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Clinical Trial
. 2024 May;17(5):e014054.
doi: 10.1161/CIRCINTERVENTIONS.124.014054. Epub 2024 May 2.

Angiogenic Gene Therapy for Refractory Angina: Results of the EXACT Phase 2 Trial

Kenta Nakamura  1 , Timothy D Henry  2 , Jay H Traverse  3 , David A Latter  4 , Nahush A Mokadam  5 , Geoffrey A Answini  6 , Adam R Williams  7 , Benjamin C Sun  3 , Christopher R Burke  8 , Faisal G Bakaeen  9 , Marcelo F DiCarli  10 , Bernard R Chaitman  11 , Mark W Peterson  12 , Dawn G Byrnes  12 , E Magnus Ohman  13 , Carl J Pepine  14 , Ronald G Crystal  15 , Todd K Rosengart  16 , Elaine Kowalewski  17 , Gary G Koch  17 , Howard C Dittrich  12 , Thomas J Povsic  13 ; EXACT Trial Investigators
Affiliations
Clinical Trial

Angiogenic Gene Therapy for Refractory Angina: Results of the EXACT Phase 2 Trial

Kenta Nakamura et al. Circ Cardiovasc Interv. 2024 May.

Abstract

Background: XC001 is a novel adenoviral-5 vector designed to express multiple isoforms of VEGF (vascular endothelial growth factor) and more safely and potently induce angiogenesis. The EXACT trial (Epicardial Delivery of XC001 Gene Therapy for Refractory Angina Coronary Treatment) assessed the safety and preliminary efficacy of XC001 in patients with no option refractory angina.

Methods: In this single-arm, multicenter, open-label trial, 32 patients with no option refractory angina received a single treatment of XC001 (1×1011 viral particles) via transepicardial delivery.

Results: There were no severe adverse events attributed to the study drug. Twenty expected severe adverse events in 13 patients were related to the surgical procedure. Total exercise duration increased from a mean±SD of 359.9±105.55 seconds at baseline to 448.2±168.45 (3 months), 449.2±175.9 (6 months), and 477.6±174.7 (12 months; +88.3 [95% CI, 37.1-139.5], +84.5 [95% CI, 34.1-134.9], and +115.5 [95% CI, 59.1-171.9]). Total myocardial perfusion deficit on positron emission tomography imaging decreased by 10.2% (95% CI, -3.1% to 23.5%), 14.3% (95% CI, 2.8%-25.7%), and 10.2% (95% CI, -0.8% to -21.2%). Angina frequency decreased from a mean±SD 12.2±12.5 episodes to 5.2±7.2 (3 months), 5.1±7.8 (6 months), and 2.7±4.8 (12 months), with an average decrease of 7.7 (95% CI, 4.1-11.3), 6.6 (95% CI, 3.5-9.7), and 8.8 (4.6-13.0) episodes at 3, 6, and 12 months. Angina class improved in 81% of participants at 6 months.

Conclusions: XC001 administered via transepicardial delivery is safe and generally well tolerated. Exploratory improvements in total exercise duration, ischemic burden, and subjective measures support a biologic effect sustained to 12 months, warranting further investigation.

Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04125732.

Keywords: angiogenesis; coronary artery disease; genetic therapy; positron emission tomography; vascular endothelial growth factor A.

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Conflict of interest statement

Disclosures Dr Nakamura received institutional research support from XyloCor Therapeutics and consulting fees from XyloCor Therapeutics and Sana Biotechnology. Dr Henry received consulting fees (Steering Committee) from XyloCor Therapeutics. Dr Latter received consulting fees from and is a data and safety monitoring board (DSMB) member of XyloCor Therapeutics. Dr Mokadam received consulting fees from Abbott, Medtronic, SynCardia, and XyloCor Therapeutics and is a DSMB member of XyloCor Therapeutics, Medtronic, and Carmat. Dr Williams received consulting fees from XyloCor Therapeutics. Dr Sun received consulting fees from Abbott Vascular and is a DSMB member of 4C Medical and Abbott. Dr DiCarli received institutional research support from XyloCor Therapeutics and Gilead Sciences, consulting fees from Sanofi and MedTrace Pharma, and institutional in-kind research support from Amgen. Dr Chaitman received consulting fees and institutional research support from XyloCor Therapeutics. M.W. Peterson is an employee of XyloCor Therapeutics. D.G. Byrnes is an employee of XyloCor Therapeutics. Dr Ohman is an employee of Amgen. Dr Pepine received institutional research support from XyloCor Therapeutics, BioCardia, Caladrius, Duke Clinical Research Institute, the Gatorade Foundation, the McJunkin Family Foundation Trust, Mesoblast, National Institutes of Health/National Heart, Lung, and Blood Institute, Patient-Centered Outcomes Research Institute/National Patient-Centered Clinical Research Network, Pfizer, Sanofi, University of Florida Clinical and Translational Science Institute, and US Department of Defense and consulting fees from AbbVie, Akros, BioCardia, Bloomer Tech, Caladrius, Imbria Pharmaceuticals, Ironwood Pharmaceuticals, Milestone Pharmaceuticals, and Verily Life Sciences LLC. Dr Crystal received consulting fees from and has equity in XyloCor Therapeutics. Dr Rosengart is an advisor of, is a board of directors member of, and received consulting fees, royalties, and honoraria from XyloCor Therapeutics. Dr Kowalewski received institutional research support from XyloCor Therapeutics. Dr Koch received institutional research support from XyloCor Therapeutics. Dr Dittrich is an employee of XyloCor Therapeutics. Dr Povsic received institutional research support from XyloCor Therapeutics, CSL Behring, Priovant, Bayer, Ionis Pharmaceuticals, UCB Biopharma SRL, BodyPort, and Merck Pharmaceuticals; consulting fees from AstraZeneca, Biocardia, Boehringer Ingelheim, Caladrius Biosciences, Recardio, Veralox Therapeutics, Sana Biotechnology, Inc, Guidepoint Global LLC, and the Gerson Lehrman Group; is a DSMB member of Corvia, Novo Nordisk, and Parexel International; and has leadership or fiduciary role in the American Heart Association and the American College of Cardiology.

Figures

Figure 1.
Figure 1.
Study flow diagram. Anti-Ad5 indicates anti-adenoviral-5; CV, cardiovascular; FU, follow-up; Hgb, hemoglobin; PCI, percutaneous coronary intervention; PET, positron emission tomography; SD, study drug; and TED, total exercise duration.
Figure 2.
Figure 2.
Effect of XC001 on total exercise duration. A, Total exercise duration (mean±SEM). B, Change in total exercise duration (mean±95% CI) from baseline at 3, 6, and 12 mo after treatment.
Figure 3.
Figure 3.
Effect of XC001 on time to ST depression. A, Time to development of 1-mm ST-segment deviation on exercise tolerance testing (mean±SEM). B, Change in time to development of 1-mm ST-segment deviation on exercise tolerance testing (mean±95% CI) from baseline at 3, 6, and 12 mo after treatment.
Figure 4.
Figure 4.
Effect of XC001 on ischemia. Percentage change from baseline of total perfusion deficit (ischemia) on adenosine or regadenoson positron emission tomography imaging at 3, 6, and 12 mo (mean±95% SEM). P values are based on the Wilcoxon signed-rank statistic.
Figure 5.
Figure 5.
Canadian Cardiovascular Society (CCS) Angina Class by visit baseline to 6 mo.
See this image and copyright information in PMC

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