TYK2 Inhibition with Zasocitinib Results in Significant Skin Clearance for Psoriasis

Credit: April W. Armstrong, MD, MPH

Credit: Armstrong Research

Potent and selective inhibition of tyrosine kinase 2 (TYK2) using once-daily oral zasocitinib therapy at 5 mg or more leads to significant skin clearance improvements among patients with plaque psoriasis over 12 weeks, according to recent findings.¹

This new research was conducted with the goal of evaluating zasocitinib among individuals with moderate to severe plaque psoriasis in terms of safety, effectiveness, and tolerability. The drug was formulated as a highly selective allosteric TYK2 inhibitor, serving as a possible new oral therapy option for the skin disease.

This study, published in JAMA Dermatology, was led by investigators such as April W. Armstrong, MD, MPH, professor and chief of dermatology at UCLA and Chair Emeritus of the Medical Board of the National Psoriasis Foundation. Armstrong and colleagues also noted that the prior phase 1 trial found that this medication modulates psoriasis through its impact on the IL-23/Th-17 axis mainly.²

“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,” Armstrong and colleagues wrote.¹

Background and Design

The research team conducted the phase 2b study using a multicenter, randomized, double-blind, multiple-dose placebo-controlled trial design. They recruited participants with moderate to severe psoriasis found in 47 centers in the US and 8 in Canada, later randomizing them 1:1:1:1:1.

Subjects between 18 - 70 years of age were involved in the study, and these individuals were required to have been living with plaque psoriasis for at least 6 months before screening. Additionally, these participants were required to have reported a Psoriasis Area and Severity Index (PASI) score of 12 or higher as well as a Physician's Global Assessment (PGA) score of 3 or greater.

Those deemed eligible also had to have a body mass index (BMI) between 18 - 42, to show that their psoriasis affected 10% of their total body surface area (BSA) at least, and maintain a total body weight of over 50 kg. A substantial psoriasis flare must also not have been experienced by these subjects in the 3 months prior to screening, and the subjects must be suitable candidates for phototherapy or systemic treatment.

These subjects were stratified by prior use of biologic therapy. The participants were given 1 of 4 oral doses of zasocitinib—with the range being 2, 5, 15, or 30 mg, once-per-day—or matching oral placebo over the course of 12 weeks. The team would add an additional 4-week period for follow-up for the purposes of safety monitoring.

There was a 12-week treatment period implemented by the investigators in the study followed by a 4-week follow-up. Among the 287 participants who were randomized in the study, 90.2% were then given at least a single treatment dose.

The investigators determined their main measure of the treatment’s efficacy would be the proportion of individuals reporting a 75% or greater PASI score improvement (PASI 75) by the 12-week point, with their secondary endpoints having included PASI 90 and 100 responses.

Conclusions

Overall, there were 259 individuals randomized and given treatment over the course of the study (mean age, 47 years; 32% female). By the 12-week mark, the research team found that PASI 75 was achieved for among 18%, 44%, 68%, and 67% of the subjects given zasocitinib at the 2, 5, 15, and 30 mg doses, respectively, and 6% of those given placebo.

The investigators reported that the PASI 90 responses recorded in their study were consistent with PASI 75. They also noted that PASI 100 demonstrated a dose response at each and every dose, adding that 33% of the subjects achieved PASI 100 when treated with zasocitinib, 30 mg.

Occurrence of TEAEs was reported by the research team among 44% of the participants given placebo and 53% to 62% of those given the 4 different zasocitinib doses. The team added that there was no dose dependency and there were no clinically meaningful longitudinal distinctions observed in the laboratory parameters.

“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,” they wrote. “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.”

References

1. ^{Armstrong A, Gooderham M, Papp K, et al. Tyrosine Kinase 2 Inhibition With Zasocitinib (TAK-279) in Psoriasis: A Randomized Clinical Trial. JAMA Dermatol. Published online August 21, 2024. doi:10.1001/jamadermatol.2024.2701.}
2. ^{McElwee JJ, Garcet S, Li X, et al. 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. J Am Acad Dermatol. 2022;87(3)(suppl): AB139. doi:10.1016/j.jaad.2022.06.590.}