Envudeucitinib: Oral TYK2 inhibitor delivers high skin clearance rates in pivotal phase 3 ONWARD trials

What is envudeucitinib, and what sets it apart from currently available psoriasis treatments?

Envudeucitinib is an oral tyrosine kinase 2 (TYK2) inhibitor, a member of the Janus kinase (JAK) family. Unlike JAK1, JAK2, and JAK3, TYK2 has a more selective role in cytokine signaling, mediating pathways involving interleukin (IL)-23, IL-12, and type 1 interferons. These cytokines are central to the pathogenesis of psoriasis, particularly IL-23, which is a key driver of disease activity.

Mechanistically, TYK2 inhibitors can be considered analogous to biologics such as ustekinumab, as they inhibit IL-23 and IL-12 signaling, but with the added effect of modulating type 1 interferons. Envudeucitinibrepresents a next-generation TYK2 inhibitor designed to more selectively and effectively target TYK2 compared with earlier agents such as deucravacitinib.

While deucravacitinib demonstrated superiority over apremilast and established TYK2 inhibition as a viable oral approach, there remained a need for agents with higher efficacy approaching that of biologics. Envudeucitinib, alongside other next-generation agents such as zasocitinib, has been specifically developed to address this gap, with the goal of delivering biologic-like efficacy in an oral formulation.

Could you tell us about the aims, design and eligibility criteria of the ONWARD programme?

The ONWARD clinical program consisted of two pivotal phase III trials, ONWARD 1 and ONWARD 2, designed to evaluate the efficacy and safety of envudeucitinib in patients with moderate-to-severe plaque psoriasis.

Both studies followed a randomized design comparing envudeucitinib with placebo and the active comparator apremilast. Patients were randomized in a 2:1:1 ratio to receive envudeucitinib , placebo, or apremilast. The co-primary endpoints were achievement of a ≥75% improvement in Psoriasis Area and Severity Index (PASI 75) and a static Physician’s Global Assessment (sPGA) score of 0 or 1 at week 16.

Patients were followed through week 24. At week 16, patients in the placebo arm were switched to envudeucitinib, allowing assessment of both continued treatment effects and response following delayed initiation. Apremilast-treated patients continued through week 24, providing a longer-term active comparator.

What have the studies shown in terms of the co-primary endpoints at 24 weeks?

Envudeucitinib met both co-primary endpoints at week 16, demonstrating statistically significant improvements compared with both placebo and apremilast. PASI 75 response rates were approximately 75% across the studies, while PASI 100 rates reached around 30% at week 16, indicating a high level of skin clearance.

Importantly, efficacy continued to improve through week 24 in patients who remained on treatment. By this time point, PASI 100 rates approached 40%, representing complete clearance in a substantial proportion of patients. This pattern of deepening response over time is consistent with therapies targeting the IL-23 pathway.

Beyond the primary endpoints, clinically meaningful benefits were observed across several secondary outcomes. Approximately 75% of patients with moderate-to-severe scalp psoriasis achieved clear or almost clear status, highlighting a particular strength of TYK2 inhibition in this difficult-to-treat commonly affected area. Rapid improvements in itch were observed as early as week 2, with corresponding early gains in quality of life. Notably, these early improvements in itch and quality of life preceded significant visible skin clearance, which became more apparent from around week 4.

What have these studies, along with earlier data, shown in terms of safety and tolerability?

Envudeucitinib was generally well tolerated, with no major safety signals identified. The most common adverse events were mild and included nasopharyngitis, headache, and upper respiratory tract infections, occurring at relatively low rates.

There were no clinically meaningful abnormalities in laboratory parameters, including hematology, serum chemistry, or lipid profiles. This is notable given earlier observations with first-generation TYK2 inhibitors, such as increases in triglycerides seen with deucravacitinib. No signal was observed for serious infections, malignancy, cardiovascular events, or tuberculosis reactivation.

These findings raise the possibility that improved selectivity for TYK2 may translate not only into greater efficacy but also a favorable safety profile. However, it remains to be seen how regulatory authorities such as the FDA and EMA will interpret these data, and whether safety labeling will differ from that of earlier TYK2 inhibitors or follow a class-wide approach.

What are the potential clinical implications of these new findings?

The phase III data for envudeucitinib, alongside results for other next-generation TYK2 inhibitors such as zasocitinib, suggest a potential shift in the treatment landscape for psoriasis. These agents appear capable of delivering efficacy approaching that of biologic therapies while retaining the convenience of oral administration. This represents a meaningful advance, as it introduces the possibility of highly effective, non-injectable options for patients with moderate-to-severe disease.