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

April W Armstrong; Melinda Gooderham; Charles Lynde; Catherine Maari; Seth Forman; Lawrence Green; Vivian Laquer; Xinyan Zhang; Nathalie Franchimont; Esha A Gangolli; Jessamyn Blau; Yiwei Zhao; Wenwen Zhang; Bhaskar Srivastava; Graham Heap; Kim Papp

doi:10.1001/jamadermatol.2024.2701

. 2024 Aug 21;160(10):1066–1074. doi: 10.1001/jamadermatol.2024.2701

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

A Randomized Clinical Trial

April W Armstrong ^1,^✉, Melinda Gooderham ², Charles Lynde ³, Catherine Maari ⁴, Seth Forman ⁵, Lawrence Green ⁶, Vivian Laquer ⁷, Xinyan Zhang ⁸, Nathalie Franchimont ⁸, Esha A Gangolli ⁸, Jessamyn Blau ⁹, Yiwei Zhao ⁹, Wenwen Zhang ⁹, Bhaskar Srivastava ⁸, Graham Heap ⁹, Kim Papp ^10,¹¹

¹University of California, Los Angeles

²SKiN Centre for Dermatology and Probity Medical Research, Peterborough, Ontario, Canada

³Lynde Institute for Dermatology and Probity Medical Research, Markham, Ontario, Canada

⁴Innovaderm Research, Montreal, Quebec, Canada

⁵ForCare Medical Center, Tampa, Florida

⁶George Washington University School of Medicine, Rockville, Maryland

⁷First OC Dermatology Research, Fountain Valley, California

⁸Nimbus Discovery Inc, Boston, Massachusetts

⁹Takeda Development Center Americas Inc, Cambridge, Massachusetts

¹⁰Alliance Clinical Trials and Probity Medical Research, Waterloo, Ontario, Canada

¹¹Department of Dermatology, University of Toronto School of Medicine, Toronto, Ontario, Canada

Accepted for Publication: June 17, 2024.

Published Online: August 21, 2024. doi:10.1001/jamadermatol.2024.2701

^✉

Corresponding Author: April W. Armstrong, MD, MPH, University of California, Los Angeles (UCLA), PO Box 1155, Studio City, CA 91614 (armstrongpublication@gmail.com).

Author Contributions: Dr Armstrong had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Green, Zhao, Srivastava, Papp.

Acquisition, analysis, or interpretation of data: Armstrong, Gooderham, Lynde, Maari, Forman, Green, Laquer, X. Zhang, Franchimont, Gangolli, Blau, W. Zhang, Srivastava, Heap, Papp.

Drafting of the manuscript: Green, W. Zhang, Heap.

Critical review of the manuscript for important intellectual content: All authors.

Statistical analysis: Lynde, X. Zhang, Blau, W. Zhang, Srivastava.

Administrative, technical, or material support: Armstrong, Lynde.

Supervision: Maari, Forman, Green, Laquer, Franchimont, Blau, Zhao, Heap.

Other: Gangolli.

Conflict of Interest Disclosures: Dr Armstrong reported grants from AbbVie, ASLAN, BMS, Dermavant Sciences, Dermira, Eli Lilly, Galderma, Incyte, Janssen, Leo Pharma, Meiji Seika Pharma Co, Modernizing Medicine, Nimbus Therapeautics, Novartis, Ortho Dermatologics, Pfizer, Sanofi Genzyme, UCB, and Ventyx Biosciences; personal fees from AbbVie, ASLAN, Almirall, Amgen, Arcutis, Beiersdorf, BMS, Dermavant, EPI Health, Janssen, LEO Pharma, Mindera, Nimbus, Organon & Co, Sanofi, Sun Pharma, Takeda, Ventyx Biosciences, Incyte, Regeneron, and UCB; and data safety monitoring board service for Boehringer Ingelheim and Parexel during the conduct of the study. Dr Gooderham reported nonfinancial support from Takeda during the conduct of the study as well as personal fees from AbbVie, Amgen, Arcutis, Bristol Myers Squibb, Boehringer Ingelheim, Eli Lilly, Galderma, Incyte, Janssen, Leo Pharma, Meiji, Dermavant, Moonlake, Nektar, Nimbus, Novartis, Pfizer, Regeneron, Sanofi, Sun Pharma, Tarsus, Takeda, UCB, Union, Ventyx, and Apogee outside the submitted work. Dr Lynde reported being a principal investigator for AbbVie, Amgen, Akros, Arcutis, Bausch Health, Bayer, BioJAMP, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, CeraVe, Bioderma, Cipher, Concert, Dermavant, Eli Lilly, Devonian, Evelo, Galderma, GSK, InCyte, Intega Skin, Janssen, Kyowa Kirin, La Roche Posay, Leo Pharma, L’Oreal, Medexus, Merck, MoonLake, Nao, Nimbus, Novartis, P&G, PediaPharm, Pfizer, Regeneron, Roche, Sanofi Genzyme, Sandoz, Sentrex, SunPharma, Takeda, TEVA, Tribute, UCB, Valeant, Viatris, and Volo Health during the conduct of the study as well as personal fees from AbbVie, Amgen, Aralez, Bausch Health, Bayer, Bioderma , BioJAMP, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, CeraVe, Cipher, Dermavant, Eli Lilly, Fresnius Kabi, Gakderna, GSK, InCyte, Innovaderm, Intega Skin, Janssen, Kyowa Kirin, La Roche Posay, Leo Pharma, L’Oreal, Medexus, MedX, Merck, Naos, Novartis, P&G, PediaPharm, Pfizer, Regeneron, Roche, Sanofi Genzyme, Sandoz, Sentrex, Skinceuticals, SunPharma, Takeda, TEVA, Tribute, UCB, Valeant, Viatris, and VOLO Health outside the submitted work. Dr Maari reported a research grant from Nimbus Pharmaceutical. Dr Green reported grants from Takeda during the conduct of the study as well as grants from Amgen, Arcutis, Dermavant, BMS, Alumis, HIghlittl, Takeda, Galderma, OrthoDerm, UCB, and Janssen outside the submitted work. Dr Franchimont reported being employed by and holding equity in Nimbus during the conduct of the study as well as being a former employee of and shareholder in Biogen, holding stock and shares in and board service for OMass Therapeutics, personal fees from Bain Capital and Atara Biotherapeutics, and board service for Rome Therapeutics outside the submitted work; additionally, their spouse is an employee and shareholder of Alexion. Dr Gangolli reported employment for and stock ownership in Nimbus during the conduct of the study as well as stock ownership in Bristol Myers Squibb and AstraZeneca outside the submitted work. Dr Blau reported personal fees from Takeda Pharmaceuticals outside the submitted work. Dr Zhao reported being an employee of Takeda outside the submitted work. Dr W. Zhang reported personal fees from Takeda during the conduct of the study and outside the submitted work. Dr Srivastava reported being an employee of and shareholder in Nimbus Therapeutics during the conduct of the study and outside the submitted work. Dr Heap reported stock holdings and employment with Takeda Pharmaceuticals. Dr Papp reported committee/board service for AbbVie, Acelyrin, Akros, Alumis, Amgen, Arcutis, Bausch Health, Boehringer Ingelheim, BMS, Can-Fite Biopharma, Celltrion, Concert, Dermavant, Dermira, Dice Pharmaceuticals, Eli Lilly, Evelo Biosciences, Forbion, Galderma, Horizon Therapeutics, Incyte, Janssen, Kymab, Kyowa Hakko Kirin , Leo, Meiji Seika Pharma, Mitsubishi Pharma, Nimbus, Novartis, Pfizer, Reistone, Sanofi-Aventis, Sandoz, Sun Pharma, Takeda, Tarsus Pharmaceuticals, UCB, and Zai Lab Co during the conduct of the study. No other disclosures were reported.

Funding/Support: This study was funded by Nimbus Discovery Inc, which refers to the group of entities including Nimbus Therapeutics LLC, Nimbus Discovery Inc, and Nimbus Lakshmi, Inc. Nimbus Lakshmi Inc was acquired by Takeda Pharmaceuticals in February 2023.

Role of the Funder/Sponsor: Nimbus Discovery Inc was involved in the design of the study, provision of study drug, conduct of blinded safety monitoring, development of the analysis plan, and data collection, analysis, and interpretation. Takeda Pharmaceuticals was involved in the funding of medical writing support, review of the manuscript throughout development, and approval of the final version of the manuscript for submission.

Additional Contributions: Medical writing support, provided by Christina Nikolakopoulou, PhD, of Oxford PharmaGenesis, Oxford, UK, was funded by Takeda Development Center Americas, Inc.

Data Sharing Statement: See Supplement 4.

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Corresponding author.

PMCID: PMC11339701 PMID: 39167366

Key Points

Question

Is zasocitinib effective and sufficiently safe for treating psoriasis?

Findings

In this randomized clinical trial of 259 patients with moderate to severe plaque psoriasis, 18%, 44%, 68%, and 67% of patients receiving oral zasocitinib, 2 mg; zasocitinib, 5 mg; zasocitinib, 15 mg; and zasocitinib, 30 mg, respectively, achieved a 75% or greater improvement in Psoriasis Area and Severity Index scores from baseline to week 12 vs 6% of patients receiving placebo (significant at ≥5 mg). Treatment-emergent adverse events were reported for 53% to 62% of zasocitinib-treated and 44% of placebo-treated patients, with no dose dependency.

Meaning

The results of this trial suggest that zasocitinib, a selective tyrosine kinase 2 inhibitor, represents a potential new oral treatment for psoriasis.

Abstract

Importance

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.

Objective

To assess the efficacy, safety, and tolerability of zasocitinib in patients with moderate to severe plaque psoriasis.

Design, Setting, and Participants

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.

Intervention

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.

Main Outcomes and Measures

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.

Results

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.

Conclusions and Relevance

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.

Trial Registration

ClinicalTrials.gov Identifier: NCT04999839

This randomized clinical trial examines the efficacy, safety, and tolerability of zasocitinib in patients with moderate to severe plaque psoriasis.

Introduction

Psoriasis is a chronic immune-mediated inflammatory skin disease that is associated with several comorbidities and impairs the health-related quality of life (HRQoL) of patients.^1,2 Approximately 20% of patients with psoriasis have 10% or more of their body surface affected.³ Plaque psoriasis is the most common form and is characterized by erythematous, indurated plaques with overlying silvery scale.

The interleukin (IL)–23/T helper (Th)–17 axis plays a pivotal role in the pathogenesis of plaque psoriasis,⁴ as evidenced by the effectiveness of injectable biologics that block IL-23 or IL-17 in its treatment.⁵ However, to our knowledge, fewer oral therapies have been investigated for treating psoriasis, and none have shown the same levels of efficacy, safety, and tolerability as current biologics.⁵ The paucity of oral therapies for psoriasis underscores the need for new, effective, and well-tolerated oral agents.

A promising target for novel oral agents in treating psoriasis and other immune-mediated diseases is tyrosine kinase 2 (TYK2), a Janus kinase (JAK)–related mediator involved in intracellular signaling transduction via the JAK–signal transducer and activator of transcription pathway.⁶ Genome-wide association studies have shown that loss-of-function TYK2 variants may protect against several inflammatory diseases, including psoriasis.^{7,8,9,10,11,12} Although broadly acting oral JAK inhibitors have shown efficacy in psoriasis, atopic dermatitis, alopecia areata, and vitiligo,^13,14,15,16 their broad inhibitory effects on multiple JAK enzymes are associated with rare but serious safety concerns, including cancers, major adverse cardiovascular events (MACEs), and infections,^17,18 which have limited their use and further development in psoriasis.

Deucravacitinib, an oral allosteric TYK2 inhibitor recently approved by the US Food and Drug Administration for treating moderate to severe psoriasis, has set the clinical precedent for selectively targeting TYK2 activity in this disease.^19,20,21 In contrast to JAK1-3 inhibitors, long-term follow-up has shown that deucravacitinib is not associated with an increased risk of serious safety concerns, and efficacy has been maintained for patients experiencing an early response.^22,23

Zasocitinib (formerly TAK-279) is an oral, allosteric inhibitor of TYK2 that binds to the Janus homology 2 (JH2) pseudokinase domain of TYK2, leading to inhibition of kinase activity and subsequent downstream signaling events.²⁴ Although identical in mechanism of action to deucravacitinib, zasocitinib was identified via a computationally enabled design strategy and demonstrates a higher level of selectivity than deucravacitinib for the JH2 domain of TYK2 compared with those of JAK1 and JAK2 owing to steric occlusion from the latter via a methocyclobutyl ring.²⁴ A previous phase 1 study demonstrated that zasocitinib modulates psoriasis primarily through its effects on the IL-23/Th-17 axis, with a safety profile consistent with TYK2 inhibition.²⁵ In the present phase 2b randomized clinical trial, we assessed the efficacy, safety, and tolerability of zasocitinib at various doses in patients with moderate to severe psoriasis.

Methods

Ethics

This trial was conducted from August 11, 2021, to September 12, 2022. This study was conducted according to the Declaration of Helsinki, International Conference on Harmonization Good Clinical Practice recommendations, and all applicable regulations. The study protocol (and amendments; Supplement 1 and Supplement 2) and informed consent forms were reviewed and approved by an institutional review board and the central ethics committee of Advarra. All participants agreed to participate in the study by providing their written informed consent form. Consolidated Standards of Reporting Trials (CONSORT) reporting guidelines were followed during the development of this article.²⁶

Study Design

This was a phase 2b, randomized, multicenter, double-blind, placebo-controlled, multiple-dose trial that enrolled patients with moderate to severe psoriasis from 47 centers in the US and 8 centers in Canada. Patients were randomized 1:1:1:1:1 (stratified by previous treatment with biologics) to receive 1 of 4 oral doses of zasocitinib (2, 5, 15, or 30 mg, once daily) or matching oral placebo for 12 weeks, with an additional 4-week follow-up period for safety monitoring (eFigure 1 in Supplement 3). Protocol amendments are listed in eTable 3 in Supplement 3.

Study Population

Patients aged 18 to 70 years at the time of consent who had plaque psoriasis for 6 months or longer before the screening visit were eligible for inclusion if they had moderate to severe disease as defined by a Psoriasis Area and Severity Index (PASI)²⁷ score of 12 or greater and a Physician’s Global Assessment (PGA) score of 3 or greater at screening and day 1, plaque psoriasis covering 10% or more of their total body surface area (BSA) at screening and day 1, a body mass index (calculated as weight in kilograms divided by height in meters squared) of 18 to 42, a total body weight of more than 50 kg, no substantial flare in psoriasis for 3 months or longer before screening, and were a candidate for phototherapy or systemic therapy. Patients were excluded if they had erythrodermic, pustular, guttate, or drug-induced psoriasis; active bacterial, viral, fungal, mycobacterial, or other infections (including tuberculosis); or active herpes infection (including herpes simplex 1 and 2 and herpes zoster) within 8 weeks before the baseline (study day 1), as well as positive results for hepatitis B, hepatitis C, or HIV; a previous lack of response to any therapeutic agent targeting IL-12/IL-23, IL-17, and/or IL-23; or any use of topical or systemic treatment that could have affected psoriasis within 2 and 4 weeks before baseline, respectively. Full inclusion and exclusion criteria are available in Supplement 1.

Randomization and Masking

Patients were randomized using a randomization list generated using validated software (SAS, version 9.4; SAS Institute) that was stratified based on previous treatment with biologics (yes/no) and kept secured until the masking was broken at the end of study. During screening, investigators acquired a patient identifier number via an interactive web response system, and a randomization number was allocated to each patient. This number contained the site number and patient number and was assigned in numerical order at the screening visit based on a chronological order of screening dates. Participants, investigators, study staff, the company research organization, or the sponsor’s study team were masked to treatment and randomization information.

End Points

The primary efficacy end point was the proportion of patients achieving 75% or greater improvement in PASI score from baseline (PASI 75) at week 12. Secondary efficacy end points included the proportion of patients achieving a PASI 90 or 100 response, or a PGA score of clear (0) or almost clear (1), and change from baseline in the Dermatology Life Quality Index (DLQI) at week 12.²⁸ Exploratory efficacy end points are described in the eMethods in Supplement 3. Safety end points included the incidence of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) and changes in vital signs, clinical laboratory parameters, and electrocardiograms.

Statistical Analysis

A sample size of 250 patients (approximately 50 patients per treatment group) was determined to provide 85% power to detect a PASI 75 (≥75% improvement from baseline) response rate of 40% or greater in at least 1 of the zasocitinib treatment groups at a significance level of α = .05 using a 2-sided test, assuming a placebo response rate of 10%. Patient demographic and baseline disease characteristics were summarized using descriptive statistics (frequency and percentage). Race was determined according to what the patient felt best described them. Analyses of patient demographic characteristics, baseline disease characteristics, and the primary and secondary efficacy end points were conducted on the modified intent-to-treat analysis set (all randomized patients who received ≥1 dose of the study treatment). Analysis of the safety end points was conducted in the safety analysis set (all patients who received ≥1 dose of the study treatment). Nonresponse was imputed for missing data for binary end points. Multiplicity adjustment in the primary end point analysis used a hierarchical testing procedure, starting with the highest dose and ending with the lowest dose. No adjustments for multiple comparisons for secondary end points were made; as such, P values for secondary end points are not reported. Point estimates with unadjusted confidence intervals are reported. All analyses were conducted using SAS (version 9.4 or higher; SAS Institute).

PASI 75, 90, and 100 responses and achievement of a PGA score of 0 or 1 were assessed using descriptive statistics by visit for each group. Longitudinal line plots for PASI 75, 90, and 100 responses and achievement of a PGA score of 0 or 1 by treatment group were also created.

A Cochran-Mantel-Haenszel test (using previous biologic treatment as a stratification factor) was used to compare the proportion of patients achieving PASI 75, 90, and 100 scores and PGA 0/1 responses between each active treatment group and placebo. Change from baseline in DLQI was analyzed using a mixed model for repeated measures method. The model included treatment group, visit (weeks 4, 8, and 12), treatment-by-visit interaction, and previous treatment, with biologics as fixed effects and baseline score as a covariate.

Results

Patients

In total, 443 patients were screened for eligibility, of whom 287 (65%) were randomly allocated to 1 of the 4 active treatment groups or placebo, and 259 (58%) received at least 1 dose of study treatment. Overall, 36 patients (14%) discontinued the study prematurely, with 223 (86%) completing the 12-week treatment period (Figure 1). Discontinuations due to TEAEs were infrequent and comparable across treatment groups.

Figure 1. — AE, adverse event; LTFU, lost to follow-up.

Patient demographic and baseline disease characteristics were consistent with moderate to severe plaque psoriasis clinical trial populations and were comparable across treatment groups (Table 1). The patient population was predominantly White (215 [83%]) and male (177 [68%]), with a mean (SD) age of 47 (13) years. Approximately 41 patients (16%) had received previous treatment with biologics. The median (range) duration of psoriasis was 12 (6-22) years, mean (SD) PASI score was 18 (6), and mean (SD) BSA was 22% (13%).

Table 1. Demographic and Baseline Disease Characteristics of Patients With Moderate to Severe Psoriasis in a Phase 2b Study for Zasocitinib.

Characteristic	No. (%)
	Placebo (n = 52)	Zasocitinib, once daily				Total (N = 259)
	Placebo (n = 52)	2 mg (n = 50)	5 mg (n = 52)	15 mg (n = 53)	30 mg (n = 52)	Total (N = 259)
Demographic
Age, mean (SD), y	49 (13)	46 (14)	45 (14)	46 (13)	49 (11)	47 (13)
Sex
Female	21 (40)	12 (24)	11 (21)	19 (36)	19 (37)	82 (32)
Male	31 (60)	38 (76)	41 (79)	34 (64)	33 (63)	177 (68)
Race
Asian	5 (10)	3 (6)	7 (14)	2 (4)	3 (6)	20 (8)
Black or African American	2 (4)	4 (8)	4 (8)	3 (6)	4 (8)	17 (7)
White	44 (85)	43 (86)	40 (77)	46 (87)	42 (81)	215 (83)
Weight, mean (SD), kg	88 (16)	94 (17)	90 (19)	93 (17)	90 (18)	91 (17)
BMI, mean (SD)	31 (5)	31 (5)	30 (6)	32 (5)	30 (5)	31 (5)
Clinical
Duration of psoriasis, median (range), y	9 (6–16)	12 (6-17)	12 (7-21)	12 (6-27)	16 (8-27)	12 (6-22)
Prior treatment with biologics	8 (15)	8 (16)	8 (15)	9 (17)	8 (15)	41 (16)
PASI score, mean (SD)^a	18 (8)	18 (7)	19 (6)	16 (5)	18 (6)	18 (6)
PGA score, mean (SD)^b	3 (0)	3 (0)	3 (0)	3 (0)	3 (0)	3 (0)
PGA score^b
3: Moderate	41 (79)	30 (60)	34 (65)	40 (75)	42 (81)	187 (72)
4: Severe	11 (21)	20 (40)	18 (35)	13 (25)	10 (19)	72 (28)
BSA, mean (SD), %^c	21 (14)	25 (16)	23 (12)	18 (10)	22 (14)	22 (13)
DLQI score, mean (SD)^d	12 (7)	10 (6)	13 (7)	12 (7)	13 (7)	12 (7)

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Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); BSA, body surface area; DLQI, Dermatology Life Quality Index; PASI, Psoriasis Area and Severity Index; PGA, Physician’s Global Assessment.

^{^a}

The PASI is a composite score ranging from 0 to 72 that considers the degree of erythema, induration/infiltration, and desquamation (each scored from 0 to 4 separately) for each of 4 body regions, with adjustments for the percentage of the BSA involved for each body region and proportion of the body region to the whole body. For PASI calculation, the 4 main body regions were assessed: the head, the trunk, and the upper and lower extremities, corresponding to 10%, 20%, 30%, and 40% of the total body area, respectively. The area of psoriatic involvement of these 4 main regions was given a numerical value: 0 indicating no involvement, 1 indicating less than 10% psoriatic involvement, 2 indicating 10% to less than 30% psoriatic involvement, 3 indicating 30% to less than 50% psoriatic involvement, 4 indicating 50% to less than 70% psoriatic involvement, 5 indicating 70% to less than 90% psoriatic involvement, and 6 indicating 90% to 100% psoriatic involvement.²⁷

^{^b}

The PGA score is a 5-point morphological assessment of overall disease severity. For the purposes of this study, the PGA score ranged from 0 to 4, with 0 representing clear skin and 4 representing severe disease.

^{^c}

The overall BSA affected by plaque psoriasis was evaluated from 0% to 100%. The palmar surface of 1 hand (using the patient’s hand and including the fingers) represented 1% of the total BSA.

^{^d}

The DLQI is a 10-question validated questionnaire structured with each question having 4 alternative responses: not at all, a little, a lot, or very much, with corresponding scores of 0, 1, 2, and 3, respectively. The questionnaire also includes a “not relevant” answer scored as 0. The DLQI is calculated by summing the score of each question, resulting in a maximum of 30 and minimum of 0. The higher the score, the greater the impairment of quality of life.²⁸

Efficacy

At week 12, the primary efficacy end point (PASI 75) was achieved in patients receiving zasocitinib at doses of 5 mg and higher: 9 (18%), 23 (44%), 36 (68%), and 35 (67%) patients in the zasocitinib 2-, 5-, 15-, and 30-mg groups, respectively, and in 3 patients (6%) in the placebo group. PASI 75 responses increased from 2 mg to 15 mg but were similar at 15 mg and 30 mg (Table 2).

Table 2. Efficacy at Week 12 in Patients With Moderate to Severe Psoriasis in a Phase 2b Study for Zasocitinib.

End point^a	Placebo (n = 52)	Zasocitinib, once daily
End point^a	Placebo (n = 52)	2 mg (n = 50)	5 mg (n = 52)	15 mg (n = 53)	30 mg (n = 52)
PASI 75 (primary end point), No. (%)	3 (6)	9 (18)	23 (44)	36 (68)	35 (67)
P value vs placebo	NA	.05	<.001	<.001	<.001
Proportion difference vs placebo, % (95% CI)^b	NA	12 (0 to 25)	39 (24 to 53)	62 (48 to 76)	62 (47 to 76)
PASI 90, No. (%)	0	4 (8)	11 (21)	24 (45)	24 (46)
Proportion difference vs placebo, % (95% CI)^b	NA	8 (1 to 16)	21 (10 to 32)	45 (32 to 59)	46 (33 to 60)
PASI 100, No. (%)	0	1 (2)	5 (10)	8 (15)	17 (33)
Proportion difference vs placebo, % (95% CI)^b	NA	2 (−2 to 6)	10 (2 to 18)	15 (5 to 25)	33 (20 to 45)
PGA score of 0 or 1, No. (%)	2 (4)	5 (10)	14 (27)	26 (49)	27 (52)
Proportion difference vs placebo, % (95% CI)^b	NA	6 (−4 to 16)	23 (10 to 36)	45 (31 to 60)	48 (34 to 63)

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Abbreviations: NA, not applicable; PASI, Psoriasis Area and Severity Index; PASI 75, at least 75% improvement in PASI; PASI 90, at least 90% improvement in PASI; PASI 100, 100% improvement in PASI; PGA, Physician’s Global Assessment.

^{^a}

^{^b}

Proportion differences for achievement of PASI 75, PASI 90, PASI 100, and a PGA of 0 or 1 were calculated using the Mantel-Haenszel method. The P value for the primary end point was derived from a Cochran-Mantel-Haenszel test, with previous treatment with biologics included as a stratification factor, and compared with the proportion of patients achieving PASI 75 in each dose group of zasocitinib vs placebo. P values for secondary end points were not reported because these values have not been adjusted for multiple comparisons; 95% CIs are unadjusted.

PASI 90 was achieved for 4 (8%), 11 (21%), 24 (45%), and 24 patients (46%) receiving zasocitinib at 2, 5, 15, and 30 mg, respectively, and for no patients in the placebo group. The pattern of the dose-response association for PASI 90 was similar to PASI 75 (Table 2). PASI 100 was achieved for 1 (2%), 5 (10%), 8 (15%), and 17 (33%) patients receiving zasocitinib at 2, 5, 15, and 30 mg, respectively, and for no patients in the placebo group. An increase in PASI 100 was observed across all doses tested, with the highest response in the 30-mg group (Table 2). The effects of zasocitinib treatment on PASI responses were also apparent as early as week 4 and persisted through to the end of the 12-week treatment period (Figure 2, A-C; eTable 1 in Supplement 3).

Figure 2. — A, Proportion of patients with at least a 75% improvement from baseline in the Psoriasis Area and Severity Index (PASI) score (PASI 75; primary end point). B, Proportion of patients with at least a 90% improvement in the PASI score (PASI 90). C, Proportion of patients with a 100% improvement in the PASI score (PASI 100). D, Percentages of patients with a Physician’s Global Assessment (PGA) score of 0 or 1 (on a scale from 0 to 4, with higher scores indicating greater disease severity). Patients with missing values at each point and patients with assessments collected on the day of, or after the start of, a prohibited medication that was considered a major protocol deviation were imputed as nonresponders.

A PGA score of 0 or 1 was achieved at week 12 for 5 (10%), 14 (27%), 26 (49%), and 27 (52%) patients receiving zasocitinib at 2, 5, 15, and 30 mg, respectively, and for 2 patients (4%) in the placebo group (Table 2). As with PASI 75 and PASI 90, the proportion of patients achieving a PGA score of 0 or 1 at week 12 increased between the 2-mg and 15-mg doses of zasocitinib, with similar efficacy observed with the 15-mg and 30-mg doses (Figure 2D). In a post hoc analysis, a PGA score of 0 (clear skin) was achieved for 1 of 50 (2%), 5 of 52 (10%), 8 of 53 (15%), and 17 of 52 (33%) patients receiving zasocitinib at 2, 5, 15, and 30 mg, respectively, and for no patients in the placebo group.

No difference in DLQI score was observed at any visit for patients receiving zasocitinib, 2 mg, compared with placebo and only at week 8 and beyond for zasocitinib, 5 mg. Greater changes from baseline were observed in patients receiving zasocitinib at 15 mg, and 30 mg compared with placebo, which were observed at week 4 and maintained through week 12 (eFigure 2 in Supplement 3). Changes from baseline in affected BSA generally mirrored the findings for the primary and secondary end points (eFigure 3 in Supplement 3). The findings for other exploratory efficacy outcomes are presented in the eResults in Supplement 3.

Harms

TEAEs occurred at a higher rate in the zasocitinib treatment groups (53%-62%) compared with placebo (44%); however, there was no dose-response association for any specific TEAE (Table 3). COVID-19, acne/acneiform dermatitis, and diarrhea were the most frequently reported events (reported by 3 or more patients in any treatment group) (Table 3). TEAEs leading to study treatment discontinuation occurred for 1 to 2 patients (2%-4%) in the zasocitinib treatment groups and 1 patient (2%) in the placebo group. Two SAEs were reported in a single patient receiving zasocitinib, 15 mg (severe pleural effusion and severe pericardial effusion); however, these were considered unrelated to study drug (Table 3). There were no MACE, thromboembolic events, or opportunistic infections.

Table 3. Summary of Harms in Patients With Moderate to Severe Psoriasis in a Phase 2b Study for Zasocitinib.

Adverse Event	No. (%)
	Placebo (n = 52)	Zasocitinib, once daily
	Placebo (n = 52)	2 mg (n = 50)	5 mg (n = 52)	15 mg (n = 53)	30 mg (n = 52)
Deaths	0	0	0	0	0
SAEs	0	0	0	1 (2)	0
TEAEs	23 (44)	31 (62)	28 (54)	28 (53)	31 (60)
TEAEs leading to study treatment discontinuation^a	1 (2)	1 (2)	1 (2)	1 (2)	2 (4)
Most frequent TEAEs^b
COVID-19^c	1 (2)	6 (12)	4 (8)	6 (11)	7 (14)
Acne^c	0	0	1 (2)	3 (6)	2 (4)
Acneiform dermatitis^c	0	0	1 (2)	1 (2)	3 (6)
Diarrhea^c	1 (2)	3 (6)	1 (2)	1 (2)	0

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Abbreviations: SAE, serious adverse event; TEAE, treatment-emergent adverse event.

^{^a}

TEAEs leading to drug discontinuation and early termination in 5 patients included increased creatine kinase levels (30 mg), pericardial effusion and pleural effusion (15 mg), tachycardia and syncope (5 mg), decreased lymphocyte cell counts (2 mg), and atrial fibrillation (placebo).

^{^b}

TEAEs reported by 3 or more patients in any treatment group (events elicited by laboratory testing are not included).

^{^c}

All events of COVID-19 and acneiform dermatitis were grade 1 (mild) or grade 2 (moderate) in severity and resolved by the end of the study. All events of acne and diarrhea were grade 1 (mild) in severity, and most were resolved by the end of the study.

No clinically meaningful longitudinal differences were observed in laboratory parameters for cholesterol levels, blood cell counts, liver enzyme levels, or estimated glomerular filtration rates with zasocitinib compared with placebo. Creatine kinase elevations were more common in the zasocitinib treatment groups compared with placebo, but there was no evidence of dose dependence (eFigures 13-15 in Supplement 3). Clinically significant TEAEs associated with creatine kinase elevation were observed at similar rates between the zasocitinib treatment groups and placebo, and there were no cases of rhabdomyolysis. A full list of all TEAEs is contained in eTable 4 in Supplement 3.

Discussion

In this randomized clinical trial, the primary end point of PASI 75 response at week 12 was achieved for patients receiving zasocitinib at doses of 5 mg and higher. The secondary end points of PASI 90 and 100 and a PGA score of 0 or 1 were concordant with the primary end point. A trend for a dose-response association was observed for PASI 75 and 90 up to zasocitinib, 15 mg, with similar efficacy achieved with zasocitinib, 30 mg. By contrast, the trend for a dose-response association for PASI 100 continued past zasocitinib, 15 mg, with the highest response with zasocitinib, 30 mg. This suggests that higher coverage of the target is more likely to result in complete skin clearance without the risk of clinically significant toxic effects characteristic of JAK1-3 inhibition.

The current study also investigated the effect of zasocitinib on the HRQoL of patients using the DLQI. Previous studies using DLQI and the Psoriasis Symptom Inventory have shown that complete skin clearance (PASI 100) is associated with clinically meaningful improvements in the HRQoL and psoriasis symptoms of patients compared with almost complete skin clearance (PASI 90 to <100).^29,30,31,32 In the current study, patients receiving zasocitinib, 30 mg, had the greatest reduction in DLQI from baseline compared with all other zasocitinib treatment groups and placebo, indicating a dose-responsive improvement in HRQoL. Greater DLQI reductions from baseline in the zasocitinib, 15 mg, and zasocitinib, 30 mg, treatment groups relative to placebo were observed from as early as week 4.

The incidence of TEAEs was higher in the zasocitinib groups compared with placebo, but there was no clear dose dependence for any individual TEAE. The incidence of TEAEs of 44% in the placebo arm aligned with previous clinical trial results of treatments in plaque psoriasis, for which TEAEs occurred at similar rates between treatment and placebo groups.^19,33,34 COVID-19, acne/acneiform dermatitis, and diarrhea were the most frequently reported TEAEs. No treatment-related SAEs or opportunistic infections or psychiatric sequelae (eg, suicide attempts) were reported during the study. In addition, rates of study discontinuation due to TEAEs were low overall and comparable between the placebo and active treatment groups. Some asymptomatic, transient, and/or reversible change in some laboratory parameters were also observed, such as creatine kinase elevation; however, these were not considered meaningful by the investigators, and there were no cases of rhabdomyolysis. Additionally, there were no dose-dependent associations between zasocitinib use and changes in liver function or hematology parameters. Consistent with the phase 3 randomized clinical trials of deucravacitinib,^20,21 there were no MACE or thromboembolic events observed in this trial. The efficacy and safety results from the current study were also consistent with previous studies on zasocitinib.^25,35

The lack of JAK-related safety signals was consistent with the high level of selectivity that zasocitinib demonstrates for the JH2 domain of TYK2 (K_D [dissociation constant] = 0.0038 nM) relative to the JH2 domains of JAK1 and JAK2 (K_D = 4975 and 23 000 nM, respectively).²⁴ This level of selectivity is achieved through the presence of a methoxycyclobutyl ring that fits into the binding pocket of the TYK2 JH2 domain (defined by Val603 and Lys642) but is sterically occluded from the JAK1 and JAK2 JH2 domains owing to the presence of Ile597 and Ile559 residues.²⁴ Such a selectivity profile could potentially elicit fewer off-target SAEs than currently available JAK1-3 inhibitors, allowing for exploration of higher doses of zasocitinib. By contrast, deucravacitinib binds with a lower binding affinity for TYK2 than that demonstrated by zasocitinib.²⁴ Whether these differences translate into corresponding levels of clinical efficacy remains to be confirmed in further clinical trials.

Limitations

As with any phase 2 trial, this study had limitations, including a potential lack of power due to the small sample size and short study duration. In addition, less than 8% of the patient population was Black or African American, and the study was conducted at centers in North America only and involved a restricted range of patient weights and body mass indices. Therefore, these findings may not be generalizable to more diverse populations in other geographic regions.

Conclusions

In this randomized clinical trial, zasocitinib, an advanced, potent, and highly selective oral TYK2 inhibitor bioengineered to optimize target coverage and functional selectivity, achieved biologic-level efficacy with complete skin clearance observed after only a 12-week treatment period in up to one-third of patients, with a low incidence of known tolerability issues and absence of serious toxic effects that are characteristic of JAK1-3 inhibition. Two phase 3 studies of longer duration and with larger populations (NCT06088043 and NCT06108544) have been initiated to confirm these early observations.

Supplement 1.

Trial protocol

jamadermatol-e242701-s001.pdf^{(3.2MB, pdf)}

Supplement 2.

Statistical analysis plan

jamadermatol-e242701-s002.pdf^{(1MB, pdf)}

Supplement 3.

eAppendix. List of Investigators

eMethods.

eResults.

eFigure 1. Design of Phase 2b Study of Zasocitinib in Patients With Moderate-to-Severe Plaque Psoriasis

eFigure 2. Change from Baseline in DLQI in Patients With Moderate-to-Severe Psoriasis in a Phase 2b Study of Zasocitinib (mITT Analysis Set)

eFigure 3. Change from Baseline in BSA Affected by Psoriasis in Patients With Moderate-to-Severe Psoriasis in a Phase 2b Study of Zasocitinib (mITT Analysis Set)

eFigure 4. Time Course of PASI 50 Response Rates In Patients With Moderate-to-Severe Psoriasis in a Phase 2b Study of Zasocitinib (mITT Analysis Set)

eFigure 5. Change from Baseline in PASI in Patients With Moderate-to-Severe Psoriasis in a Phase 2b Study of Zasocitinib (mITT Analysis Set)

eFigure 6. Percent Change from Baseline in PASI in Patients With Moderate-to-Severe Psoriasis in a Phase 2b Study of Zasocitinib (mITT Analysis Set)

eFigure 7. Change from Baseline in PGA in Patients With Moderate-to-Severe Psoriasis in a Phase 2b Study of Zasocitinib (mITT Analysis Set)

eFigure 8. Proportion of Patients Achieving a ≥2-Grade Decrease from Baseline in PGA at Weeks 2, 4, 8, and 12 in Patients With Moderate-to-Severe Psoriasis in a Phase 2b Study of Zasocitinib (mITT Analysis Set)

eFigure 9. Change from Baseline in Pruritus NRS in Patients With Moderate-to-Severe Psoriasis in a Phase 2b Study of Zasocitinib (mITT Analysis Set)

eFigure 10. Proportion of Patients with a Baseline Pruritus NRS Score of ≥4 Achieving a ≥4-Point Decrease from Baseline at Weeks 2, 4, 8, and 12 in Patients With Moderate-to-Severe Psoriasis in a Phase 2b Study of Zasocitinib (mITT Analysis Set)

eFigure 11. Change from Baseline in Pain NRS Among Patients with Concomitant Psoriatic Arthritis, in Patients With Moderate-to-Severe Psoriasis in a Phase 2b Study for Zasocitinib (mITT Analysis Set)

eFigure 12. Time Course of Affected BSA ≤1% Response in Patients With Moderate-to-Severe Psoriasis in a Phase 2b Study for Zasocitinib (mITT Analysis Set)

eFigure 13. Change from Baseline in Hematologic Parameters and Creatine Kinase in Patients With Moderate-to-Severe Psoriasis in a Phase 2b Study for Zasocitinib (Safety Analysis Set)

eFigure 14. Change from Baseline in Hepatic and Renal Parameters in Patients With Moderate-to-Severe Psoriasis in a Phase 2b Study for Zasocitinib (Safety Analysis Set)

eFigure 15. Change from Baseline in Lipid Parameters in Patients With Moderate-to-Severe Psoriasis in a Phase 2b Study for Zasocitinib (Safety Analysis Set)

eTable 1. Proportion of Patients With Moderate-to-Severe Psoriasis Receiving Zasocitinib Who Achieved PASI 75, 90, and 100 Responses at Weeks 2, 4, 8, and 12 (mITT Analysis Set)

eTable 2. Proportion of Patients With Moderate-to-Severe Psoriasis Receiving Zasocitinib Who Achieved a DLQI of 0 or 1 at Weeks 4, 8, and 12 (mITT Analysis Set)

eTable 3. Protocol Amendments for Phase 2b Study of Zasocitinib in Patients With Moderate-to-Severe Psoriasis

eTable 4. Summary of TEAEs by system organ class and preferred term, all periods (safety analysis set)

jamadermatol-e242701-s003.pdf^{(1.4MB, pdf)}

Supplement 4.

Data sharing statement

jamadermatol-e242701-s004.pdf^{(16.2KB, pdf)}

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Supplementary Materials