Novel highly selective ROCK2 inhibitor (TDI01) for the treatment of chronic graft-versus-host disease: a multicenter, open-label phase Ib/II study.

Chronic graft-versus-host disease (cGVHD) remains a major complication following allogeneic hematopoietic stem cell transplantation for long-term survival. Emerging evidence highlights Rho-associated coiled-coil kinase 2 (ROCK2) as a promising therapeutic target for cGVHD, which can modulate immune responses and profibrotic reactions. TDI01, a potent and highly selective ROCK2 inhibitor, represents a potential breakthrough in cGVHD treatment. This was the dose-finding, phase Ib portion of a multicenter, open-label phase Ib/II study (NCT06169722) designed to evaluate the safety and preliminary efficacy of TDI01 in patients with moderate-to-severe cGVHD after failure of 1 to 5 prior therapies. Sixty patients were enrolled in two once-daily dosing cohorts: 200 mg (n = 30) and 400 mg (n = 30). The primary endpoints were the 24-week best overall response rate (BORR) and safety. As of January 17, 2025, 57 patients were evaluated for efficacy. The 24-week BORRs were 67.9% (200 mg cohort) and 86.2% (400 mg cohort), with an overall BORR of 77.2%. The median times to response were 44.5 days (200 mg cohort) and 30.0 days (400 mg cohort). Neither the median duration of response nor the median failure-free survival (FFS) was achieved. The probability of FFS at 24 weeks was 83.9%. The most common adverse events ( ≥ 20% of patients) were transient bilirubin elevation (total bilirubin elevation 81.7%, unconjugated 56.7%, conjugated 45.0%) and headache (23.3%), without significant increases in liver enzymes. Thus, TDI01, particularly at the 400 mg QD dose, demonstrated promising efficacy and safety in moderate-to-severe cGVHD, which will be confirmed in a forthcoming phase III randomized controlled trial.