LB15. Dose Escalation Study of Encoberminogene Rezmadenovec (Adenoviral Vector With Multiple Isoforms of Vascular Endothelial Growth Factor) in Refractory Angina: Phase 1 Results

Objective: This Phase 1/2 EXACT (Epicardial Delivery of XC001 Gene Therapy for Refractory Angina Coronary Treatment) trial (NCT04125732) investigates the direct administration of encoberminogene rezmadenovec (XC001), a replication-deficient adenoviral serotype 5 vector expressing multiple isoforms of vascular endothelial growth factor (VEGF) including 121, 165, and 189, to the ischemic myocardium of subjects with angina pectoris secondary to coronary artery disease that is refractory to drug therapy and unsuitable for revascularization. This trial is a first-in-human, multicenter, open-label, single arm cardiovascular dose escalation study to assess the safety, preliminary efficacy, and highest tolerated dose for further evaluation in the Phase 2 expansion cohort.
Methods: Twelve patients with refractory angina and Canadian Cardiovascular Society (CCS) Class 2-4 without revascularization options underwent mini thoracotomy with 15 epicardial injections of increasing doses of encoberminogene rezmadenovec (n=3/cohort; 1x10⁹, 1x10¹⁰, 4x10¹⁰, and 1x10¹¹ viral particles, respectively). Safety and efficacy evaluations were measured as serious adverse events (SAEs) and change from baseline to three months post-treatment including exercise testing, positron emission tomography (PET), and patient-reported symptomatology.
Results: No drug-related SAEs, bleeding complications or ventricular arrhythmias were observed. A total of thirteen SAEs occurred in five subjects through three months of follow up. Six of the thirteen SAEs occurred in four subjects and were attributed to the mini-thoracotomy procedure (atrial fibrillation, chest pain, heart failure, pleural effusion, type 2 MI, wound infection). None were unexpected or resulted in patient death. Changes from baseline to month 3 in Total Exercise Duration (minutes) were -1.58 (-0.15), -0.33 (-0.77), 1.18 (2.72), and 2.36 (2.12) [mean (median)], for cohorts 1-4 respectively (Figure), improvement in CCS angina class 0.7 (0), 1.7 (1.0), 1.0 (1.0), 1.7 (2.0) [mean (median)], respectively and improvement from baseline in PET perfusion defect extent of 1.8 (7.4), 0.2 (-1.2), 1.9 (0.9), 6.9 (6.0), [mean (median)], respectively.
Conclusions: In the Phase 1 portion of this open-label Phase 1/2 study treating refractory angina, epicardial administration of encoberminogene rezmadenovec expressing VEGF appears to be well-tolerated and safe at all tested doses. Further, objective criteria including exercise tolerance and PET scans suggest therapeutic potential with this therapy. This preliminary efficacy evaluation in a small sample size suggests a dose-response across several efficacy variables and supports continued investigation of 1x10¹¹ viral particle dose in the Phase 2 portion of this trial.

Nahush Mokadam, MD (1), Tim Henry (2), Jay Traverse (3), David Henderson (4), R. David Anderson (5), Geoffrey Answini (6), Benjamin Sun (7), George Arnaoutakis (5), Konstantinos Boudoulas (1), Adam Williams (8), Todd Rosengart (9), Howard Dittrich (10), Elizabeth Tarka (10), Thomas Povsic (11), (1) The Ohio State University Wexner Medical Center, Columbus, OH, (2) The Christ Hospital, Cincinati, OH, (3) Minneapolis Heart Institute, Minneapolis, MN, (4) Florida Hospital Memorial Medical Center, Daytona, FL, (5) University of Florida Health, Gainesville, FL, (6) The Christ Hospital, Cincinnati, OH, (7) Minneapolis Heart Institute, MInneapolis, MN, (8) Duke University Medical Center, Durham, NC, (9) Baylor St. Luke's Medical Center, Houston, TX, (10) XyloCor Therapeutics, Wayne, PA, (11) Duke University, Durham, NC

Pavan Atluri, MD

Moderator

Dr. Atluri is Director of Mechanical Circulatory Support and Heart Transplant and Director of Minimally Invasive and Robotic Cardiac Surgery at the University of Pennsylvania. 

Nahush Mokadam

Abstract Presenter

Dr. Nahush A. Mokadam is the Division Director of Cardiac Surgery at The Ohio State University Wexner Medical Center, where he holds the Kakos and Williams Endowed Professorship in Cardiac Surgery. His clinical expertise includes all aspects of adult cardiac surgery, including minimally invasive valve repair and replacement, all-arterial revascularization, heart and lung transplantation, mechanical circulatory support and aortic root reconstruction.  He is internationally recognized as a leader in total artificial heart implantation. Dr. Mokadam has been an avid participant in novel national and international clinical trials, especially in the field of advanced heart failure and minimally invasive LVAD implantation. He collaborates closely with basic scientists and biomedical engineers to promote ground-breaking translational research, resulting in one of the highest NIH-funded Divisions of Cardiac Surgery in the country.  Dr. Mokadam also has extensive experience in surgical education, with a focus on high fidelity surgical simulation. He is the Program Director of the integrated six-year cardiothoracic residency program and is committed to developing the next generation of cardiothoracic surgeons while advancing opportunities for women and minorities to pursue careers in cardiothoracic surgery. Under his leadership, the Division of Cardiac Surgery at The Ohio State University Wexner Medical Center has seen a substantial growth in patient volume, an improvement in quality metrics, a rejuvenation of collaborative culture, and a commitment to diversity and inclusion.

Specialties: Adult Cardiac, Adult (General), Coronary, Anatomy and Conditions, Coronary, Treatment/Procedure/Operation/Surgery, Coronary Disease, Minimally Invasive, Robotics