DENVER — The selective tyrosine kinase 2 (TYK2) inhibitor envudeucitinib emerged superior to apremilast and placebo in two phase 3 trials of people with moderate-to-severe psoriasis. The oral TYK2 inhibitor yielded better Psoriasis Area and Severity Index (PASI) 90 and PASI 100 ratings at 24 weeks, for example, as well as higher ratings of clear or almost clear skin and patient quality of life.

“I’m excited today because it’s a phase 3 reveal, and new phase 3 data often leads to approval,” Andrew Blauvelt, MD, MBA, a dermatologist and owner of Blauvelt Consulting, Annapolis, Maryland, said during a late breaker research session here at the American Academy of Dermatology (AAD) 2026 Annual Meeting. 

The primary endpoints of the combined ONWARD1 and ONWARD2 studies were met for envudeucitinib: the proportion of patients achieving 75% or greater reduction in the PASI score and the proportion achieving a score of 0 or 1 on the Static Physician Global Assessment (sPGA) at week 16. In addition, results observed at this time point continued to improve to the end of the trials.

“We know with drugs that block IL-23, we see the efficacy increasing out to week 24, and that’s what we see with envudeucitinib,” Blauvelt said.

Envudeucitinib could become the second TYK2 inhibitor approved to treat psoriasis. The FDA approved deucravacitinib in 2022 as the first TYK2 inhibitor for moderate-to-severe plaque psoriasis. Unlike deucravacitinib, however, envudeucitinib is a second-generation TYK2 inhibitor, an allosteric inhibitor designed to avoid off-target effects of JAK1, JAK2, and JAK3, which is important “because we don’t want to have side effects associated with classic JAK blockade,” Blauvelt said.

In addition to blocking IL-23, envudeucitinib also blocks IL-12 signaling and type 1 interferon signaling.

Methodology 

The ONWARD1 and ONWARD2 trials were designed identically. Both were 24-week studies with an assessment point at week 16, with patients randomly assigned 2:1:1 to envudeucitinib 40 mg twice daily, placebo, or apremilast as a comparator. 

The co-primary endpoints were the proportion of adults achieving a 75% or greater reduction in PASI score and achieving an sPGA score of 0 or 1 at 16 weeks. 

More than 1700 total participants with a plaque psoriasis diagnosis for at least 6 months, plaques covering at least 10% of their body surface area, and a baseline PASI of 12 or more were enrolled. All had sPGA scores of 3 or higher, about 70% had moderate psoriasis, around 30% had severe disease, and about half had received prior systemic therapy.

Key Findings 

Some patients showed a visual response as quickly as two weeks, Blauvelt said. His favorite before and after patient photo set clearly showed very red, widespread skin inflammation at baseline and week 16. The photos, in a patient on placebo, “are essentially the same,” he said. “Then the patient transferred over at week 16 to drug, and 8 weeks later, was essentially clear of this very extensive, very inflammatory disease.”

On average across both trials, 74% of patients of those on envudeucitinib achieved PASI 75 and 59% achieved sPGA 0/1 at week 16. 

Regarding PASI 90, “you can see it increasing over the 24-week period, much more significant than apremilast,” Blauvelt said. PASI 90 responses were reached by 59.9% in ONWARD1 and 53.1% of envudeucitinib patients in ONWARD2 at week 16 vs 4.8% and 4.3% of patients on placebo, respectively. By week 24, PASI 90 results rose to 68.0% in ONWARD1 and 62.1% in ONWARD2 among those on envudeucitinib.

“I’d like to highlight here that the PASI 100 at week 24 gets up to the 40% range,” Blauvelt said. 

PASI 100 responses were achieved by 29.4% of those in ONWARD1 and 27.7% of those in ONWARD2 at week 16 vs 0.9% among those in both placebo groups. At week 24, PASI 100 was achieved by 41.0% of ONWARD1 and 39.5% of ONWARD2 participants.

The increasing responses observed with envudeucitinib “is expected given the mechanism of action of this, predominantly working as an IL-23 blocker,” Blauvelt said. 

Regarding the co-primary endpoint, the sPGA 0/1 ratings, “what we see here is that the clear and almost clear findings mimic the PASI 90 results. And then, of course, the clear sPGA 0 mimics PASI 100 results, again, being about 40% at week 24,” Blauvelt said.

Scalp, Itch, and DLQI Changes 

Among the notable secondary outcomes, about 75% of patients achieved clear or almost clear scalp disease, Blauvelt said, a proportion significantly higher than with apremilast.

Regarding pruritus, “we see this drop and itch occurring as early as week two, and then progressively over time out to week 24,” he added. By week 16, patients on envudeucitinib achieved an average improvement of more than 4 points from baseline on the 0 to 10 Worst Pruritus Numeric Rating Scale, for example. Patients reported clinically meaningful itch relief as early as week 2.

“It is very interesting that the itch response seems to precede the improvement that we see with skin,” Blauvelt said. A similar observation occurred with Dermatology Life Quality Index (DLQI) scores. “The DLQI actually significantly starts to improve at week two prior to any real, significant changes in skin. So, the DLQI seems to be paralleling the itch response in that first month of treatment.”

By week 12, approximately 50% of patients on envudeucitinib achieved a DLQI of 0 or 1, Alumis — the manufacturer — reported in a news release.

Safety Profile 

There were no new safety signals “over and above what we have seen in the deucravacitinib days,” Blauvelt said at the meeting.

At week 16, the most common adverse events were nasopharyngitis and headache. “Importantly, we do not see any abnormalities in serum chemistries, in lipids, or any hematologic effects,” Blauvelt said. There were no tuberculosis (TB) cases or major adverse cardiac events. “So, it was a very nice safety profile at week 16 and, very similarly, the same sort of message in terms of week 24.”

In response to a conference attendee question about the need for TB monitoring, “I would postulate that TYK2 inhibitors, because they also block IL-12 signaling, would have the potential to have TB reactivation,” Blauvelt said. “So I do think theoretically, biologically there’s the potential there for this drug.”

Next Steps 

Patients who completed week 24 were eligible to enter the ONWARD3 trial, an ongoing long-term extension study assessing durability, maintenance of response, and long-term safety.

Also, a once-daily formulation of envudeucitinib is in development, and there are plans for pediatric development of this agent as well, Blauvelt said.

“It is exciting a TYK2 inhibitor that can achieve high levels of skin clearance,” Joel M. Gelfand, MD, director of the Psoriasis and Phototherapy Treatment Center at the University of Pennsylvania, Philadelphia, told Medscape Medical News when asked to comment on the results. 

“This mechanism is generally very well tolerated but is associated with acneiform reactions, headaches, as well as infections and possibly malignancy,” added Gelfand. “The drug also is dosed two times per day, which may impact adherence and effectiveness in clinical practice.” 

Alumis plans to submit a New Drug Application to the FDA in the second half of 2026. Envudeucitinib is also being evaluated a phase 2b study of patients with systemic lupus erythematosus, according to the company.

The study was funded by Alumis. Blauvelt reported the following disclosures: consultant (1099 relationship) for Alumis; Amgen; AnaptysBio; Apogee Therapeutics; Arcutis; Oruka Therapeutics; and Takeda Pharmaceuticals USA; consultant for AbbVie; Almirall; Eli Lilly and Company; Incyte Corporation; Janssen-Ortho; Leo Pharma; Novartis Pharmaceuticals; Oruka Therapeutics; Pfizer; Regeneron; Sanofi; Sun Pharmaceutical Industries; and UCB; speaker for Almirall; Eli Lilly and Company; Leo Pharma; Sanofi; and UCB; and stockholder for Lipidio Pharmaceuticals and Oruka Therapeutics. Gelfand’s disclosures include the following: consultant for AbbVie, Alumis, Arcutis, Boehringer Ingelheim, Johnson & Johnson Innovative Medicine, and Leo Pharma; investigator for Bristol Myers, Eli Lilly, and National Psoriasis Foundation; and Data Safety Monitoring Board for Inmagene and Moonlake.

Damian McNamara is a freelance contributor to Medscape Medical News. He worked full-time for Medscape and WebMD from 2018 to 2024. Damian has a BA in chemistry and an MA in science, health, and environmental reporting/journalism.