Tegavivint (TBL1→nuclear β-catenin degradation) shows 22% ORR in Wnt-mutant 2L/3L aHCC

Tegavivint is a first-in-class IV small molecule that binds TBL1 to disrupt the TBL1/β-catenin complex, driving selective degradation of nuclear β-catenin (downstream Wnt/β-catenin inhibition). In this multicenter open-label Phase 1/2 3+3 dose-escalation/backfill study in previously treated aHCC (NCT05797805), 39 patients were treated across 3–8mg/kg weekly; 8mg/kg had dose-limiting Grade 3 anemia (2/5), setting a 3–6.5mg/kg recommended dose range. In Wnt-pathway–mutant (liquid biopsy) patients evaluable within the recommended range, outcomes split by line of therapy: ≤3L (n=9) achieved ORR 22%, DCR 89%, mPFS 8 months, while later-line (n=9) had ORR 0%, DCR 56%, mPFS 4 months; no meaningful benefit was seen in non-Wnt–mutant patients—benchmarking to typical post-sorafenib TKIs, ORR is usually low (cabozantinib ORR 4%, mPFS 5.2 months; regorafenib mPFS 3.1 months), while ramucirumab in AFP-high disease has ORR 5.4% and mPFS 2.8 months. Hyperbilirubinemia (Grade ≥3: 4 cases; described as isolated/asymptomatic/reversible) and anemia (all 5 cases Grade ≥3; reversible) were the key signals to watch versus VEGFR TKIs, which more commonly drive hypertension/hand–foot syndrome rather than on-study bilirubin/anemia patterns.