TDI01, a highly selective ROCK2 inhibitor, generated a high level of responses and displayed a manageable safety profile in patients with moderate-to-severe chronic graft-vs-host disease (cGVHD), according to data from a multicenter, open-label phase 1b/2 study (NCT06169722) published in Signal Transduction and Targeted Therapy.1
Findings showed that efficacy-evaluable patients (n = 57) achieved a 24-week best overall response rate (BORR) of 77.2% (95% CI, 64.2%-87.3%), which comprised a 24-week BORR of 86.2% (95% CI, 68.3%-96.1%) in the 400-mg once-daily cohort (n = 29) and 67.9% (95% CI, 47.6%-84.1%) in the 200-mg cohort (n = 28). The ORR at 24 weeks was 52.6% (95% CI, 39.0%-66.0%) overall.
The median duration of response was not reached, with responses lasting at least 6 months in 64.6% (95% CI, 28.0%-86.1%) of patients. The median failure-free survival (FFS) was also not reached; the 24-week FFS probability was 89.2% (95% CI, 70.1%-96.4%) in the 400-mg cohort and 78.6% (95% CI, 58.4%-89.8%) in the 200-mg cohort. The 6-month overall survival (OS) rate was 98.2% (95% CI, 88.2%-99.8%).
“TDI01…exerted favorable clinical effects and demonstrated an acceptable safety profile among heavily pretreated patients with moderate-to-severe cGVHD, including those with prior ruxolitinib [Jakafi] exposure and difficult-to-treat organ involvement,” lead study author Xiaodong Mo, MD, of Peking University People's Hospital in Beijing, China, and colleagues wrote in a publication of the data.
Following allogeneic hematopoietic stem cell transplantation (allo-HSCT), cGVHD remains a leading cause of non-relapse morbidity, and options for patients whose disease progresses on or after standard immunosuppression are limited. The ROCK2 inhibitor Belumosudil (Rezurock) and ruxolitinib are among the agents used in the refractory setting; real-world data have shown that ruxolitinib combined with extracorporeal photopheresis drives responses in steroid-refractory cGVHD.2
TDI01 is a next-generation ROCK2 inhibitor reported to have more than 1000-fold selectivity for ROCK2 over ROCK1.1
The phase 1b/2 study enrolled 60 patients across 23 sites in China between February 2024 and January 2025. Eligible patients were 18 to 75 years of age and needed to have an ECOG performance status of 0 to 2. Additionally, 1 to 5 prior lines of systemic therapy for cGVHD were required.
Patients were sequentially assigned to receive TDI01 at 200 mg (n = 30) or 400 mg (n = 30) once daily. The primary end points were 24-week BORR and safety.
At baseline, patients in the overall population (n = 60) had a median age of 37.0 years (range, 19-55), and 70.0% were male. Underlying disease histologies prompting the indication for transplant included acute myeloid leukemia (41.7%), myelodysplastic syndromes (16.7%), acute lymphoblastic leukemia (13.3%), chronic myeloid leukemia (8.3%), aplastic anemia (5.0%), acute promyelocytic leukemia (3.3%), and other (11.7%). Most patients received stem cells from peripheral blood (75.0%); HLA matching status comprised matched (36.7%), partially matched (38.3%), unknown (5.0%), and missing (21.7%).
The median duration of cGVHD before enrollment was 1.80 years; 73.3% of patients had received prior ruxolitinib, and 65.0% had lung involvement. Patients had either moderate (38.3%) or severe (61.7%) cGVHD.
Responses were observed across multiple organ systems. Across the overall population, 24-week BORR was 52.6% in the liver, 50.0% in the esophagus, and 50.0% in the upper gastrointestinal tract. In the lungs, 23.7% (95% CI, 11.4%-40.2%) of patients achieved a response by symptom score, and 18.4% (95% CI, 7.7%-34.3%) achieved at least a 10% improvement in FEV1. The median time to response was 30.0 days in the 400-mg cohort and 44.5 days in the 200-mg cohort.
Symptom improvement, defined as a reduction of at least 7 points on the modified Lee Symptom Scale, occurred in 29.8% of patients. Among the 32 patients receiving glucocorticoids at baseline, 19.4% achieved at least a 50% reduction in corticosteroid dose by week 24.
All 60 patients in the safety population experienced treatment-emergent adverse effects, and 96.7% had treatment-related adverse effects (TRAEs). Grade 3 or higher TRAEs occurred in 36.7% of patients. The most common AE was total bilirubin elevation, reported in 81.7% of patients (unconjugated, 56.7%; conjugated, 45.0%), followed by headache (23.3%). Grade 3 or higher bilirubin elevations included unconjugated bilirubin elevation (16.7%), total bilirubin elevation (15.0%), and conjugated bilirubin elevation (5.0%). The investigators reported that bilirubin elevations were generally transient and typically not accompanied by concurrent increases in liver transaminases, indicating a lack of hepatocellular injury.
Hematologic toxicity was infrequent, with neutropenia occurring in 11.7% of patients and leukopenia, thrombocytopenia, and anemia each in 3.3%; no cytomegalovirus infections were observed.
Serious AEs occurred in 25.0% of patients, including 8.3% deemed treatment-related. AEs led to treatment discontinuation in 6.7% of patients. One death (1.7%), due to COVID-19 pneumonia, was deemed unrelated to the study drug.
Based on these results, China's Center for Drug Evaluation cleared TDI01 to advance to a phase 3 randomized trial (CTR20252713), which will compare it with investigator's choice of therapy in patients with moderate-to-severe cGVHD who have received 2 to 5 prior lines of therapy.
