A novel, highly selective ROCK2 inhibitor (TDI01) for cGvHD: Results from a phase Ib/II trial

Results from a multicenter, open-label, phase Ib/II trial (NCT06169722) evaluating TDI01, a highly selective Rho-associated coiled-coil containing protein kinase 2 (ROCK2) inhibitor, in patients with moderate-to-severe chronic graft-versus-host disease (cGvHD) were published in Signal Transduction and Targeted Therapy by Mo et al. Patients had received a median of 3 prior lines of systemic therapy (range, 1–5) and were treated with TDI01 at 200 mg or 400 mg once daily (QD; n = 30 per group). The primary endpoints were best overall response rate (BORR) at any time within 24 weeks, as well as safety and tolerability.

Key data: Among patients evaluated for efficacy (n = 57), the 24-week BORR was 77.2% (200 mg cohort, 67.9%; 400 mg cohort, 86.2%). Median duration of response (DOR) was not reached; the overall DOR rates were 84.1% and 64.6% at 3- and 6 months, respectively. Median failure-free survival (FFS) was also not reached; the overall probability of FFS at 24 weeks was 83.9% (200 mg cohort, 78.6%; 400 mg cohort, 89.2%). Among patients evaluated for safety (n = 60), the most common adverse events (AEs) were bilirubin elevation (total bilirubin elevation, 81.7%; unconjugated, 56.7%; conjugated, 45.0%) and headache (23.3%); bilirubin elevations were generally transient and typically not associated with concurrent elevations in hepatic transaminases.

Key learning: TDI01 demonstrated encouraging efficacy, particularly at the 400 mg QD dose, and was well tolerated in heavily pretreated patients with moderate-to-severe cGvHD, supporting further evaluation in a phase III randomized controlled trial.