MODULAATE (Part 1): An Open-Label, Dose-Finding Phase 2 Evaluation of Alpha-1 Antitrypsin for the Prevention of Graft-Versus-Host Disease in Patients Receiving Hematopoietic Cell Transplantation

Introduction Acute graft-versus-host disease (aGVHD) occurs in 30–50% of patients (pts) post-hematopoietic cell transplant (HCT). Pilot studies suggest that exogenous alpha-1 antitrypsin (AAT) may improve severe steroid-refractory aGVHD. Objectives To evaluate safety, tolerability, and pharmacokinetics (PK) of AAT for GVHD prophylaxis and establish a dose for the Phase 3 (Part 2), double-blind, placebo-controlled part of MODULAATE (NCT03805789). Methods Pts ≥18 years old were screened up to 56 days prior to planned HCT. Pts received background calcineurin inhibitor (CNI) and methotrexate. On Day -1, pts received an AAT loading dose (90, 120 and 180mg/kg in Cohorts [Cts] 1, 2 and 3, respectively). Following HCT (Day 0), AAT was administered twice weekly (2x/W) for 28 days (60, 90 and 120mg/kg in Cts 1, 2 and 3, respectively), and then once weekly (1x/W) for 4 additional weeks. CNI tapering started at Day 90 in pts without GVHD. Pts were monitored for aGVHD through Day 180, for chronic GVHD (cGVHD) from Days 100 to 365, for systemic infections through Day 180, and for malignancy relapse and GVHD-free, relapse-free survival throughout the study. Ct 2 began after review of safety and PK results from ≥10 Ct 1 pts completing Day 28 assessments; Ct 3 began after review of safety and PK results from ≥10 Ct 2 pts completing Day 28 assessments. Results Baseline characteristics were similar across cohorts, except for HCT source. In Ct 1 (N=16), 50.0% of transplants were from bone marrow; in Cts 2 (N=14) and 3 (N=19), 78.6% and 100.0% of pts, respectively, received peripheral blood stem cells. Dose escalation proceeded as planned without any dose-limiting toxicities. Only Ct 3 achieved the pre-specified median trough AAT level of ≥3.5mg/mL (Figure 1) by Day 28, but this level was not sustained by 1x/W dosing. Serious adverse events (SAEs) were less frequent in Ct 3 vs Cts 1 and 2 (Table 1). Through Day 180, incidence of adjudicated Grade 2˗4 aGVHD was similar across cohorts (Ct 1: 43.8%; Ct 2: 42.9%; Ct 3: 57.9%), occurring more frequently between weeks 5 and 8, after dosing was reduced to 1x/W to determine if target trough was maintained. Incidence of lower gastrointestinal aGVHD was 18.8% in Ct 1, 7.1% in Ct 2 and 21.1% in Ct 3; all resolved with treatment except for 1 pt death in Ct 1 (unrelated to GVHD). Incidence of moderate-to-severe cGVHD through Day 365 was 50.0% in Ct 1, 21.4% in Ct 2, and 26.3% in Ct 3. Primary malignancy relapse rates were low in all cohorts (Table 1). Overall survival through Day 365 was 81.2%, 71.4% and 89.5% in Cts 1, 2 and 3, respectively. There was 1 GVHD-related death (Table 1). Conclusions AAT was well-tolerated in post-HCT pts with no evidence of increased infection risk. At 1 year, SAEs due to infection, cGVHD, and primary relapse rates were low in Cts 2 and 3. These safety and PK data support using an AAT 180mg/kg loading dose followed by 120mg/kg 2x/W for 56 days in Phase 3 (Part 2) of MODULAATE.