Itolizumab, a Novel Targeted Anti-CD6 Therapy, in Combination with Corticosteroids, Is Well-Tolerated, with Rapid Pharmacodynamic and Clinical Response in Newly Diagnosed Acute Graft-Versus-Host Disease

• Published in: Blood 2021-11, Vol.138 (Supplement 1), p.2891-2891
• Main Authors: Koreth, John, Ritz, Jerome, Chinn, Leslie, Ng, Cherie, Acevedo, Lisette M, Chu, Dalena, Fung, Maple, Rothman, Joel, Connelly, Stephen, Thomas, Dolca, Cutler, Corey
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2021-145721

Introduction: Itolizumab is a first-in-class monoclonal antibody against the co-stimulatory receptor CD6 that blocks its interaction with activated leukocyte cell adhesion molecule (ALCAM), thereby inhibiting T effector (T eff) cell activity and trafficking to target organs. It is being evaluated as a treatment for immuno-inflammatory diseases where T eff cells play a central role including acute graft-versus-host disease (aGVHD). Previous studies reported that ex vivo depletion of donor CD6+ cells in allogeneic hematopoietic cell transplantations lowers the incidence of aGVHD, justifying therapeutically targeting CD6 in aGVHD. Here we present interim clinical and pharmacokinetic/dynamic (PK/PD) results from the EQUATE study (NCT03763318), an ongoing US-based Phase 1b/2 study of itolizumab (a non-depleting anti-CD6 mAb) to treat subjects with newly diagnosed aGVHD, highlighting the relationship of early response to itolizumab concentrations. Methods: To date, 22 adult subjects with Grade III-IV aGVHD who initiated steroid treatment within 7 days prior to the first dose of itolizumab have enrolled in EQUATE at 0.4 mg/kg (n=4), 0.8 mg/kg (n=9), or 1.6 mg/kg (n=9), administered IV every 2 weeks x 5 doses. The median follow-up is 146 days (range: 14-355 days). Primary endpoints included itolizumab safety, tolerability, and optimal dose levels, and secondary endpoints included PK/ PD effects (change in CD6 surface expression on CD4+ cells) and clinical activity. Results: Patients: At baseline, study subjects had a mean (SD) age of 54 (14) and 68% were male; all had Grade III or IV aGVHD and 91% had lower GI involvement. All subjects received at least one dose and 15 received at least 2 doses of itolizumab. Safety: All subjects experienced at least 1 AE. Serious AEs occurred in 14 subjects (64%), with 9 (41%) reporting infection-related SAEs. There were 8 deaths. Six subjects (27.3%) had SAEs leading to death (3 at 0.8 mg/kg and 3 at 1.6 mg/kg): sepsis (n=1), Staphylococcal sepsis (n=1), Klebsiella sepsis (n=1), intestinal infarction (n=1), cardiac arrest (n=1), and GVHD (n=1). Another 2 deaths occurred >100 days post- last dose due to progressive aGVHD (n=1) and primary disease relapse (n=1). Efficacy and Survival: Across all doses, the complete response (CR) rate was 55% at both Day 15 and Day 29, and the overall response rate (ORR) was 73% at Day 15 and 68% at Day 29. At Day 169 (n=20), non-relapse mortality (NRM) was 35%, overall survival was 65%. Of note, t