janus kinase-signal transducer and activator of transcription inhibitors (JAK-STATi) may be at higher risk of major adverse cardiovascular events (MACE) and venous thromboembolism (VTE). Most existing literature has focused on indications that may confer a higher MACE and VTE risk than that among patients with isolated dermatological indications.
To evaluate risk of MACE, VTE, serious adverse events (SAEs), and tolerability of systemic JAK-STATi compared with placebo, in those with a dermatologic indication.
A systematic review of the literature was carried out to June 2023, using databases Embase, MEDLINE, SCOPUS, Cochrane Library of Registered Trials, and registered Clinical Trials. The analysis was reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines. The analysis itself took place in June 2023.
Placebo-controlled randomized clinical trials that compared systemic JAK-STATi with placebo, and investigated the safety in patients with alopecia areata, psoriasis, vitiligo, atopic dermatitis, lichen planus or hidradenitis suppurativa.
Study selection and data extraction by 2 authors working independently using a standardized template. Crude numbers for MACE, VTE, SAEs, and study discontinuation due to treatment emergent adverse events (TEAEs) were pooled and underwent meta-analysis.
Incidence of MACE, VTE, SAE, and study discontinuation due to TEAEs. Analysis of these values against person exposure years to determine the incidence rate (IR). Risk ratios (RRs) compared incidence rates among treatment and placebo comparator arms.
Forty-five randomized clinical trials were eligible for inclusion, with 12 996 patients receiving active JAK-STATi therapy and 4925 allocated to placebo treatment. Meta-analysis found no significant increase in MACE (I2 = 0.00%; RR, 0.47; 95% CI, 0.28-0.80) or VTE (I2 = 0.00%; RR, 0.46; 95% CI, 0.26-0.80) between placebo and JAK-STATi comparator arms. There was also no significant difference in SAEs (I2 = 12.38%; RR, 0.92; 95% CI, 0.72-1.20) and discontinuations between JAK-STATi and placebo (I2 = 23.55%; RR, 0.94; 95% CI, 0.76-1.19).
This meta-analysis did not identify a significant increase in the risk of MACE and VTE in dermatology patients receiving JAK-STATi for median duration of 16 weeks. The results of this review suggest there is insufficient evidence that JAK-STATi confer an increased risk of cardiovascular complications in dermatological patients, especially when used for short time frames.

Short-Term Cardiovascular Complications in Dermatology Patients Receiving JAK-STAT Inhibitors: A Meta-Analysis of Randomized Clinical Trials.

Short-Term Cardiovascular Complications in Dermatology Patients Receiving JAK-STAT Inhibitors

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