Mona Shahriari, MD, reviews Phase 3 ONWARD data for envudeucitinib, including PASI 75/90/100 outcomes and key safety observations

In this News Alert, Mona Shahriari, MD, reviews Phase 3 data from the ONWARD1 and ONWARD2 trials evaluating envudeucitinib (ESK-001) in patients with moderate to severe plaque psoriasis. The discussion is based on a poster presented at the 2026 American Academy of Dermatology Annual Meeting.  

Reframing oral therapy in the biologic era

Biologic therapies have redefined expectations in psoriasis, particularly around the degree and consistency of skin clearance. Within that context, newer oral agents are increasingly being evaluated not just for convenience or tolerability, but for their ability to approach biologic-level outcomes.

Dr Shahriari positions the ONWARD program within this shift, noting that the bar for oral therapies has changed. The question is no longer whether an oral agent is “good enough,” but whether it can deliver meaningful efficacy in a landscape shaped by highly effective injectables. 

Mechanism and early clinical experience

Envudeucitinib is a next-generation, highly selective allosteric TYK2 inhibitor targeting IL-23, IL-12, and type 1 interferon signaling pathways central to psoriasis pathogenesis. Its design aims to maintain consistent TYK2 inhibition over a 24-hour period, which may contribute to its clinical activity.

Earlier Phase 2 data from the STRIDE program demonstrated relatively rapid skin clearance with sustained efficacy through one year, alongside a safety profile aligned with selective TYK2 inhibition rather than broader JAK pathway effects. These findings supported progression into the Phase 3 ONWARD trials.  

ONWARD trial design

ONWARD1 and ONWARD2 were randomized, double-blind, placebo- and active comparator–controlled trials enrolling patients with moderate to severe plaque psoriasis. Participants were assigned to envudeucitinib 40 mg twice daily, placebo, or apremilast.

The coprimary endpoints at week 16 were achievement of PASI 75 and an sPGA score of 0 or 1 (clear or almost clear).  

Efficacy outcomes

As early as week 16, envudeucitinib demonstrated statistically significant improvements versus both placebo and apremilast across primary and secondary endpoints:

• ~75% achieved PASI 75  
• ~60% achieved sPGA 0/1  
• ~50% achieved PASI 90
• ~30% achieved PASI 100  

Responses continued to deepen through week 24:

• ~65% achieved PASI 90  
• ~40% achieved PASI 100  

Notably, response curves had not plateaued at week 24, suggesting the potential for continued improvement with ongoing therapy. In terms of onset, separation from placebo was observed by week 4, with some patients demonstrating visible improvement as early as week 2.

Taken together, these data point to a combination of relatively rapid onset, increasing efficacy over time, and substantial depth of response.  

High-impact areas and patient-reported outcomes

The trials also evaluated outcomes in high-impact anatomical sites and patient-reported measures:

• ~75% achieved scalp PGA 0/1 at week 24  
• ~30% reached this endpoint as early as week 4
• ~50% achieved DLQI 0/1 as early as week 12  

These findings highlight the importance of assessing disease burden beyond total body surface area, particularly in patients with involvement of functionally or socially sensitive sites.  

Safety and tolerability

The safety profile in ONWARD was consistent with prior studies, with no new safety signals identified. Treatment was generally well tolerated, with the most commonly reported adverse events including nasopharyngitis, headache, and upper respiratory tract infections.

There were no reported signals for major adverse cardiovascular events, tuberculosis reactivation, or clinically meaningful hematologic, metabolic, or lipid abnormalities in the available data.  

Clinical perspective

Dr Shahriari notes that these data contribute to an ongoing shift in how oral therapies are positioned in psoriasis management. Rather than being viewed as a step below biologics, certain oral agents may begin to approach comparable levels of efficacy in select patients.

She highlights potential relevance for patients who prefer oral therapy, those hesitant to initiate injectables, and individuals with limited body surface area involvement but significant disease burden in high-impact areas. At the same time, she emphasizes the need for longer-term data, comparative studies, and further evaluation in broader patient populations.  

Key takeaways

• Envudeucitinib demonstrated high levels of efficacy in Phase 3 trials, including substantial PASI 90 and PASI 100 responses  
• Clinical responses appeared to deepen through week 24, with no clear plateau observed  
• Improvements were seen relatively early, with separation from placebo by week 4  
• Meaningful outcomes were observed in high-impact areas and quality-of-life measures  
• The safety profile was consistent with prior data, with no new safety signals identified  
• These findings support continued consideration of oral TYK2 inhibition as a potential option alongside biologics in appropriate patients