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I – Gene & Cell Therapy Trials in Progress -> Gene & Cell Therapy Trials in Progress

Preliminary Safety, Tolerability and Efficacy of Direct Epicardial Administration of Encoberminogene Rezmadenovec to Ischemic Myocardium in Patients with Refractory Angina: Six Month Phase 1 Data

Type: Oral Abstract Session

Presentation Details
Session Title: Late-Breaking Abstracts II
Location: Ballroom C
Start Time: 5/18/2022 9:30
End Time: 5/18/2022 9:45

Rationale: Safety concerns in gene therapy trials have generally been associated with high viral particle loads administered systemically. Encoberminogene rezmadenovec (XC001) is a replication-deficient adenoviral serotype 5 (Ad5) vector expressing multiple isoforms of vascular endothelial growth factor (VEGF) including isoforms -121, -165 and -189. This construct shown to have superior angiogenesis when compared to vectors expressing single VEGF isoforms is currently being studied in the Phase 1/2 EXACT (Epicardial Delivery of XC001 Gene Therapy for Refractory Angina Coronary Treatment) Trial (NCT04125732) where epicardial administration of the vector allows for lower doses yielding high gene expression in target tissue compared with systemic administration. In preclinical toxicology studies in human equivalent doses up to 1x1012 viral particles of XC001, biodistribution analysis demonstrated high levels of vector in the heart relative to liver and other organs.
Objective: Phase 1 of the EXACT trial is a first-in-human, multicenter, open-label, single arm dose escalation study to evaluate safety, tolerability, and preliminary efficacy of epicardial injections of encoberminogene rezmadenovec to ischemic myocardium in refractory angina patients.
Methods: Twelve subjects with refractory angina and Canadian Cardiovascular Society (CCS) Class 2-4 without revascularization options underwent mini thoracotomy with one-time administration of XC001 in increasing doses per cohort (n=3/cohort; 1x109, 1x1010, 4x1010, and 1x1011 viral particles, respectively) divided in 15 injections of 0.1 ml each across the left ventricular free wall with emphasis on ischemic zones. Anti-Ad5 neutralizing antibody (nAb) titers less than 1:320 were required for eligibility and titers were measured post-dosing through twelve months. Safety and tolerability were monitored via adverse event (AE) and serious adverse event (SAE) reporting as well as laboratory and electrocardiographic parameters. Preliminary key efficacy evaluation was change from baseline to six months post-treatment in exercise capacity.
Results: Over the 6 months of follow up, there were 17 SAEs in 7 subjects, and none were related to the study drug. Six SAEs in 4 subjects were related to the mini-thoracotomy procedure and none of these were unexpected or resulted in patient death. Eleven SAEs were related to either the underlying disease process or other causes. Three AEs related to study drug were reported in 2 subjects in the highest dose group and these events were fever, fatigue, and lip swelling. As expected, all treated subjects developed sustained nAbs. Improvements from baseline to month 6 in Total Exercise Duration (minutes) [mean (median)], were 0.6 (0.9), 0.5 (0.7), 1.1 (1.1), and 2.0 (2.2) for dose cohorts 1-4, respectively.
Conclusion: In the Phase 1 portion of this Phase 1/2 Study treating refractory angina, direct epicardial administration of encoberminogene rezmadenovec appears to be well-tolerated and safe at all tested doses. Preliminary efficacy evaluation in a small sample size suggests a possible dose-response and therapeutic potential with this therapy. Based on observed safety, tolerability, and preliminary efficacy with 1x1011 viral particle dose, continued investigation of the direct epicardial approach at this dose in the Phase 2 expansion portion of this trial has begun.

Thomas J. Povsic1, Jay H. Traverse2, Timothy D. Henry3, Todd K. Rosengart4, Ronald G. Crystal5, Howard C. Dittrich6, Elizabeth A. Tarka6, Nahush A. Mokadam7

1Duke University Medical Center, Durham, NC,2Minneapolis Heart Institute, Minneapolis, MN,3The Christ Hospital, Cincinnati, OH,4Baylor College of Medicine, Houston, TX,5Weill Cornell Medicine, New York, NY,6XyloCor Therapeutics, Wayne, PA,7The Ohio State University Wexner Medical Center, Columbus, OH
  T.J. Povsic: 1; Commercial Interest i.e. Company X; XyloCor. 1; What was received? i.e. Honorarium; Research grant. 1; For what role? i.e. Speaker; Principal Investigator.

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