TDI01 in the treatment of moderate to severe chronic graft-versus-host disease: Updated results from a multicenter, OPEN-label phase IB/II study (An Update)

Abstract Introduction:This multicenter, open-label Phase Ib/II study evaluated TDI01 in patients with moderate or severe chronic graft-versus-host disease (cGVHD) after 1-5 lines prior therapies. Our previous analysis in 57 evaluable patients showed 24-week best overall response rates (BORRs) of 67.9% (200 mg), 86.2% (400 mg), and 77.2% (total) (EBMT 2025). Here, we presented the updated results with extended follow-up, focusing on response durability, long-term safety, overall survival, pharmacokinetics (PK), and exposure–response (E–R) analysis.Methods:After a safety lead-in, patients with moderate or severe cGVHD who had failed 1–5 lines prior systemic therapies were sequentially assigned to receive TDI01 200 mg once daily (QD) (n = 30) or 400 mg QD (n = 30) until experiencing GVHD progression or unacceptable toxicity (NCT06169722). Data were collected on overall response rate (ORR), duration of response (DOR), failure-free survival (FFS), overall survival (OS), PK, E–R, and long-term safety, and are reported here.Results:As of July 18, 2025, 60 patients were evaluable for safety, PK and E–R, and 57 for efficacy. Median follow-up was 48.1 (95% CI, 48.0, 48.3) weeks and 72% (41/57) of evaluable patients had been previously treated with ruxolitinib. At week 24, ORR was 50.0% in 200 mg cohort and 55.2% in 400 mg cohort. Over the entire treatment course, the overall BORR reached 75.0% in 200 mg cohort and 86.2% in 400 mg cohort. Several subgroups (e.g., severe cGVHD and heavily pretreated patients) showed similarly high best ORR (BORR), which was 80.0%, 80.6%, 86.2%, and 80.5%, respectively, in patients with severe cGVHD, with ≥4 organs involved, with ≥3 prior lines of therapy, and those with prior ruxolitinib treatment. The median DOR was not reached in either cohort, with a lower 95% CI of 23.1 months in 200 mg cohort and 31.0 months in 400 mg cohort. At 9 months, FFS rates were 53.6% and 77.7% in 200 mg and 400 mg cohorts, respectively, while OS rates at 12 months were 88.1% and 92.5%.Organ-specific analyses demonstrated BORRs of 52.6% (10/19) in liver, 50.0% (4/8) in esophagus, 50.0% (4/8) in upper gastrointestinal (GI) tract, 47.6% (10/21) in joints/fascia, 46.3% (19/41) in mouth, 38.1% (16/42) in skin, 35.6% (16/45) in eyes, 18.4% (7/38) in lungs, and 0% (0/1) in lower GI tract. On the modified Lee Symptom Scale, 29.8% (17/57) of the patients had ≥7-point improvement.All patients had ≥1 TEAE and TRAEs occurred in 96.7% of patients. Grade ≥3 TEAEs and TRAEs were reported in 51.7% and 38.3% of patients, respectively. SAEs occurred in 31.7%, including 10% that were considered drug-related. One death occurred in the 400 mg cohort was deemed unrelated to the study drug. The most commonly reported TRAEs (≥20%) were elevations of total bilirubin (81.7%), unconjugated bilirubin (60.0%) and conjugated bilirubin (48.3%), upper-respiratory infections (25.0%), headache (23.3%), diarrhea (20.0%), and cough (20.0%). Grade ≥3 hyperbilirubinaemia occurred in 16.7% of patients, but no grade ≥ 3 ALT and/or AST elevations were observed. Treatment discontinuation due to TEAEs occurred in 6.7% of patients. TDI01 was well tolerated without dose-limiting toxicities in both dosage cohorts.PK analysis in all 60 patients showed TDI01 was rapidly absorbed with median Tmax of 4.1-4.5 hours after single doses. Plasma exposure (Cmax and AUC) increased dose-proportionally. Steady-state was achieved by day 15 with moderate accumulation (RAAUC0-t: 1.6-1.9). E–R analysis demonstrated significant correlation between TDI01 exposure parameters (Cmax,ss, AUCss, Ctrough) and 24-week BORR (p < 0.05), with 400 mg approaching maximum efficacy. A positive trend between exposure and FFS was also observed. Notably, no correlation existed between TDI01 exposure and grade ≥3 bilirubin elevations.Conclusion:TDI01 demonstrated durable responses in moderate-to-severe cGVHD. The 400 mg cohort showed a higher ORR, a longer DOR, and a favorable FFS/OS than that of 200 mg cohort. Safety was manageable with primarily reversible hyperbilirubinemia. Our data supported 400 mg QD as the recommended dose of phase III randomized controlled trial which is planned.