The new oral TYK2 inhibitor claims to be more selective than deucravacitinib, and more studies are on the way.
A new investigational therapy targeting psoriatic arthritis has delivered promising results in a phase 2b clinical trial, offering fresh hope to patients battling the chronic inflammatory disease.
Zasocitinib (TAK-279), a highly selective and potent oral TYK2 inhibitor, significantly improved joint and skin symptoms in patients with active PsA after just 12 weeks of treatment.
Zasocitinib is already drawing comparisons with deucravacitinib – the first oral TYK2 inhibitor approved by the TGA in 2022 for the treatment of moderate to severe PsA.
Both drugs work by blocking TYK2 activity through the JH2 pseudokinase domain, making them more selective than traditional JAK inhibitors, which have been linked to serious safety concerns like cancer and cardiovascular events.
But zasocitinib may take TYK2 selectivity a step further. Developed through a computational design approach, it includes a unique methocyclobutyl ring that enhances its ability to specifically target TYK2 while avoiding similar enzymes like JAK1 and JAK2. This structural difference could translate to fewer off-target effects, potentially improving both safety and tolerability.
While deucravacitinib has already demonstrated durable efficacy with a favourable safety profile, researchers hope that zasocitinib’s enhanced selectivity might offer comparable, or even superior results with a lower risk of side effects.
The latest randomised, double-blind, placebo-controlled study enrolled 290 adults with PsA symptoms for at least six months. Results have been published in the Annals of the Rheumatic Diseases this month.
Zasocitinib is an investigational, oral, allosteric, highly selective, and potent TYK2 inhibitor being developed for the treatment of immune-mediated inflammatory diseases (IMIDs), including PsA and plaque psoriasis.
It was designed to maximise specific TYK2 inhibition and prevent inhibition of Janus kinase (JAK)1, JAK2, and JAK3. In vitro studies of zasocitinib have demonstrated selectivity for the TYK2 Janus homology (JH)2 domain over the JAK JH1 domain, without affecting JAK-mediated signalling
As part of the study, participants were assigned to receive 30mg, 15mg or 5mg of zasocitinib, or placebo once daily.
Eligible patients were aged over 18 years with active PsA and a history of PsA symptoms for ≥6 months before screening (screening occurred ≤30 days before day one of the study); had ≥3 tender and ≥3 swollen joints; and met the Classification Criteria for Psoriatic Arthritis (CASPAR).
Additionally, eligible patients had active PsA despite previous therapy with nonsteroidal anti-inflammatory drugs; DMARDs including azathioprine, chloroquine, ciclosporin, hydroxychloroquine, leflunomide, methotrexate, and sulfasalazine or tumour necrosis factor inhibitors (TNFis).
“Patients were excluded if they previously had a lack of response to any therapeutic agent targeting IL-12, IL-17 and/or IL-23 (and/or received one of these therapies ≤6 months before baseline [day one]) or to more than one TNFi or had any other disease that might confound evaluation of the benefit of zasocitinib,” the researchers wrote.
At the end of the 12-week treatment period, more than half of those taking 30mg (54.2%) or 15mg (53.3%) achieved the American College of Rheumatology 20 (ACR20) response – a benchmark for meaningful clinical improvement – compared to 29.2% of patients on placebo.
Higher doses also delivered stronger results across secondary measures, including ACR50, skin clearance (PASI75) and minimal disease activity (MDA).
Notably, nearly one-third of patients on 30mg reached MDA, compared to 12.5% on placebo.
Mild to moderate adverse events were more common at higher doses but were consistent with prior studies, with no new safety signals or significant lab abnormalities detected.
The study had some limitations, including a potential lack of statistical power and a lack of hierarchical testing approach for secondary and exploratory endpoints, owing to the small sample size.
“This was particularly evident for endpoints with impacts on domains only present in subsets of patients, such as dactylitis and enthesitis,” the researchers wrote.
“Larger studies are required to further assess the effect of zasocitinib on these disease domains.”
As a selective TYK2 inhibitor, zasocitinib targets key proinflammatory pathways involved in PsA without broadly suppressing the immune system, a potential advantage over older treatments, they said.
“These results highlight the potential of zasocitinib as a new oral therapeutic option in patients with active PsA,” the authors concluded.
“Consequently, phase 3 studies are ongoing (NCT06671483 and NCT06671496) to explore its full potential and to confirm these preliminary results in larger, more diverse patient populations, aiming to improve management and outcomes for patients with PsA.”
