(VP005) A RANDOMIZED, MULTI-CENTER, PHASE 2 TRIAL OF RBT-1 VERSUS PLACEBO EVALUATING CYTOPROTECTIVE BIOMARKERS AND POSTOPERATIVE OUTCOMES IN PATIENTS UNDERGOING CARDIAC SURGERY ON CARDIOPULMONARY BYPASS

Background: Among patients undergoing cardiac surgery with cardiopulmonary bypass (CPB), postoperative complications are common and significantly impact long-term outcomes. We conducted a Phase 2 clinical trial of RBT-1, a pharmacologic preconditioning drug, to assess cytoprotective biomarkers and clinical outcomes. We are reporting our final results.

METHODS AND RESULTS:
This randomized, blinded, placebo-controlled trial enrolled 152 patients in US, Canada, and Australia who were scheduled to undergo CABG and/or valve surgery on CPB. Eligible patients were randomized to receive one intravenous dose of RBT-1 (low or high dose) or placebo 24 to 48 hours before surgery. The primary endpoint was a cytoprotective preconditioning response, measured by a composite of biomarkers representing antioxidant, anti-inflammatory, and iron scavenging pathways (i.e., heme oxygenase-1, interleukin-10, and ferritin). Key secondary/exploratory endpoints included ventilator, ICU, and hospital days; readmission rates, and incidence of AKI and major adverse kidney events (MAKE).

Results:
Baseline characteristics were: mean age 65 years, heart failure rate of 15%, Stage 3 or 4 CKD at 25%, and 23% of patients underwent combined CABG/valve surgery. Both low and high doses of RBT-1 significantly increased the biomarker response by >160% (p < 0.0001), meeting our primary endpoint. RBT-1 yielded a significant reduction in ICU days (p=0.0101) and 30-day cardiopulmonary readmission rates (p=0.0391). RBT-1 yielded a meaningful reduction in hospital days, atrial fibrillation, and MAKE at Day 30 (MAKE30). RBT-1 was well tolerated with only transient photosensitivity (19.8% incidence) as the primary adverse event and more commonly seen in the high dose group. A post-hoc hierarchical composite (win ratio) of clinical outcomes (in rank-order of death, AKI requiring dialysis, ICU days, cardiopulmonary readmission, atrial fibrillation, and hospital days) achieved a statistically significant win ratio of 1.63 (p=0.0161), suggesting RBT-1 improved clinical outcomes post-cardiac surgery.

Conclusion: RBT-1 is a novel preconditioning drug used safely in the setting of CABG/valve surgery requiring CPB. Treatment with RBT-1 resulted in favorable changes in cytoprotective biomarkers and suggested benefits on multiple clinical outcomes of relevance. Based on these findings, FDA has granted Fast Track designation to advance clinical development of RBT-1 to reduce the risk of postoperative complications in patients undergoing cardiac surgery.