EXACT Trial : Results of the Phase 1 Dose-Escalation Study
BACKGROUND: New therapies are needed for patients with refractory angina. Encoberminogene rezmadenovec (XC001), a novel adenoviral-5 vector coding for all 3 major isoforms of VEGF (vascular endothelial growth factor), demonstrated enhanced local angiogenesis in preclinical models; however, the maximal tolerated dose and safety of direct epicardial administration remain unknown.
METHODS: In the phase 1 portion of this multicenter, open-label, single-arm, dose-escalation study, patients with refractory angina received increasing doses of encoberminogene rezmadenovec (1×109, 1×1010, 4×1010, and 1×1011 viral particles) to evaluate its safety, tolerability, and preliminary efficacy. Patients had class II to IV angina on maximally tolerated medical therapy, demonstrable ischemia on stress testing, and were angina-limited on exercise treadmill testing. Patients underwent minithoracotomy with epicardial delivery of 15 0.1-mL injections of encoberminogene rezmadenovec. The primary outcome was safety via adverse event monitoring over 6 months. Efficacy assessments included difference from baseline to months 3, 6 (primary), and 12 in total exercise duration, myocardial perfusion deficit using positron emission tomography, angina class, angina frequency, and quality of life.
RESULTS: From June 2, 2020 to June 25, 2021, 12 patients were enrolled into 4 dosing cohorts with 1×1011 viral particle as the highest planned dose. Seventeen serious adverse events were reported in 7 patients; none were related to study drug. Six serious adverse events in 4 patients were related to the thoracotomy, 3 non-serious adverse events were possibly related to study drug. The 2 lowest doses did not demonstrate improvements in total exercise duration, myocardial perfusion deficit, or angina frequency; however, there appeared to be improvements in all parameters with the 2 higher doses.
CONCLUSIONS: Epicardial delivery of encoberminogene rezmadenovec via minithoracotomy is feasible, and up to 1×1011 viral particle appears well tolerated. A dose response was observed across 4 dosing cohorts in total exercise duration, myocardial perfusion deficit, and angina class. The highest dose (1×1011 viral particle) was carried forward into phase 2.
REGISTRATION: URL: https://www.
CLINICALTRIALS: gov; Unique identifier: NCT04125732.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:16 |
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| Enthalten in: |
Circulation. Cardiovascular interventions - 16(2023), 8 vom: 26. Aug., Seite e012997 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Povsic, Thomas J [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 17.08.2023 Date Revised 17.08.2023 published: Print-Electronic ClinicalTrials.gov: NCT04125732 Citation Status MEDLINE |
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| doi: |
10.1161/CIRCINTERVENTIONS.123.012997 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM36003571X |
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| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Povsic, Thomas J |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a EXACT Trial |b Results of the Phase 1 Dose-Escalation Study |
| 264 | 1 | |c 2023 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
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| 500 | |a Date Completed 17.08.2023 | ||
| 500 | |a Date Revised 17.08.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a ClinicalTrials.gov: NCT04125732 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a BACKGROUND: New therapies are needed for patients with refractory angina. Encoberminogene rezmadenovec (XC001), a novel adenoviral-5 vector coding for all 3 major isoforms of VEGF (vascular endothelial growth factor), demonstrated enhanced local angiogenesis in preclinical models; however, the maximal tolerated dose and safety of direct epicardial administration remain unknown | ||
| 520 | |a METHODS: In the phase 1 portion of this multicenter, open-label, single-arm, dose-escalation study, patients with refractory angina received increasing doses of encoberminogene rezmadenovec (1×109, 1×1010, 4×1010, and 1×1011 viral particles) to evaluate its safety, tolerability, and preliminary efficacy. Patients had class II to IV angina on maximally tolerated medical therapy, demonstrable ischemia on stress testing, and were angina-limited on exercise treadmill testing. Patients underwent minithoracotomy with epicardial delivery of 15 0.1-mL injections of encoberminogene rezmadenovec. The primary outcome was safety via adverse event monitoring over 6 months. Efficacy assessments included difference from baseline to months 3, 6 (primary), and 12 in total exercise duration, myocardial perfusion deficit using positron emission tomography, angina class, angina frequency, and quality of life | ||
| 520 | |a RESULTS: From June 2, 2020 to June 25, 2021, 12 patients were enrolled into 4 dosing cohorts with 1×1011 viral particle as the highest planned dose. Seventeen serious adverse events were reported in 7 patients; none were related to study drug. Six serious adverse events in 4 patients were related to the thoracotomy, 3 non-serious adverse events were possibly related to study drug. The 2 lowest doses did not demonstrate improvements in total exercise duration, myocardial perfusion deficit, or angina frequency; however, there appeared to be improvements in all parameters with the 2 higher doses | ||
| 520 | |a CONCLUSIONS: Epicardial delivery of encoberminogene rezmadenovec via minithoracotomy is feasible, and up to 1×1011 viral particle appears well tolerated. A dose response was observed across 4 dosing cohorts in total exercise duration, myocardial perfusion deficit, and angina class. The highest dose (1×1011 viral particle) was carried forward into phase 2 | ||
| 520 | |a REGISTRATION: URL: https://www | ||
| 520 | |a CLINICALTRIALS: gov; Unique identifier: NCT04125732 | ||
| 650 | 4 | |a Multicenter Study | |
| 650 | 4 | |a Clinical Trial, Phase I | |
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a angina pectoris | |
| 650 | 4 | |a coronary artery disease | |
| 650 | 4 | |a genetic therapy | |
| 650 | 4 | |a ischemia | |
| 650 | 4 | |a myocardial revascularization | |
| 650 | 4 | |a vascular endothelial growth factor | |
| 650 | 7 | |a Vascular Endothelial Growth Factor A |2 NLM | |
| 700 | 1 | |a Henry, Timothy D |e verfasserin |4 aut | |
| 700 | 1 | |a Traverse, Jay H |e verfasserin |4 aut | |
| 700 | 1 | |a Anderson, R David |e verfasserin |4 aut | |
| 700 | 1 | |a Answini, Geoffrey A |e verfasserin |4 aut | |
| 700 | 1 | |a Sun, Benjamin C |e verfasserin |4 aut | |
| 700 | 1 | |a Arnaoutakis, George J |e verfasserin |4 aut | |
| 700 | 1 | |a Boudoulas, Konstantinos D |e verfasserin |4 aut | |
| 700 | 1 | |a Williams, Adam R |e verfasserin |4 aut | |
| 700 | 1 | |a Dittrich, Howard C |e verfasserin |4 aut | |
| 700 | 1 | |a Tarka, Elizabeth A |e verfasserin |4 aut | |
| 700 | 1 | |a Latter, David A |e verfasserin |4 aut | |
| 700 | 1 | |a Ohman, E Magnus |e verfasserin |4 aut | |
| 700 | 1 | |a Peterson, Mark W |e verfasserin |4 aut | |
| 700 | 1 | |a Byrnes, Dawn |e verfasserin |4 aut | |
| 700 | 1 | |a Pepine, Carl J |e verfasserin |4 aut | |
| 700 | 1 | |a DiCarli, Marcelo F |e verfasserin |4 aut | |
| 700 | 1 | |a Crystal, Ronald G |e verfasserin |4 aut | |
| 700 | 1 | |a Rosengart, Todd K |e verfasserin |4 aut | |
| 700 | 1 | |a Mokadam, Nahush A |e verfasserin |4 aut | |
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