Zasocitinib delivers rapid, deep responses in phase 3 plaque psoriasis trials

Current limitations include challenges inherent to biologic therapies, including cold-chain storage requirements, injection aversion, injection site reactions, potential loss of efficacy related to anti-drug antibody development, and access or reimbursement barriers.

In addition, existing oral options often involve an efficacy trade-off, leading many patients to transition to biologics because of inadequate response or concerns about cumulative toxicity and end-organ effects associated with conventional systemic agents such as methotrexate or cyclosporine.

Q. How does zasocitinib differ from other available therapies currently used ?

Zasocitinib is a highly selective and potent TYK2 inhibitor that targets signalling pathways central to psoriasis pathogenesis, including interleukin-23 (IL-23), as well as IL-12 and type I interferons.

While deucravacitinib is currently the only approved TYK2 inhibitor, zasocitinib has demonstrated greater potency and enhanced selectivity within the class.

By comparison, apremilast is a phosphodiesterase 4 (PDE4) inhibitor, and its clinical utility can be limited by tolerability concerns, particularly gastrointestinal adverse events and headaches.

Q. Could you outline the aims, study design, and key eligibility criteria of the two pivotal phase 3 trials?

The pivotal phase 3 trials comprised two global, multicentre, randomized, double-blinded, placebo- and active comparator-controlled studies comparing zasocitinib 30 mg once-daily (OD) versus placebo and apremilast 30 mg twice-daily (BID) in adults with moderate-to-severe plaque psoriasis.

Eligible patients had a Psoriasis Area and Severity Index (PASI) ≥12, a static Physician’s Global Assessment (sPGA) ≥3 and body surface area (BSA) involvement ≥10%. The studies were conducted in 21 countries and enrolled 693 and 1,108 participants, respectively.

The co-primary endpoints include the proportion of participants achieving sPGA 0/1 and PASI 75 versus placebo at Week 16. Ranked secondary endpoints included PASI 90, PASI 100, and sPGA 0 comparisons versus placebo (Week 16), and versus apremilast (Weeks 16 and 24) among others. Additional key endpoints included assessments of safety and tolerability.

Q. What did the phase 3 studies demonstrate in terms of the efficacy and safety of zasocitinib?

Both phase 3 studies met their co-primary endpoints, as well as all secondary endpoints. Efficacy results showed that more than half of patients who received zasocitinib achieved PASI 90, and about 30% achieved PASI 100 by Week 16. There was a rapid onset observed, with early separation of PASI 75 at week 4 of zasocitinib, compared to placebo.

Zasocitinib was generally well tolerated, with a safety profile consistent with prior studies. The most common adverse events were nasopharyngitis, upper respiratory tract infection and acne.

Q. Where do you see zasocitinib fitting within the current treatment paradigm for moderate-to-severe plaque psoriasis, and what key questions or future studies remain? 

I see zasocitinib being used early in the management of psoriasis for patients who want biologic-like efficacy in an oral agent. Given its rapid onset of action, deep levels of response and convenience of once-daily dosing, it could be considered as a first-line agent.

Key questions include how zasocitinib compares with the current tyrosine kinase 2 (TYK2) inhibitor on the market, deucravacitinib; this study (NCT06973291) is currently ongoing, and results are expected in the near future. Comparisons with biologic agents would also be of interest.

Further questions arising from the pivotal studies also remain, including durability of response and withdrawal behaviour . Ongoing studies will provide long-term safety data, and further exploration in other immune-mediated diseases, such as psoriatic arthritis and inflammatory bowel disease, will assess impact beyond the skin.

Disclosures: Dr Melinda Gooderham reports serving as an advisory board participant, principal investigator, speaker, or consultant for AbbVie, Acelyrin Inc., Alumis Inc., Amgen Inc., AnaptysBio, Apogee Therapeutics, Arcutis Pharmaceuticals Inc., Aristea Therapeutics, Attovia Therapeutics Inc., Bausch Health, Boehringer Ingelheim International GmbH, Bristol Myers Squibb, Dermavant, Dermira Inc., Eli Lilly and Company, Galderma SA, GlaxoSmithKline, Incyte Biosciences, Insmed Inc., JAMP Pharma, Janssen Inc., LEO Pharma, L’Oréal, Meiji Seika, Merck, MoonLake Immunotherapeutics, Novartis Pharmaceuticals, Oruka Therapeutics, Pfizer Inc., Q32 Bio Inc., Regeneron Pharmaceuticals Inc., Reistone Biopharma, Sanofi Genzyme, Sun Pharmaceuticals, Takeda, Tarsus, UCB, Union Therapeutics, Ventyx, and Vyne Therapeutics.