PS1533 KD025–208: A PHASE 2A TRIAL OF KD025 FOR PATIENTS WITH CHRONIC GRAFT‐VERSUS‐HOST DISEASE (CGVHD) – UPDATED SAFETY AND EFFICACY
Authors: Salhotra A. , Zoghi B. , Essell J. , Bachier C.R. , Weisdorf D.J. , Lazaryan A. , Green L.S. , Schueller O. , Huang L. , Yang Z. , Eiznhamer D. , Aggarwal S.K. , Blazar B.R. , Lee S.J. , Jagasia M. 
Published: June 2019

Background:KD025 is an inhibitor of ROCK2 in a pivotal clinical trial for chronic graft‐versus‐host disease (cGVHD). Inhibition of ROCK2 downregulates TH17 and Tfh cells while upregulating regulatory T (Treg) cells, helping to resolve the immune dysregulation seen in cGVHD. In addition, KD025 decreases myofibroblast formation and proliferation, inhibiting the fibrotic components of cGVHD.Aims:KD025–208 is an open‐label, Phase 2 study of KD025 in patients with steroid‐dependent or refractory cGVHD.Methods:Three cohorts (200 mg QD [n = 17], 200 mg BID [n = 16] and 400 mg QD [n = 21]) were enrolled sequentially. The primary endpoint is the overall response rate, defined per the 2014 NIH Consensus criteria.Results:Patients enrolled in all three cohorts received a median of 2 prior lines of cGVHD therapy. The median corticosteroid dose at baseline was 0.19 mg/kg/day. The most frequently involved organs were eyes (78%), skin (74%), mouth (65%), joints/fascia (61%) and lungs (31%). Forty‐eight percent (48%) of patients had involvement of ≥ 4 organs. As of 13 September, 2018, twenty patients (6 in Cohort 1, 3 in Cohort 2 and 11 in Cohort 3) remain on treatment with KD025, with a median treatment duration of 89, 68 and 34 weeks, respectively. The Overall Response Rate (ORR) was 65% in Cohort 1, 63% in Cohort 2 and 52% in Cohort 3. Responses were rapid, with 75% of responders achieving a response by the first assessment (at 8 weeks). Nine of 11 responders (82%) in Cohort 1 have sustained a response for ≥ 20 weeks. In patients with ≥ 2 prior lines of therapy and in patients with ≥ 4 organs involved, the ORR pooled across the cohorts was 58% and 62%, respectively. Responses were observed across all affected organ systems, including CRs in upper GI, lower GI, esophagus, mouth, skin, joints, eyes and liver. Two partial responses were observed in lung. The median corticosteroid dose reduced by 44% in Cohort 1, 23% in Cohort 2 and 10% in Cohort 3 while on study. Seven patients completely discontinued corticosteroid treatment while receiving KD025. Seventy‐two percent (72%) of responders across all three cohorts achieved a clinically meaningful improvement (≥ 7‐point reduction) in the Lee cGVHD Symptom Scale Score. KD025 was well tolerated. Commonly reported AEs were URTI, AST/ALT elevations, fatigue, nausea and diarrhea. SAEs occurred in 20 patients; none were related to KD025. No increased risk of infection was observed and no CMV infections were reported. Eighteen of 54 patients discontinued treatment due to progression of cGVHD, 6 due to voluntary withdrawal, 3 due to recurrence of underlying malignancy, 2 due to an AE, 2 due to death, 2 due to investigator decision and 1 due to noncompliance. Preliminary pharmacodynamic results demonstrate a decrease in TH17 cells and an increase in Treg cells in responders to KD025 treatment, consistent with the proposed mechanism of action. Failure‐free survival (FFS) data will be presented for the first time at the EHA meeting.Summary/Conclusion:Treatment with KD025 has resulted in clinically meaningful and durable responses across all affected organ systems. Corticosteroid doses were reduced in both responders and non‐responders. KD025 treatment was well tolerated with an AE profile consistent with that expected in cGVHD patients receiving corticosteroids. No apparent increased risk of infection was observed. Pharmacodynamic results support the proposed KD025 mechanism of action. FFS data will be presented at the meeting.