Zasocitinib: New Frontier in Tyrosine Kinase 2 Inhibition

Samantha R. Adam¹ and Maxwell Sauder, MD, FRCPC, FAAD, FCDA^2,3
1Wilfrid Laurier University, Waterloo, ON, Canada
²Division of Dermatology, Department of Medicine, University of Toronto, Toronto, ON, Canada
³Probity Medical Research, Waterloo, ON, Canada

Disclosures: Maxwell Sauder has been an investigator for Alumis, Amgen, AbbVie, Bristol-Myers-Squibb, Janssen, and Takeda. He has been a consultant for Amgen, AbbVie, Arcutis, Bausch Health, Eli Lilly Canada, Janssen, LEO Pharmaceuticals, Novartis, Sun Pharmaceuticals, and UCB Canada. Samantha R. Adam has no disclosures.
Funding sources: None.

ABSTRACT
Zasocitinib is a novel highly selective tyrosine kinase 2 (TYK2) inhibitor that is in late phase development for the treatment of psoriasis and psoriatic arthritis. This article will review its efficacy, safety and tolerability. Currently, deucravacitinib is the only TYK2 inhibitor with regulatory approval from most major authorities. Zasocitinib offers potential benefits, as it has higher target selectivity and affinity of the Janus homology 2 (JH2) domain of TYK2 as compared to deucravacitinib. This selectivity leads to minimal inhibition of Janus kinase (JAK) 1, JAK2 and JAK3 (JAK1-3), and therefore may result in less off-target effects that have been associated with other molecules.

Keywords: psoriasis, tyrosine kinase 2, TYK2, zasocitinib, Janus kinase inhibitor, JAK

Introduction

Introduction Psoriasis is an autoimmune disease that significantly impacts quality of life (QoL) and affects approximately 125 million people worldwide.¹ Plaque psoriasis presents as erythematous plaques surmounted by silvery scales. The disease can be dry, itchy and painful.² When limited in its distribution, chronic plaque psoriasis can often be controlled with topical medications. Moderate disease, defined as covering ≥3-10% body surface area (BSA) is often hard to control with only topical therapies.³ For moderate to severe patients, phototherapy or systemic therapy are generally required. The introduction of biologics in the last 20 years has revolutionized the management of psoriasis. More recently, novel oral small molecules have been introduced for the management of autoimmune disease including phosphodiesterase-4 inhibitors and Janus kinase (JAK) inhibitors.² The latest entrant in the novel oral small molecule space are allosteric tyrosine kinase 2 (TYK2) inhibitors.⁴ This article will discuss zasocitinib, an investigational, novel, oral allosteric TYK2 inhibitor.

Pathogenesis of Plaque Psoriasis

In a genetically predisposed individual exposed to certain unknown environmental factors, antigenic stimuli along with interferon gamma (IFN-γ), interferon alpha (IFN-α), and tumor necrosis factor-alpha (TNF-α), lead to the differentiation of plasmacytoid dendritic cells into myeloid dendritic cells (MDC). This promotes the increased production of interleukin-12 (IL-12) and IL-23 by the MDCs which helps promulgate T helper type 1 (TH1), TH22 and TH17 cell populations. These pathogenic T cells further secrete IL-17 and IL-22 and drive keratinocyte activation and proliferation, as well as increase the density of tissue-resident memory T cells in the epidermis. This leads to a chronic inflammatory positive feedback loop by promoting the release of inflammatory cytokines, further driving the disease process.²

Rationale for Targeting TYK2 in Plaque Psoriasis Treatment

Zasocitinib has a higher affinity for inhibiting TYK2 as opposed to JAK1-3; this is favorable because blockade of JAK1-3 can induce off-target effects and occasionally severe adverse effects (SAEs) can occur due to the inhibition of the adenosine triphosphate (ATP) active domain. Off-target inhibition of the physiologic functioning of JAK1-3 can lead to problems with myelopoiesis, granulopoiesis, lymphoid cell maturation and function, hematopoiesis, growth factor response, metabolic activity regulation, and lipid metabolism.³ Zasocitinib is designed to bind to the regulatory JH2 pseudokinase domain of TYK2.⁵ When TYK2 is inhibited, cytokine signaling pathways that depend on TYK2 cannot activate downstream STAT transcription factors. As a result, these signals do not reach the nucleus and are unable to increase pro-inflammatory gene expression, primarily decreasing production of IL-23, IL-12 and type I IFN.²

Zasocitinib vs. Deucravacitinib

Zasocitinib is a potent inhibitor of TYK2 signaling, as it binds to the TYK2 regulatory domain. This inhibition blocks downstream signaling by cytokines such as IL-23, IL-12 and type I IFN and diminishes polarization of T cells.⁶ Studies have shown that JAK1-3 inhibitors that bind to the active domain of the enzyme lead to off-target effects, limiting the medication’s therapeutic range. As zasocitinib binds to the regulatory domain, it can have a much larger therapeutic range without increasing these risks.^6-8 Deucravacitinib, currently the only TYK2 inhibitor approved by both U.S. Food and Drug Administration and Health Canada, is indicated for the treatment of chronic plaque psoriasis and has an 87-fold greater binding selectivity for TYK2 as compared to JAK1-3. By contrast, zasocitinib has over a million-fold greater binding selectivity for TYK2 as compared to JAK1-3. Furthermore, zasocitinib has demonstrated superior efficacy and a much longer duration of effect than deucravacitinib.^6-8 At a 30 mg daily dose of zasocitinib, plasma concentrations were maintained above the TYK2 inhibitory constant 90 (IC90) threshold for 24 hours. At the approved 6 mg daily dose of deucravacitinib, IC90 engagement was not observed without impacting JAK1-3 signaling.^6-8

Efficacy of Zasocitinib: Key Evidence from Phase 2b Trial

In a 12-week, double-blind, phase 2b study, patients with moderate to severe psoriasis were dosed once daily (QD) and randomized to five groups, placebo (n=52), and ascending doses of zasocitinib: 2 mg (n=50), 5 mg (n=52), 15 mg (n=53), and 30 mg (n=52).⁴

The primary endpoint was Psoriasis Area and Severity Index (PASI) 75 at Week 12, meaning a ≥75% reduction from baseline. Secondary endpoints at Week 12 were a Physician’s Global Assessment (PGA) score of 0 or 1, PASI 90, PASI 100 and change from baseline in the Dermatology Life Quality Index (DLQI).⁴

The PASI 75 response rates for patients on 2 mg, 5 mg, 15 mg, and 30 mg of zasocitinib at Week 12 (18.0%, 44.2%, 67.9%, 67.3%) was significantly higher than the placebo group (5.8%).⁴ The secondary endpoints of the study were also met. PASI 90, while not achieved in the placebo group, was seen in 8.0%, 21.2%, 45.3%, and 46.2% of the populations in the 2 mg, 5 mg, 15 mg and 30 mg groups, respectively. PASI 100 rates were 2%, 9.6%, 15.1% and 32.7% in the zasocitinib dose groups. PASI 100 was not achieved in the placebo group. PGA 0/1 and least-squares mean change from baseline in DLQI were also found to be significantly different between placebo and all dosing arms (Table 1).⁴

Table 1:

Zasocitinib: Safety and Tolerability Profile

Treatment emergent adverse effects (TEAE) occurred at higher rates in the zasocitinib groups (52.8%-62.0%) compared to the placebo group (44.2%).⁴ There was no TEAE that was dose-dependent. The most common TEAE was the coronavirus disease 2019 (COVID-19), occurring in 1.9% of patients in the placebo group and in 12.0%, 7.7%, 11.3%, and 13.5% of patients receiving zasocitinib at 2 mg, 5 mg, 15 mg, and 30 mg, respectively. Acne and acneiform dermatitis were not seen in the placebo arm but were seen in the zasocitinib arms ranging from 1.9%-6% with a trend for the higher doses.⁴ Diarrhea as an adverse event ranged from 0-6% amongst the different dosing groups and placebo with a non-dose dependent distribution between groups. Lab abnormalities were infrequent and not dose dependent except for a subtle trend for creatine kinase (CPK) elevation in the higher doses of zasocitinib (Table 2).⁴

Table 2:

Discussion

The inhibitory constant of a drug is a measure of how tightly it binds to its target. Lower values for the inhibitory constant correspond to stronger binding. Zasocitinib’s inhibitory constant is 0.0087 nM which demonstrates over a one-million-fold selectivity for TYK2 over JAK1. In comparison, deucravacitinib’s inhibitory constant is 0.02 nM, showing only an 87-fold selectivity for TYK2 over JAK1.⁶ The reason why zasocitinib has a much higher affinity for binding to TYK2 is because, unlike deucravacitinib, a methocyclobutyl ring was computationally designed for zasocitinib. This molecule causes a steric occlusion, preventing zasocitinib from physically binding to JAK1-3, but still allowing it to bind to TYK2.⁸ Only targeting TYK2 reduces the amount of off-target effects such as serious infections, malignancies, thrombosis, and major adverse cardiovascular events that have been seen mostly in other non-psoriasis populations treated with oral JAK inhibitors.³

Patients treated with zasocitinib achieved PASI 75, 90, and 100 results at rates significantly greater than those on placebo. This trend persisted in the PGA 0/1 scores and in least-squares mean change from baseline in DLQI. The 5 mg, 15 mg, and 30 mg groups showed a two-fold or greater decrease in their DLQI scores compared to the placebo group.⁴

All groups shared similar adverse effects with no dose-dependency, highlighting the safety and tolerability of zasocitinib.⁴

Given the promising phase 2 results discussed above, zasocitinib is well into phase 3 development in both psoriasis and psoriatic arthritis.

Conclusion

This novel, emerging class of highly selective oral TYK2 inhibitors has yielded positive clinical responses. If approved, zasocitinib will give dermatologists and patients a potent, well tolerated medication, with which to treat moderate to severe chronic plaque psoriasis. With a once-daily oral dose, the ease and convenience of this medication will be a welcome option in the management of this chronic disease.