Inside Zasocitinib: a new model for TYK2 inhibition in immune-mediated diseases

Zasocitinib is a highly selective, investigational allosteric tyrosine kinase 2 (TYK2) inhibitor currently in clinical development by Takeda for the treatment of immune-mediated inflammatory diseases (IMIDs), including psoriasis (PsO), psoriatic arthritis (PsA) and inflammatory bowel disease (IBD).^1-9

The dermatology programme is led by Dr Warren Winkelman, a board-certified dermatologist and global medical unit head for dermatology at Takeda. He is responsible for shaping Takeda’s global dermatology strategy, with a focus on developing a potential targeted therapy that addresses key limitations in existing immune-modulating treatments. Under his leadership, zasocitinib has progressed through multiple clinical stages and is now being evaluated in ongoing Phase III studies in moderate-to-severe plaque PsO.^4,5

According to Dr Winkelman, “All our data to date suggest that zasocitinib has the potential to be a promising oral treatment option for people with certain immune-mediated inflammatory diseases.”^1-3

Read on to learn why zasocitinib was developed, how it differs from JAK inhibitors and what early data suggest about its potential IMIDs.

Targeting TYK2

IMIDs are a heterogeneous group of chronic conditions caused by dysregulation of the immune system, leading to sustained inflammation across various organs and tissues.¹¹ Conditions such as PsO, PsA, IBD and vitiligo affect millions of individuals worldwide and are often associated with morbidity and reduced quality of life.^12-17

Although the introduction of biologic and small-molecule therapies has advanced the management of IMIDs, important treatment gaps remain – particularly that offer favourable benefit-risk profiles, tolerability and convenience profiles.¹⁸

Zasocitinib was originally discovered through a collaboration between Nimbus Therapeutics and Schrödinger, and is now in clinical development by Takeda.¹⁹ Using artificial intelligence-assisted, structure-based design and advanced computational modelling, the team developed a highly selective allosteric TYK2 inhibitor.¹⁹

Tyrosine kinase 2 (TYK2) is part of the Janus kinase (JAK) family and plays a key role in mediating cytokine signalling involved in inflammation and immune response.²⁰ Inhibiting TYK2 can help modulate overactive immune pathways implicated in IMIDs and potentially mitigate the risk of suppressing the immune system.²¹

Unlike conventional JAK inhibitors, which bind to a region shared across many related enzymes (the JH1 domain), zasocitinib targets a different part of TYK2 called the JH2 domain. This region is less like the corresponding areas in JAK1, JAK2 and JAK3, allowing zasocitinib to block TYK2 selectively without affecting the other JAK enzymes.²

“Zasocitinib takes a fundamentally different approach to that of JAK inhibitors,” explains Winkelman.²

This allosteric binding approach – where the inhibitor attaches to a site on the enzyme distinct from its main active site – enables selective inhibition of TYK2 by targeting the less conserved JH2 domain.²

Preclinical evidence supporting selectivity and potency

Recent in vitro and simulation-based studies published in the Journal of Investigative Dermatology provide compelling evidence of zasocitinib’s high selectivity and potency. In biochemical binding assays, zasocitinib demonstrated more than 1-million-fold selectivity for TYK2 over other JAK enzymes. In human whole-blood assays, it showed potent and sustained inhibition of TYK2-mediated signalling pathways.²

In pharmacokinetic simulations, a 30mg dose of zasocitinib maintained greater than 90 percent inhibition of TYK2 signalling over a 24-hour period across multiple cytokine assays. ²

“Zasocitinib exhibited more potent and sustained inhibition of TYK2-mediated signalling compared to deucravacitinib, with over 90 percent daily inhibition and 24-hour IC50 coverage at clinically relevant doses,” says Winkelman.²

In comparison, deucravacitinib – a currently approved TYK2 inhibitor – showed lower levels of sustained TYK2 inhibition and some measurable off-target activity at JAK1/3. Zasocitinib, by contrast, showed no measurable inhibition of JAK1, JAK2 or JAK3 in these models. ²

In simple terms, this means that in vitro zasocitinib more effectively and consistently blocks the TYK2 pathway – which is central to inflammation in conditions like psoriasis – without interfering with related immune pathways controlled by other JAK enzymes. This selectivity is important because it may reduce the likelihood of unwanted side effects linked to broader immune suppression.²

Yet Dr Winkelman warns:

“We should interpret the potential clinical meaningfulness of these data cautiously, as in vitro data and simulation modelling have limitations and may not directly translate to clinical outcomes.”

Comparative pharmacology and translational modelling

To better understand how these findings might inform clinical development, the team conducted simulation modelling based on pharmacokinetic data. Simulated exposures of zasocitinib at 30mg demonstrated full 24-hour coverage of TYK2 inhibition across multiple assays (IL-12, IL-23 and type I IFN pathways). Deucravacitinib, in contrast, showed variable inhibition (20.0–74.5 percent) and less sustained TYK2 coverage at its approved 6mg dose.²

In simple terms, this in vitro data suggests that zasocitinib may maintain more consistent and effective blockade of key inflammatory pathways over a full day with a single dose, whereas deucravacitinib’s effect may weaken between doses. Sustained inhibition is important in chronic inflammatory diseases, where continuous control of immune signalling is needed to reduce flare-ups and maintain therapeutic benefit. ²

Importantly, neither drug affected JAK1, JAK2 or JAK3 signalling at the tested doses, which supports their selectivity for TYK2. ² However, direct comparison in clinical trials is still needed to confirm how they perform in patients.

Overcoming design challenges through computational chemistry

The structural similarity between TYK2 and other JAK kinases has long posed a challenge to selective inhibition. Zasocitinib’s development required medicinal chemistry to overcome this.²

“The initial step began with a library of compounds… From there, the chemists at Nimbus Therapeutics used an AI-assisted approach of computationally guided structure-based drug design.”

Early hits from the JH2-binding compound library were refined using crystal structure analysis, AI-driven modelling and iterative screening for solubility, selectivity and metabolic stability. One key breakthrough involved eliminating PDE4 off-target activity – a common issue in early leads – to improve tolerability and reduce the risk of gastrointestinal side effects.

The final candidate, zasocitinib, was selected based on its optimal binding potency, solubility and pharmacokinetic properties, enabling once-daily oral dosing in clinical studies.

Clinical development programme: focus and future directions

Zasocitinib is currently under evaluation in a robust clinical development programme across multiple IMIDs^4-10,22:

• Phase III studies in moderate-to-severe plaque PsO
• Phase II trials in IBD, including Crohn’s disease and ulcerative colitis
• Phase III studies in PsA
• A planned Phase II study in vitiligo
• A future Phase III trial comparing zasocitinib with deucravacitinib in PsO.

Early results from a Phase IIb study in plaque PsO have shown promising outcomes, and Takeda plans to further explore its potential across additional indications and patient populations.^3-10

Conclusion

Zasocitinib is part of a novel class of allosteric TYK2 inhibitors with the potential to reshape the treatment paradigm for IMIDs. Its selective mechanism of action, robust pharmacological profile and promising early clinical results position it as a leading  candidate in a competitive but evolving therapeutic landscape.²

As further data emerge from ongoing Phase III trials, the clinical community will gain greater clarity on the true potential of this investigational therapy.^4,5 Should the promise of selective TYK2 inhibition translate into consistent efficacy and safety across IMID indications, zasocitinib may offer a meaningful advancement in targeted, oral immunomodulation.^1-3

References:

1. Leit S, J, Greenwood Carriero S, et al. Discovery of a potent and selective tyrosine kinase 2 inhibitor: TAK-279. J Medicinal Chemistry. 2023;66(15):10473-10496. doi.org/10.1021/acs.jmedchem.3c00600
2. Mehrotra, S et al. Pharmacological Characterization of Zasocitinib (TAK-279): An Oral, Highly Selective and Potent Allosteric TYK2 Inhibitor. May 26, 2025. J Invest Dermatol. 2025 May 27:S0022-202X(25)00531-7. doi: 10.1016/j.jid.2025.05.014. Online ahead of print.
3. Armstrong AW, Gooderham M, Lynde C, et al. Tyrosine Kinase 2 Inhibition With Zasocitinib (TAK-279) in Psoriasis: A Randomized Clinical Trial. August 21, 2024. JAMA Dermatol. 2024 August 21;160;(10):1066- 1074. doi:10.1001/jamadermatol.2024.2701
4. gov. A Phase 3, Randomized, Multicenter, Double-Blind, Placebo- and Active Comparator-Controlled Study With a Randomized Withdrawal and Retreatment Period to Evaluate the Efficacy, Safety, and Tolerability of TAK-279 in Subjects With Moderate-to-Severe Plaque Psoriasis. Available at: https://clinicaltrials.gov/study/NCT06108544?cond=Psoriasis&intr=Tak-279&rank=2. Last accessed: August 2025.
5. gov. A Phase 3, Randomized, Multicenter, Double-Blind, Placebo- and Active Comparator-Controlled Study to Evaluate the Efficacy, Safety, and Tolerability of TAK-279 in Subjects With Moderate-to-Severe Plaque Psoriasis. Available at: ttps://clinicaltrials.gov/study/NCT06088043?cond=plaque%20psoriasis%20&intr=TAK-279&rank=. Last accessed: August 2025.
6. gov. A Phase 2b, Multicenter, Randomized, Double-Blind Induction, Placebo-Controlled, Dose-Ranging Study to Evaluate the Efficacy and Safety of Oral TAK-279 in Subjects With Moderately to Severely Active Crohn’s Disease. Available at: https://clinicaltrials.gov/study/NCT06233461?intr=TAK-279&rank=1. Last accessed: August 2025.
7. gov. A Phase 2, Multicenter, Randomized, Placebo-Controlled, Double- Blind Induction Study to Evaluate the Efficacy and Safety of Oral TAK-279 in Subjects With Moderately to Severely Active Ulcerative Colitis. Available at: https://classic.clinicaltrials.gov/ct2/show/study/NCT06254950. Last accessed: August 2025.
8. A Study of Zasocitinib in Adults With Psoriatic Arthritis Who Have Not Taken Biologic Medicines. ClinicalTrials.gov Identifier: NCT06671483. Updated November 4, 2024. https://clinicaltrials.gov/study/NCT06671483?cond=Psoriatic%20Arthritis&term=tak-279&rank=2. Last accessed: August 2025.
9. A Study of Zasocitinib in Adults With Psoriatic Arthritis Who Have or Have Not Been Treated With Biologic Medicines. ClinicalTrials.gov Identifier: NCT06671496. Updated November 12, 2024. https://clinicaltrials.gov/study/NCT06671496?cond=Psoriatic%20Arthritis&term=tak- 279&rank=1. Last accessed: August 2025.
10. Takeda Presentation. Quarterly Results – Quarter 4 FY2024. Available at: https://assets-dam.takeda.com/image/upload/v1746669209/Global/Investor/Financial- Results/FY2024/Q4/qr2024_q4_p01_en.pdf. Last accessed: August 2025.
11. Ortega MA, García-Montero C, Fraile-Martinez O, et al. Immune-Mediated Diseases from the Point of View of Psychoneuroimmunoendocrinology. Biology (Basel). 2022 Jun 28;11(7):973.
12. Feng Y, Lu Y. Advances in vitiligo: Update on therapeutic targets. Front Immunol. 2022 Aug 31;13:986918. doi: 10.3389/fimmu.2022.986918.
13. AIQassimi S, AIBrashdi S, Galadari H, Hashim MJ. Global burden of psoriasis – comparison of regional and global epidemiology, 1990 to 2017. Int J Dermatol. 2020 May;59(5):566-571. doi: 10. llll/ijd.14864

14. Scotti L, Franchi M, Marchesoni A, Corrao G. Prevalence and incidence of psoriatic arthritis: A systematic review and meta-analysis. Semin Arthritis Rheum. 2018;48(1):28- 34. doi: 10.1016/j.semarthrit.2018.01.003.
15. GBD 2017 Inflammatory Bowel Disease Collaborators. The global, regional, and national burden of inflammatory bowel disease in 195 countries and territories, 1990-2017: A systematic analysis for the Global Burden of Disease Study 2017. Lancet Gastroenterol Hepatol. 2020;5(1):17-30. doi: 10.1016/S2468-1253(19)30333-4
16. Picardo M, Dell’Anna M, Ezzedine K, et al. Nat Rev Dis Primers. 2015 (1):15011.
17. United Nations. Department of Economic and Social Affairs. Population Division. World Population Prospects 2024. Available at: https://population.un.org/wpp/graphs?loc=900&type=Demographic%20Profiles&categ ory=Line%20Charts. Last accessed: August 2025.
18. Liang Z, Xie H, Wu D. Immune mediated inflammatory diseases: moving from targeted biologic therapy, stem cell therapy to targeted cell therapy. Front Immunol. 2025 Apr 7;16:1520063. doi: 10.3389/fimmu.2025.1520063. PMID: 40260258; PMCID: PMC12009864.
19. Nimbus Therapeutics [Press Release]. Takeda to Acquire Nimbus Therapeutics’ Highly Selective, Allosteric TYK2 Inhibitor to Address Multiple Immune-Mediated Diseases. Available at: https://www.nimbustx.com/2022/12/13/takeda-to-acquire-nimbus-therapeutics-highly-selective-allosteric-tyk2-inhibitor-to-address-multiple-immune-mediated-diseases/. Last Accessed: August 2025.
20. Feng Y, Lu Y. Advances in vitiligo: Update on therapeutic targets. Front Immunol. 2022 Aug31;13:986918. doi: 10.3389/fimmu.2022.986918
21. Rusiñol L, Puig L. Tyk2 Targeting in Immune-Mediated Inflammatory Diseases. Int J Mol Sci. 2023;24(4):3391. Published 2023 Feb 8. doi:10.3390/ijms24043391
22. gov. A Study Comparing Zasocitinib (TAK-279) With Deucravacitinib in Adults With Plaque Psoriasis. Available at: https://clinicaltrials.gov/study/NCT06973291#study-overview. Last accessed: August 2025.