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

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.

WHAT IS KNOWN

• Angiogenic gene therapy with VEGF (vascular endothelial growth factor) is a promising strategy to treat no option refractory angina.

• XC001 is a novel replication-deficient adenovirus-5 vector designed to express all major isoforms of VEGF-A in a ratio that enhances safety and improves potency in preclinical models; phase 1 data from the EXACT trial (Epicardial Delivery of XC001 Gene Therapy for Refractory Angina Coronary Treatment) demonstrated no safety issues with the study drug, feasibility of transepicardial administration, and suggested a dose effect.

WHAT THE STUDY ADDS

• Phase 2 of EXACT was a single-arm, multicenter, open-label extension study of XC001 in no option refractory angina.

• In 32 patients dosed, there were no severe adverse events attributed to the study drug; 20 expected severe adverse events in 13 patients were related to the surgical administration.

• XC001 demonstrated improvements in total exercise duration, perfusion imaging by positron emission tomography, and anginal symptoms at 3, 6, and 12 months, suggesting a biologic effect.

Refractory angina is a chronic, debilitating condition with increasing global prevalence.^1–3 Improved survival from acute coronary syndromes and the aging population have contributed to an increased prevalence of patients living with advanced coronary artery disease worldwide and a growing subset of patients with demonstrable ischemia yet no option refractory angina (NORA).^2–4 Though the epidemiology is poorly understood, an estimated 5% to 10% of patients undergoing cardiac catheterization and upward of 1.8 million people in the United States experience angina despite antianginal therapy and coronary revascularization.³ In the large, contemporary European-based CLARIFY registry (Prospective Observational Longitudinal Registry of Patients With Stable Coronary Artery Disease), nearly a quarter of patients with stable coronary artery disease reported angina with 3.9% reporting severe Canadian Cardiovascular Society (CCS) class III or IV symptoms.⁵

While antianginal therapy is effective in most, a subset of patients suffer disabling symptoms for whom no effective therapy currently exists.^2,3 Only 2 antianginal agents, ranolazine and ivabradine, and 2 approved therapies, external counterpulsation and transmyocardial laser revascularization, have entered practice in the last 40 years. These therapies have shown mixed results in clinical practice⁶ and are cumbersome and morbid for patients. Although the prognosis of NORA is favorable with regard to mortality,⁷ quality of life in those with severe, disabling angina remains poor often requiring palliative approaches.^8,9

Angiogenesis is mediated by endogenous proangiogenic growth factors, most prominently VEGF (vascular endothelial growth factor).¹⁰ Despite favorable preclinical evidence, clinical investigations of protein,^11,12 plasmid,^13,14 and adenoviral-based¹⁵ growth factor therapy have shown limited success.

One possible explanation is that most genes are expressed naturally as multiple isoforms, while gene therapies have explored only single isoforms. XC001 is a novel replication-deficient, nonintegrating recombinant adenovirus-5 vector engineered to transiently increase myocardial expression of the 3 predominant VEGF-A isoforms found in humans (VEGF-121, -165, and -189), the latter 2 of which have enhanced heparin binding that promotes retention and expression in ischemic tissue.¹⁶ In a rat hind limb ischemia model, mixed expression of multiple VEGF isoforms was 10- to 100-fold more effective at the same dose compared with vectors expressing each isoform individually (VEGF-121, -165, or -189).¹⁷ Additionally, XC001 contains alternative splicing of the 3 isoforms, whereby VEGF-189 is preferentially expressed, which improves safety and is more efficacious compared with a more balanced expression.¹⁸

The EXACT trial (Epicardial Delivery of XC001 Gene Therapy for Refractory Angina Coronary Treatment) is a phase 1/2 open-label, single-arm multicenter study evaluating transepicardial administration of XC001 via surgical minithoracotomy in patients with NORA.^19,20

METHODS

Because of the sensitive nature of the data collected for this study, requests to access the dataset from qualified researchers trained in human subject confidentiality protocols may be sent to Eric Duckers at Xylocor Therapeutics.

Study Overview

The rationale and design of the EXACT trial (NCT04125732) have been published.²⁰ The first-in-human phase 1 dose-escalation portion of EXACT demonstrated tolerability of the highest tested dose and suggested a dose response.¹⁹ Twenty-nine additional patients were enrolled in the phase 2 trial at the highest dose. As prespecified, the 3 phase 1 patients and 29 phase 2 patients dosed identically at 1×10¹¹ viral particles (VPs) were included in this analysis. The study protocol was approved by institutional review boards and internal biosafety committees at enrolling sites, and all patients provided written informed consent.

Study Population

Full inclusion and exclusion criteria are included in the Supplemental Material. Patients aged 18–80 years with CCS Angina Scale Class II to IV angina despite optimal medical therapy including a minimum of 2 antianginal medications (to be continued throughout the trial), reversible myocardial ischemia, and lacking revascularization options (as assessed by a review committee consisting of independent cardiologists and cardiothoracic surgeons) were eligible.

Patients were required to have exercise-limiting angina between 90 and 540 seconds on modified Bruce protocol exercise treadmill testing and inducible ischemia on stress positron emission tomography (PET) imaging.

Gene Therapy Administration

Enrolled participants underwent open-label intramyocardial dosing of XC001 (1×10¹¹ VP) within 50 days of providing consent. Minithoracotomy was performed between the fifth and seventh intercostal spaces. XC001 was administered in 15 transepicardial 0.1-mL injections into the mid-myocardium using a 27-gauge 6.5-inch spinal needle. Each injection was separated by 1.5–2.0 cm, guided by areas of ischemia on PET and other imaging. Targeting of ischemic regions was guided by screening PET-CT imaging, other functional assessments, and known coronary anatomy and determined in advance during a presurgical staging meeting of the site surgeon, principal investigator, and a representative of the eligibility review committee.

End Points

Safety was assessed via adverse event (12 months), laboratory (6 months), and routine ECG monitoring (postprocedure). An independent data safety and monitoring committee adjudicated all grade 3 (severe) and grade 4 (life-threatening) serious adverse events (SAEs) for expectedness and relatedness to the procedure or drug. A clinical events committee independently adjudicated all potential major adverse cardiovascular events.

Exploratory efficacy end points included change from baseline to 3, 6, and 12 months in total exercise duration on standardized exercise treadmill test; time to ST depression in assessable patients; total myocardial perfusion deficit, myocardial defect extent difference, coronary flow reserve, and stress myocardial blood flow assessed on PET imaging; and angina symptoms assessed by CCS Angina Class (through 6 months), number of angina episodes and nitroglycerin use, and quality of life using the Seattle Angina Questionnaire.

Statistical Considerations

The primary goal was to assess the safety and explore the efficacy of transepicardial delivery of XC001 across an array of end points. No formal efficacy analysis was prespecified, and efficacy end points were assessed for descriptive purposes and hypothesis generation. Changes in efficacy parameters are described as means with 95% CIs based on t distributions and reflect changes in individual patient data.

RESULTS

Enrollment

Including the final cohort of the dose-escalation phase 1 portion of the trial (n=3), a total of 32 patients (of 65 screened) were treated at 13 sites between March 2021 and July 2022, with complete follow-up in all patients (Figure 1). The most common reasons for exclusion were lack of angina limitation ≤9 minutes on initial exercise tolerance test evaluation (n=12), hemoglobin A1C >8.5 (n=6), and no demonstrable ischemia on stress PET imaging (n=5). One patient was screened and underwent thoracotomy but was not treated due to ischemic complications during surgery before study drug administration. Specifically, this patient had a single patent bypass graft and had been taken off antithrombotic therapy before surgery. Following thoracotomy and during epicardial exposure, manipulation of the graft resulted in clinical instability and graft occlusion requiring extracorporeal life support and emergent percutaneous coronary intervention. As this patient was not dosed, per protocol this patient was not included in the formal safety/efficacy analysis and was followed through hospital discharge.

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.

The mean (SD) and median ages of treated patients were 64.4 (8.5) and 64 (range, 39–80) years (Table 1). Most were White (n=27 [84%]) and male (n=21 [66%]). All patients had undergone prior revascularization, with 88% having undergone prior percutaneous coronary intervention and 75% prior coronary artery bypass graft surgery. The mean (SD) and median left ventricular ejection fraction were 54.3% and 56%.

Table 1.

Baseline Demographics and Characteristics

Patients were well managed medically; 90% were on β-blockers, 94% on nitrates, 45% on calcium channel blockers, 81% on ranolazine, and 94% on lipid-lowering therapy (Table 2). Medical therapy remained stable during the follow-up period (Table S1).

Table 2.

Baseline Medication Use

All patients who were dosed successfully completed treatment. The median number of injections was 15 (14–15). The mean (SD) and median duration of the injection process were 10.6 (5.7) and 9.0 (4–30) minutes. The mean and median hospital stays were 4.5 and 6 (1–14) nights. Seventeen (53%) of the 32 enrolled in-patients were discharged after 2 (n=8) or 3 (n=9) nights.

Safety

Serious Adverse Events

As previously noted, 1 patient undergoing thoracotomy was not dosed due to intraoperative complications and was followed to hospital discharge.

No SAEs were determined to be related to the study drug, and no systemic constitutional or off-target effects related to the drug were observed. Six possible immunologic adverse events (AEs) were noted by investigators, with 2 grade 1 AEs (lip swelling and fever) felt possibly related to the study drug (Table S2). Lip swelling occurred intermittently and resolved spontaneously and was first reported on day 32 after treatment. The fever occurred on day 9 after surgery and resolved by day 14.

Twenty SAEs in 13 (41%) patients were possibly related to the surgical procedure, all of which were expected and resolved (Table S3). Seven SAEs in 5 patients were cardiovascular, including 2 patients with pericardial effusion, 1 with ventricular tachycardia, and 1 with atrial tachycardia. There was 1 postoperative wound infection. The most common SAE postoperatively was pleural effusion (n=6), 1 of which developed into a pneumothorax. No unexpected SAEs were reported.

Fifty-seven SAEs were observed in 20 of 32 dosed patients (63%) over the 12-month follow-up period. One noncardiovascular death occurred 2 months after dosing due to respiratory failure and COVID-19 infection deemed unrelated to the procedure or study drug. Seven patients (22%) suffered a total of 21 grade 3 or 4 (severe) SAEs (Table S4).

Major Adverse Cardiac Events

A total of 19 major adverse cardiovascular events in 10 patients were adjudicated by the clinical events committee. Four occurred in patients during the initial hospital stay (2 heart failure events and 2 myocardial injury events). During 12 months of follow-up, there were 3 myocardial infarctions in 3 patients (2 type I and 1 type II), 2 admissions for congestive heart failure in 2 patients, and 10 other cardiovascular hospitalizations in 5 patients (7 for chest pain not meeting myocardial infarction or unstable angina criteria, 2 transient ischemic attacks, and 1 pericarditis), which were adjudicated.

Arrhythmias

One patient with lamin A/C gene-associated cardiomyopathy (ejection fraction, 50%) had 2 episodes of ventricular tachycardia; the first was 9 days after surgery, which was asymptomatic and successfully treated with a previously implanted cardioverter defibrillator without drug therapy. A second episode 2 months after surgery occurred during a hospitalization for ultimately fatal COVID-19 pneumonia with severe hypoxia. The former was deemed possibly related to the procedure and the latter unrelated to the study drug or procedure. Two episodes of atrial fibrillation on days 4 and 9 after the procedure were related to the procedure and resolved within 3 days of onset.

Laboratory Safety Evaluation and ECG Monitoring

As expected, there was a procedural-related decrease in hemoglobin that fully recovered by months 3 to 6 (Figure S1). Cardiac troponin values were increased as expected in the periprocedural period (Figure S2). Circulating VEGF levels rose transiently after administration of the vector but returned to normal or below normal by the first-month follow-up visit (Figure S3). No other effects on chemistries or liver function tests were observed. Routine ECG analysis in all patients postoperatively was most consistent with postoperative pericardial inflammation (Supplemental Appendix).

Efficacy Analyses

Total Exercise Duration

At baseline (n=31), 3 (n=31), 6 (n=30), and 12 (n=28) months, patients exercised for a mean (SD) of 359.9 (105.6), 448.2 (168.5), 449.2 (175.9), and 477.6 (174.7) seconds (Figure 2A and 2B). Improvement in exercise time was 88.3 (95% CI, 37.1–139.5), 84.5 (95% CI, 31.4–134.9), and 115.5 (95% CI, 59.1–171.9) seconds at 3, 6, and 12 months compared with baseline (Figure 2B).

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.

An objective measure of ischemia during exercise is the time to development of ST depression during exercise tolerance testing. Mean (SD) time to onset of 1-mm ST depression in those with interpretable ECGs was 293.5 (121.2 [n=11]), 382.7 (175.1 [n=7]), 381.2 (171.6 [n=9]), and 433.1 (58.2 [n=8]) seconds at baseline, 3, 6, and 12 months. The improvement in time to ST depression was 105.2 (95% CI, –27.9 to 238.3 [n=6]), 113.6 (95% CI, 28.8–198.4 [n=8]), and 103.1 (95% CI, 26.7–179.5 [n=8]) seconds at 3, 6, and 12 months, respectively (Figure 3A and 3B).

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.

Myocardial Perfusion

The change in total myocardial perfusion deficit for ischemic nonseptal segments as measured by PET imaging was −10.2% (95% CI, +3.1% to −23.5%), −14.3% (95% CI, −2.8% to −25.7%), and −10.2% (95% CI, +0.8% to −21.2%) at 3, 6, and 12 months compared with baseline (Figure 4). Other measures of ischemia and coronary flow showed similar qualitative results (Table S5).

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.

Angina Symptoms and Quality of Life

CCS Angina Class decreased from a median of 3 at baseline to 2 at 3 and 6 months (Figure 5). Twenty-three of 31 (74%) patients improved by at least 1 category at months 3 and 25 of 31 (81%) improved by at least 1 category at month 6; 13 of 30 patients (43%) had no angina with ordinary activity at 6 months.

Figure 5.

Canadian Cardiovascular Society (CCS) Angina Class by visit baseline to 6 mo.

Angina frequency measured during 14-day diary collections decreased by −7.7 (95% CI, −4.1 to −11.3), −6.6 (95% CI, −3.5 to −9.7), and −8.8 (95% CI, −4.6 to −13.0) episodes at 3, 6, and 12 months from a mean (SD) of 12.2 (12.5) episodes at baseline to 5.2 (7.3) at 3 months, 5.1 (7.8) at 6 months, and 2.7 (4.8) at 12 months (Figure S4). Nitroglycerin use during this period decreased by −4.4 (95% CI, −2.0 to −6.8), −4.2 (95% CI, −1.4 to −7.0), and −4.7 (95% CI, −0.5 to −9.0) doses at 3, 6, and 12 months, respectively, compared with baseline (Figure S5).

The mean (SD) Seattle Angina Questionnaire angina frequency score improved from 41.3 (24.3) to 67.7 (26.4) at 3 months and 67.4 (25.6) at 6 months for a mean difference of 27.0 (95% CI, 16.6–37.4) and 26.1 (95% CI, 16.3–35.9). Other Seattle Angina Questionnaire domains including physical limitation, angina stability, treatment satisfaction, and quality of life scale showed similar trends toward improvements (Table S6).

DISCUSSION

In 32 patients with NORA and CCS class II to IV angina, transepicardial administration of 1×10¹¹ VP of the novel proangiogenic gene therapy XC001 via surgical minithoracotomy demonstrated no safety concerns related to the study drug itself; however, expected and temporary SAEs related to surgical drug delivery were observed. In this open-label study, administration of XC001 resulted in improvements in exercise time, myocardial perfusion, and angina symptoms as assessed using a variety of measures, an effect that was durable for at least 12 months.

Safety

The phase 1 portion of this trial demonstrated no immediate safety signal associated with dose escalation from 1×10⁹ to 1×10¹¹ VPs (19), achieving a 2.5–5-fold higher dose than previous VEGF vector studies.¹⁵ In phase 2, no SAEs or grade 3 to 4 AEs were identified by the independent data safety and monitoring committee as related to the study drug. No adverse events commonly observed with high-dose systemic adenoviral administration including transaminitis or other constitutional or off-target effects related to the drug were observed, nor were any direct cardiac toxicity or proarrhythmia detected, supporting the safety profile of this gene therapy vector as locally delivered.

During follow-up, cardiovascular admissions occurred in 9 (28%) patients, with 3 myocardial infarctions and 7 hospitalizations for chest pain or angina (in 3 patients). For context, in a modeling exercise of patients that may be eligible for NORA trials from the Duke Cardiovascular Databank, 3-year major adverse cardiovascular event rates were 52%,²¹ while 2-year rates of 30% to 38% were reported in treated and placebo groups enrolled in the Baxter CD34⁺ cell program.²² Similar to the pattern observed in EXACT, these event rates were driven by presentation with chest pain, with myocardial infarction/stroke/death as rare events.

Compared with systemic or regional administration such as intravenous and intracoronary approaches, intramyocardial delivery results in the highest local retention of product^23–25 and, in some studies, has translated to improved clinical efficacy.²⁵ A surgical minithoracotomy approach allows the administration of drug under direct visualization, ensuring transfer and retention in the target myocardium and minimizing the risk of inadequate drug delivery; however, it was associated with expected complications.

Catheter-based transendocardial delivery is a potentially safer alternative that may additionally allow delivery to the left ventricular septum. In a study utilizing both methodologies, catheter delivery resulted in fewer periprocedural AEs compared with surgical delivery but similar rates of AEs after 6 days.²⁶ Importantly, percutaneous delivery is not benign as ventricular perforation and death have been reported.^14,27 Additionally, without direct visualization, concerns about drug delivery and retention remain potentially significant confounders.^24,28 The observed risks associated with surgery in this trial have important implications to both define the risk/benefit profile of this approach and inform future partially or fully blinded studies.

Efficacy

EXACT was a single-arm, open-label trial. The preliminary efficacy end points presented are descriptive, and the study was not designed or powered to formally assess benefit. Nonetheless, consistent and correlative improvement on various assessments of patient functional capacity, well-being, and objective myocardial ischemia warrant consideration.

First, the benefit observed on total exercise duration, the most common efficacy measure reported in the NORA literature, is not only clinically meaningful but exceeds what might be the result of expectation bias or a placebo effect. A patient-level analysis of over 300 patients with NORA with similar enrollment criteria randomized in 3 double-blind, placebo-controlled trials demonstrated an improvement of 31–50 seconds in placebo patients utilizing the same modified Bruce protocols that were utilized in EXACT.²² The observed improvement in total exercise duration of 85–115 seconds in EXACT compares favorably, especially given that the surgical approach may result in a longer period of initial inactivity and recovery compared with the percutaneous approach utilized in all of the cell therapy trials. The degree of benefit also exceeds that observed in the REVASC trial (Randomized Evaluation of VEGF for Angiogenesis), which also utilized open-label surgical delivery,¹⁵ supporting the preclinical optimization of this vector-gene construct to express multiple VEGF isoforms, as well as the 2.5-fold increase in dose.

Similarly, the effect on angina frequency (decreases of 6.6–8.8 angina episodes per 2 weeks) compares favorably with antianginal medications, such as ranolazine, which decreased angina by 0.5 episodes per week compared with placebo,²⁹ and enhanced external counterpulsation, which improved angina by about 0.2 episodes per day.³⁰

Second, the reduction in ischemic burden utilizing objective blinded assessment of myocardial ischemia by stress PET imaging is notable, as previous attempts, such as the REVASC and NORTHERN (NOGA Angiogenesis Revascularization Therapy: Assessment by Radionuclide Imaging) trials, failed to corroborate subjective benefit with objective improvement in myocardial perfusion.^13,15 This may suggest that XC001 is a more potent angiogenic agent, or PET is a superior imaging modality for the measurement of ischemic burden in NORA. A phase 1/2a trial using adenoviral delivery of a more promiscuous member of the VEGF family, VEGF-D, in NORA demonstrated mild improvements in myocardial perfusion via PET at 1 year.³¹ Given the open-label design of EXACT, this observation on objective measures of ischemia is important to establish the mechanism and support the supposition that a biological effect underpins the clinical benefit.

Finally, we observed durable effects on both objective and subjective measures for at least 12 months after a single treatment of XC001. Few angiogenic gene- and cell-based therapies have been evaluated beyond 1 year although CD34+ cells improved some outcomes for up to 2 years.³² This observation is encouraging, suggesting that improvements in patient well-being in the short term will impart long-term benefits.

Limitations

EXACT is an open-label, single-arm study. The lack of a placebo group limits conclusions about efficacy; nonetheless, we think that the totality of the data on both subjective and objective assessments supports a biological effect. Notably, other therapies (eg, transmyocardial revascularization) for unmet medical needs such as NORA that could not be evaluated in a blinded fashion were developed clinically based on similar trial designs.^33,34

The number of patients enrolled was small, and no primary end point was prespecified for efficacy; thus, our findings should be considered exploratory and supportive of the need for further investigation.

Outcomes are reported to 12 months. The findings within this timeframe are reassuring but cannot inform long-term benefits. Reassuringly, transient expression of the gene construct would argue against any long-term risk, and prior studies have reported safety for up to 12 years.^35,36

No systematic assessment of arrhythmias not resulting in an AE event was performed. While this study included significantly more women than earlier studies, we acknowledge that most participants were men and White. Ethnicity was generally not reported in prior trials. Future studies will aim to better reflect the diversity of patients with NORA and improve the generalizability of the findings.

Conclusions

In 32 patients with NORA, transepicardial injection of 1×10¹¹ VP of XC001 was well tolerated with no SAEs related to the study drug but was associated with expected surgical morbidity. Increases in exercise duration, decreases in ischemia on imaging, and benefits on angina burden suggest therapeutic angiogenesis leading to durable clinical improvements to 12 months. These findings warrant further clinical investigation in this patient population with limited treatment options. The safety profile observed with surgical delivery in this trial may inform future trial designs.

ARTICLE INFORMATION

Acknowledgments

The authors are grateful to the following committee members for their service: Clinical Events Committee: Bernard Chaitman (chair), David Waters, and Lee Fleisher; Independent Data Monitoring Committee: Douglas Weaver (chair), Michael Mack, and Marc Jolicoeur; and Eligibility Review Committee: Carl Pepine, David Latter, Geoffrey Answini, E. Magnus Ohman, Adam Williams, and Jay Traverse.

Sources of Funding

The EXACT trial (Epicardial Delivery of XC001 Gene Therapy for Refractory Angina Coronary Treatment) was supported by XyloCor Therapeutics, Chesterbrook, PA.

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.

Supplemental Material

EXACT Investigators

Supplemental Methods

Supplemental Results

Figures S1–S5

Tables S1–S6

Supplementary Material

hcv-17-e014054-s001.pdf ^{(671.4KB, pdf)}