Long-Term Safety and Efficacy of the Highly Selective Tyrosine Kinase 2 Inhibitor Zasocitinib for the Treatment of Inflammatory Bowel Disease: Design of a Phase 2 Open-Label Extension Trial
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Authors
Parkes G.
Rajendra S.G.
Zaru L.
Nguyen V.A.
Ayodele L.
Nordio F.
Freeney T.
Sears L.
Singh, N.
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2025
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Abstract
Introduction: Tyrosine kinase 2 (TYK2) inhibitors block signaling downstream of multiple pro-inflammatory cytokines involved in immune-mediated inflammatory diseases, including inflammatory bowel disease, and may have an improved safety profile relative to Janus kinase inhibitors. Phase 2 studies of the highly selective and potent TYK2 inhibitor zasocitinib in Crohn's disease (CD; NCT06233461) and ulcerative colitis (UC; NCT06254950) are ongoing.1,2 Here, we describe the design of a combined open-label extension trial (NCT06764615), which will include patients from both parent trials who are responsive to treatment. Aims and Methods: Patients are eligible for the phase 2 parent studies in CD and UC if they are aged 18-75 years with moderately to severely active disease, and have inadequate or loss of response to, or intolerance of, >= 1 standard or advanced therapy. Patients who have failed treatment with >= 3 classes of advanced therapy are excluded. Patients are randomized to one of three (CD) or two (UC) doses of zasocitinib, or placebo, for a 12- week double-blind induction phase followed by a 40-week sponsor-open (CD) or open-label (UC) maintenance period. At the end of the parent trials, patients will be eligible for the combined open-label extension if they are clinical (CD) or symptomatic (UC) responders at Week 52, defined as: (1) CD: a >= 30% decrease in average daily very soft or liquid stools and/or a >= 30% decrease in average daily abdominal pain from baseline; and (2) UC: a >= 1-point and >= 30% decrease from baseline in partial modified Mayo score, and a >= 1-point decrease from baseline in rectal bleeding (RB) subscore or achievement of an absolute RB subscore of <= 1. All enrolled patients will receive the same dose of open-label, oral, once-daily zasocitinib for a maximum of 108 weeks, with study visits every 12 weeks, followed by a 4-week safety follow-up period. Data analysis will be descriptive, with no formal statistical comparisons performed. Result(s): The primary objective of the study is to determine long-term safety and tolerability, assessed through the incidence of treatment-emergent adverse events or adverse events of special interest. Secondary endpoints will assess the long-term efficacy of zasocitinib, including clinical, symptomatic, or endoscopic response or remission by visit or at Weeks 48 and 108, according to indication, and effects on patient-reported outcomes, including fatigue, bowel urgency, abdominal pain, and disease-specific health-related quality of life. Conclusion(s): This open-label extension trial will provide data on the longterm safety of zasocitinib, as well as durability of treatment response among patients with CD or UC who experience treatment benefit in the phase 2 parent studies.
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United.Eur.Gastroenterol.J.