Epicardial delivery of XC001 gene therapy for refractory angina coronary treatment (The EXACT Trial): Rationale, design, and clinical considerations

Am Heart J. 2021 Nov;241:38-49. doi: 10.1016/j.ahj.2021.06.013. Epub 2021 Jul 2.

Abstract

Background: Patients with refractory angina (RA) have poor quality of life and new therapies are needed. XC001 is a novel adenoviral vector expressing multiple isoforms of vascular endothelial growth factor (VEGF) promoting an enhanced local angiogenic effect.

Methods: The Epicardial Delivery of XC001 Gene Therapy for Refractory Angina Coronary Treatment (EXACT) trial is a 6-month (with 6-month extension) phase 1/2, first-in-human, multicenter, open-label, single-arm, dose-escalation study to evaluate the safety, tolerability, and preliminary efficacy of XC001 in patients with RA. The trial will enroll 33 patients in an initial (n = 12) ascending dose-escalation phase (1 × 109, 1 × 1010, 4 × 1010, and 1 × 1011 viral particles), followed by phase 2 (n = 21) assessing the highest tolerated dose. Patients must have stable Canadian Cardiovascular Society (CCS) class II-IV angina on maximally tolerated medical therapy without options for conventional revascularization, demonstrable ischemia on stress testing, and angina limiting exercise tolerance. XC001 will be delivered directly to ischemic myocardium via surgical transthoracic epicardial access. The primary outcome is safety via adverse event monitoring through 6 months. Efficacy assessments include difference from baseline to month 6 in time to 1 mm of ST segment depression, time to angina, and total exercise duration; myocardial blood flow at rest, and stress and coronary flow reserve by positron emission tomography; quality of life; CCS functional class; and angina frequency.

Conclusions: The EXACT trial will determine whether direct intramyocardial administration of XC001 in patients with RA is safe and evaluate its effect on exercise tolerance, myocardial perfusion, angina and physical activity, informing future clinical investigation.

Clinical trial registration: NCT04125732.

Keywords: Angina; Angiogenesis; Clinical trial; Coronary artery disease; Gene therapy; Refractory angina.

Publication types

  • Clinical Trial Protocol
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoviridae
  • Aged
  • Angina Pectoris* / diagnosis
  • Angina Pectoris* / physiopathology
  • Angina Pectoris* / therapy
  • Angiogenesis Inducing Agents / pharmacology
  • Cardiovascular Agents / therapeutic use
  • Clinical Trials, Phase II as Topic
  • Drug Delivery Systems / methods
  • Exercise Tolerance
  • Female
  • Genetic Therapy / methods*
  • Genetic Vectors
  • Humans
  • Male
  • Maximum Tolerated Dose
  • Pericardium / surgery
  • Treatment Outcome
  • Vascular Endothelial Growth Factors* / genetics
  • Vascular Endothelial Growth Factors* / pharmacology

Substances

  • Angiogenesis Inducing Agents
  • Cardiovascular Agents
  • Vascular Endothelial Growth Factors

Associated data

  • ClinicalTrials.gov/NCT04125732