Investigative Treatments for Moderate to Severe Psoriasis Reviewed

NEW YORK — No fewer than four investigative therapies, ranging from an oral interleukin-23 receptor antagonist to oral tyrosine kinase inhibitors and a long-acting biologic, have the potential to change how dermatologists treat moderate to severe psoriasis, Bruce R. Strober, MD, said at the New York University (NYU) Langone Advanced Seminar in Psoriasis and Psoriatic Arthritis.

“There’s quite a pipeline of oral therapeutics for psoriasis,” said Strober, clinical professor of dermatology at Yale University, New Haven, Connecticut. “There’s also longer-interval biologic dosing, which is very exciting to me.”

At the meeting, Stober reviewed four investigative candidates for the treatment of psoriasis, currently in clinical trials.

Icotrokinra

Icotrokinra, also known as JNJ-77242113, is an oral interleukin (IL)-23 receptor antagonist that is being evaluated for moderate to severe psoriasis in phase 3 trials. “One caveat,” Strober noted, is that “you’re going to have to have your patients take this drug on an empty stomach for best bioavailability.”

Phase 2b 52-week results were reported in October 2024. “The data look really good over the course of a year,” Strober said. In the FRONTIER 2 study, 76.2% of treated patients on 100 mg twice a day achieved up to a 75% improvement in Psoriasis Area and Severity Index (PASI 75), and 64.3% achieved PASI 90 at 52 weeks, “which would make it the highest performing oral therapeutic we have ever had,” he commented.

One-year safety outcomes were also in line with other IL-23 inhibitors, Strober said.

The 16-week phase 3 results“were a little lower, about 50% achieved a PASI 90, and in that phase 2 it was 60%, but if you go out to week 24, they get to the same point, two out of three get to PASI 90,” Strober said.

“So I think in phase 3 you’re going to see slower responses, but ultimately the same degree for that number of patients getting to various metrics, PASI 90 and PASI 75,” he added. “It’s probably going to be a little slower in the real world.” 

Investigative Tyrosine Kinase 2 (TYK2) Inhibitors

Two oral TYK2 inhibitors, zasocitinib (formerly TAK-279) and ESK-001, are also being studied in early trials, Strober said.

He called zasocitinib “a very promising TYK2 inhibitor, maybe though not quite as efficacious as” icotrokinra. “But it might only be a 5% difference.” 

In a phase 2b trial of zasocitinib, 68% and 67.3% of patients in the two highest dose groups, 15 mg and 30 mg once a day, respectively, achieved PASI 75 vs 6% of those in the placebo group at week 12 (P P .001).

“The real issue is, is this going to require more monitoring?” Strober said. “There may be more adverse events associated with it being a different mechanism of action.” 

However, data reported in 2024 demonstrated similar hematological, hepatic/renal and lipids outcomes in all zasocitinib dosing groups and placebo group, Strober said. “The only adverse event that tracks with zasocitinib more than placebo is acne, which we typically see with TYK2 inhibitors, but it wasn’t a big signal,” he added.

Another highly selective oral TYK2 inhibitor is ESK-001. A phase 2 trial of patients with moderate to severe psoriasis showed that 64% of those on high-dose treatment (40 mg twice daily) achieved PASI 75 at 12 weeks, whereas almost 39% achieved PASI 90, Strober said. An open-label extension trial of patients who continued on therapy, excluding those who dropped out, showed that 93% achieved PASI 75 and 72% achieved PASI 90, Strober noted. A phase 3 study of ESK-001 was launched in 2024.

Long-Acting Biologics

Investigative long-acting biologics have the potential to improve efficacy with greater convenience and safety, Strober said.

“If we could dose down on biologics and keep the efficacy akin to what we currently do, then I think we’ll have a lot of happier patients, especially if they might be able to get themselves dosed every 6 months and possibly every year,” he said.

One such candidate is ORKA-001, a novel monoclonal antibody that targets IL-23p19, Strober said. He explained that the technology behind ORKA-001 “causes greater recycling of the antibody as opposed to greater degradation of the antibody in the lysosome, so essentially these modified antibodies don’t break down and as a consequence, their half-life is extended.”

The mechanism is modeled after that of risankizumab with regard to IL-17 inhibition, Strober said. Laboratory studies, reported at the 2024 European Academy of Dermatology and Venereology Congress, demonstrated an overlapping of properties between the two biologics.

“They wanted to make a risankizumab with a longer half-life and highlighted their half-life extension in nonhuman primates, which is of course a surrogate for what would happen in humans,” Strober said of the ORKA-001 researchers. Those nonhuman primate studies demonstrated a half-life three times that of risankizumab, he noted.

“There is a possibility that there is an even greater difference in humans,” he said. Laboratory modeling demonstrated a 75-day half-life, “which probably is not going to happen,” Strober added. However, he said, the modeling demonstrated the possibility of dosing every 6 months in humans, after a loading dose.

Ongoing study of ORKA-001 is going to evaluate various loading doses at different intervals, Strober added. “It’s left to be seen whether it’s a 6-month or yearly drug,” he said. “I would say even a 6-month interval would be a huge advance for a lot of patients and a year would feel like a cure to many patients.”

A phase 1 trial of ORKA-001, which is administered subcutaneously, in healthy volunteers started enrollment in late 2024.

Strober disclosed financial relationship with AbbVie, Acelyrin, Alamar, Alumis, Almirall, Amgen, Arcutis, Arena, Aristea, Asana, Boehringer Ingelheim, Kangpu Pharmaceuticals, Bristol Myers Squibb, Capital One, Celltrion, Connect Biopharma, CorEvitas, Dermavant, Inmagenebio, Janssen, Leo, Eli Lilly, Maruho, Mindera Health, Okura, Meiji Seika Pharma, Protagonist, Monte Carlo, Takeda, Novartis, Pfizer, UCB Pharma, Rapt, Regeneron, Sanofi-Genzyme, SG Cowen, and Union Therapeutics.

Richard Mark Kirkner is a medical journalist based in the Philadelphia area.