The novel tyrosine kinase 2 (TYK2) inhibitor envudeucitinib (ESK-001) produced high levels of skin clearance with a reassuring tolerability profile in the phase 3 ONWARD 1 and 2 trials. By week 24, Psoriasis Area and Severity Index (PASI) 90 was achieved by approximately 65% of patients with moderate-to-severe plaque psoriasis, and complete clearance (PASI 100) by 40% of patients, approaching response levels typically associated with biologic therapy.
TYK2 inhibition has emerged as an attractive oral strategy in psoriasis, as it enables selective modulation of interleukin-23 (IL-23) and type I interferon signalling without broader inhibition of the Janus kinase (JAK) pathway, which is associated with known adverse effects. As Dr Andrew Blauvelt (University of Maryland School of Medicine, MD, USA) noted, envudeucitinib achieves sustained TYK2 inhibition throughout the 24-hour dosing interval. But does this translate into clinical benefit? This question was now answered by the ONWARD 1 (NCT06586112) and ONWARD 2 (NCT06588738) pivotal trials, presented in a late-breaking research session [1].
Both randomised, double-blind studies enrolled more than 1,700 adults with moderate-to-severe plaque psoriasis and compared envudeucitinib 40 mg twice daily with apremilast and placebo. Co-primary endpoints at week 16 were PASI 75 and a Physician’s Global Assessment (PGA) score of 0/1. Both trials met all primary and secondary endpoints, demonstrating clinically meaningful separation from comparators; approximately 75% of patients receiving envudeucitinib achieved PASI 75 at week 16, compared with substantially lower response rates in the apremilast and placebo groups. At the same time point, 59% of patients achieved PGA 0/1.
Response depth continued to increase through week 24, consistent with the delayed efficacy often observed with agents modulating the interleukin-23 (IL-23) pathway. At week 24, approximately 80% of patients achieved PASI 75, around 65% reached PASI 90, and 40% attained complete PASI 100. Envudeucitinib outperformed apremilast across all PASI endpoints at week 24 (P<0.0001). Dr Blauvelt emphasised the clinical relevance of achieving a 40% PASI 100 rate with an oral therapy, a level of efficacy historically associated with biologic agents.
The safety signal was favourable and consistent with prior experience with TYK2. The most frequently reported adverse events were nasopharyngitis and upper respiratory tract infections. No signals were observed for major adverse cardiovascular events, tuberculosis reactivation, or laboratory abnormalities, including lipid elevations.
Looking ahead, Dr Blauvelt suggested that the typical regulatory timeline for late-breaking phase 3 dermatology data may apply, with potential market entry within the following year. A long-release once-daily formulation is under development to replace the current 40 mg twice-daily regimen, and paediatric studies are planned.
With PASI 100 achieved in approximately 40% of patients at week 24 and no new safety concerns identified, envudeucitinib, described by Dr Blauvelt as a “next-generation or second-generation TYK2 inhibitor,” may expand the oral treatment landscape for moderate-to-severe plaque psoriasis, offering a biologic-like efficacy profile for patients who prefer oral therapy.
- Blauvelt A. Envudeucitinib (ESK-001) in moderate-to-severe plaque psoriasis: 24-week results from the randomised, double-blind, active comparator- and placebo-controlled, phase 3 ONWARD 1 and 2 studies. AAD 2026, 27–31 March, Denver, CO, USA.
Copyright ©2026 Medicom Education B.V.
In patients with psoriatic arthritis (PsA) and coexisting overweight or obesity, adding the glucagon-like peptide-1 (GLP-1) agonist tirzepatide to the interleukin-17A (IL-17A) inhibitor ixekizumab substantially improved both articular and metabolic outcomes. In a phase 3 randomised trial, nearly one-third of patients receiving the combination achieved a composite endpoint of the American College of Rheumatology 50% improvement criteria (ACR50) plus ≥10% weight loss at week 36, compared with fewer than 1% of patients receiving ixekizumab monotherapy.
Approximately half of adults with PsA are affected by obesity [1]. This burden is increasingly recognised as contributing to reduced response to biologic therapy [2], increasing cardiometabolic risk, and impaired patient-reported outcomes. Against this background, dual targeting of inflammatory disease activity and adiposity has emerged as a rational therapeutic strategy. This approach was evaluated in the phase 3b TOGETHER-PsA head-to-head trial (NCT06588296), presented by Prof. Joseph Merola (UT Southwestern Medical Center, TX, USA) [3].
Adults with PsA and overweight or obesity, along with at least 1 weight-related comorbidity (n=271), were randomised to receive ixekizumab plus tirzepatide or ixekizumab alone and were followed for 36 weeks. The primary composite endpoint required achievement of both ACR50 and ≥10% body-weight reduction. At week 36, this endpoint was met by 31.7% of patients in the combination arm, compared with fewer than 1% of the ixekizumab monotherapy arm.
Hierarchical secondary analyses supported the primary findings. The proportions of patients achieving ACR50 (33.5% vs 20.4%; P<0.05), ≥10% weight loss (84.5% vs 4.5%; P<0.001), or the alternative composite of ACR20 plus ≥5% weight reduction (69.7% vs. 10.3%; P<0.001) were all significantly higher with combination therapy. Additional articular outcomes and patient-reported measures, including overall symptom burden and quality of life, also consistently favoured the dual-therapy approach.
According to Prof. Merola, the early and statistically robust separation in ACR50 was particularly notable and may signal a potential paradigm shift. He further emphasised that effective management of obesity as a core comorbidity is likely to translate into long-term improvements in quality of life and potentially survival in this population.
For dermatologists managing PsA in patients with overweight or obesity, the combination of ixekizumab and tirzepatide may offer meaningful benefits for skin-joint disease activity and cardiometabolic health, supporting an integrated treatment approach.
- Siebert S, et al. Joint Bone Spine 2025;92(5):105904.
- Di Minno M, et al. Arthritis Care Res (Hoboken) 2013:65(1):141-147.
- Merola JF. Ixekizumab plus tirzepatide in patients with psoriatic arthritis and overweight or obesity: a phase III randomised trial. S034: Late-breaking Research Session 2. AAD 2026, 27–31 March, Denver, CO, USA.
Copyright ©2026 Medicom Education B.V.
Positive results for the treatment of psoriasis with zasocitinib were demonstrated in 2 phase 3 trials. After 16 weeks of treatment with the tyrosine kinase 2 (TYK2) inhibitor, approximately 70% of patients achieved clear or almost clear skin on the static Physician Global Assessment (sPGA).
Zasocitinib is a potent and highly selective oral TYK2 inhibitor, with more than a million-fold greater selectivity for TYK2 over Janus kinase 1 (JAK1) [1]. Dr Melinda Gooderham (SKiN Centre for Dermatology, ON, Canada) presented late-breaking data from the phase 3 LATITUDE-PsO-3001 (NCT06088043) and LATITUDE-PsO-3002 (NCT06108544) trials, which evaluated zasocitinib in patients with moderate-to-severe plaque psoriasis [2]. In addition to the zasocitinib treatment arms, the trials included placebo and an active comparator (apremilast).
Results for the primary endpoint across the 2 trials, comprising a total of 1,801 patients, showed significantly higher rates of sPGA 0/1 with zasocitinib compared with both apremilast and placebo: 71.4% and 69.2% for zasocitinib versus 32.1% and 29.7% for the active comparator, and 10.7% and 12.6% for placebo (P<0.001). Findings for the co-primary endpoint, Psoriasis Area and Severity Index (PASI) 75, were consistent with these results.
PASI 90 responses were achieved by 61.3% and 51.9% of participants receiving zasocitinib compared with 16.8% and 15.9% with apremilast and 5.0% and 4.0% with placebo at week 16. The more stringent secondary endpoint, PASI 100, was reached by 33.4% and 25.2% of patients on zasocitinib versus 2.9% and 4.3% with apremilast and 0.7% and 1.1% with placebo (P<0.001). Treatment responses with zasocitinib continued to improve through week 24.
To assess the durability of response, a withdrawal phase from week 40 to week 60 was included in the trial programme. Patients who achieved PASI 75 at week 40 were re-randomised to either continue zasocitinib or switch to placebo. At week 60, for example, more than 90% of patients who continued TYK2 inhibition in LATITUDE-PsO-3002 maintained their response.
The safety profile of zasocitinib was consistent with previous studies, with no new safety signals identified. The most common adverse events were upper respiratory infections (10.1%), acne (6.5%), and nasopharyngitis (6.2%). Treatment-emergent adverse events through week 16 occurred in 62.1% receiving zasocitinib, compared with 50.5% with apremilast and 46.9% with placebo.
- Mehrotra S, et al. J Invest Dermatol. 2026;146(1):214-222.
- Gooderham M, et al. Once-daily Oral Zasocitinib Demonstrates Rapid and Reproducible Skin Clearance with a Consistent Safety Profile in Moderate-to-Severe Plaque Psoriasis: Results from Two Randomized Phase 3 Trials (LATITUDE-PsO-3001 and 3002). S034 Late-Breaking Research: Session 2. AAD 2026, 27–31 March, Denver, CO, USA.
Copyright ©2026 Medicom Education B.V.