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Induction of Intestinal Graft-versus-host Disease and Its Mini-endoscopic Assessment in Live Mice
Published on: February 11, 2019
Novel highly selective ROCK2 inhibitor (TDI01) for the treatment of chronic graft-versus-host disease: a multicenter,
Xiaodong Mo1, Xuejun Zhang2, Rong Guo3
1Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Cell and Gene Therapy for Hematologic Malignancies, Peking University, Beijing, China.
Abstract:
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.
Insights
TDI01, a ROCK2 inhibitor, shows promising results for chronic graft-versus-host disease (cGVHD) treatment. The 400mg dose demonstrated high response rates and good safety, warranting further investigation in Phase III trials.
Area of Science:
- Hematology
- Immunology
- Pharmacology
Background:
- Chronic graft-versus-host disease (cGVHD) is a significant complication after allogeneic hematopoietic stem cell transplantation.
- Rho-associated coiled-coil kinase 2 (ROCK2) is identified as a potential therapeutic target for cGVHD due to its role in immune and fibrotic pathways.
Purpose of the Study:
- To evaluate the safety and preliminary efficacy of TDI01, a selective ROCK2 inhibitor, in patients with moderate-to-severe cGVHD.
- To determine the optimal dose of TDI01 in a dose-finding Phase Ib study.
Main Methods:
- A multicenter, open-label, Phase Ib/II study enrolled 60 patients with cGVHD who had failed prior therapies.
- Patients received TDI01 once daily at either 200mg or 400mg.
- Primary endpoints included the 24-week best overall response rate (BORR) and safety assessment.
Main Results:
- The 24-week BORRs were 67.9% for the 200mg cohort and 86.2% for the 400mg cohort, with an overall BORR of 77.2%.
- Median time to response was faster in the 400mg cohort (30 days vs. 44.5 days).
- The most common adverse events were transient bilirubin elevation and headache; no significant increase in liver enzymes was observed.
Conclusions:
- TDI01, particularly at the 400mg QD dose, demonstrated promising efficacy and safety in patients with moderate-to-severe cGVHD.
- These findings support further evaluation of TDI01 in a Phase III randomized controlled trial for cGVHD treatment.
