A 26-Week (with 26 Week Extension) Randomized, Multi-Center, Double-Blind Phase 2 Study to Evaluate the Efficacy and Safety of XC001 Gene Therapy as an Adjunct to Coronary Artery Bypass Graft Surgery for Patients with Symptomatic Coronary Artery Disease with Left Ventricular Dysfunction at Risk for Incomplete Revascularization

The primary objective of this study is to evaluate the effects of XC001 versus placebo on residual ischemic burden in participants at risk for incomplete revascularization by coronary artery bypass graft (CABG) surgery as quantified by cardiac cardiovascular magnetic resonance imaging (CMR) with adenosine or regadenoson stress perfusion, including ischemic burden and left ventricular (LV) contractile function. This primary endpoint is clinically relevant as incomplete revascularization following CABG remains associated with persistent myocardial ischemia and impaired ventricular function, which may contribute to adverse cardiovascular outcomes in patients with coronary artery disease and left ventricular dysfunction.

The secondary objective is to evaluate the effect of XC001 versus placebo on CMR variables including cardiac volumes, myocardial scar volume, global and regional strain (longitudinal, circumferential, radial), and left atrial (LA) volume and function (contractile, reservoir, total), as a measurement of diastolic LV function.

This clinical trial enrolled a total of **26 participants** with **chronic angina** and **left ventricular dysfunction** secondary to **coronary artery disease** who were deemed at high risk for incomplete revascularization via **coronary artery bypass grafting (CABG)**. The study population included both **male and female** participants aged **18 to 80 years**. Participants presented with symptomatic **multivessel epicardial coronary artery disease** and were clinically indicated for elective, stand-alone, on-pump CABG following multidisciplinary cardiovascular team assessment. All participants had **left ventricular ejection fraction (LVEF)** ranging from **25% to 50%** as measured by standard quantitative imaging techniques. The trial population was selected based on the presence of non-acute rest or exertional anginal symptoms or angina-equivalent complaints, typically exertional dyspnea, with severity equivalent to **Canadian Cardiovascular Society (CCS) Angina Class 2-4**. Anatomical findings on **coronary angiography** or stress imaging indicated increased likelihood of incomplete revascularization post-CABG, including features such as diffuse distal coronary artery atherosclerotic disease, small coronary target vessels unsuitable for grafting, multiple segmental lesions, or ungraftable vessels due to failed stents. Participants were required to use highly effective contraception methods for six months following the study procedure. The selection process involved verification by an independent Eligibility Review Committee to confirm high-risk status for incomplete revascularization.

This is a randomized, multi-center, double-blind, placebo-controlled Phase 2 clinical trial designed to evaluate the efficacy and safety of **XC001** gene therapy as an adjunct to **coronary artery bypass graft surgery** in participants with symptomatic **coronary artery disease** and **left ventricular dysfunction** who are at high risk for incomplete revascularization. The study investigates the effects of XC001, containing **encoberminogene rezmadenovec**, a structurally diverse substance administered via **intracardiac use** as a solution for injection, compared to placebo. The investigational medicinal product is administered as a single dose of 2.2 milliliters during the surgical procedure. Auxiliary medicinal products used in the trial include **gadobutrol** (solution for injection in pre-filled syringe, administered via injection), **adenosine** (solution for injection/infusion, administered via infusion), and **regadenoson** (solution for injection, administered via injection) for cardiac imaging purposes, along with Diluent A195 as placebo. The trial employs **cardiovascular magnetic resonance imaging** with adenosine or regadenoson stress perfusion to assess residual **ischemic burden** and left ventricular contractile function.

The primary objective is to evaluate the effects of XC001 versus placebo on residual ischemic burden in participants at risk for incomplete revascularization by coronary artery bypass graft surgery, as quantified by cardiac cardiovascular magnetic resonance imaging, including ischemic burden and left ventricular contractile function. The primary endpoint is the change from baseline (post-CABG at Day 4-6) in treated segments comparing XC001 and placebo in CMR imaging parameters at Weeks 12 and 26 post-surgery, specifically the proportion of qualifying segments that improve as determined by myocardial ischemic burden. Secondary endpoints include changes from baseline in treated segments comparing XC001 and placebo in CMR parameters at 12 and 26 weeks, as well as at 52 weeks during the extension period.

The total trial duration is estimated to span from September 2025 to September 2027, with recruitment commencing in September 2025. The study consists of a 26-week primary evaluation period followed by a 26-week extension period, resulting in a total participant involvement of approximately 52 weeks. The sequence of study visits includes a screening and eligibility assessment phase, during which participants undergo comprehensive evaluation including coronary angiography and stress imaging. Following enrollment and confirmation of eligibility by an independent Eligibility Review Committee, participants undergo the scheduled coronary artery bypass graft surgery, during which the investigational medicinal product or placebo is administered. A baseline cardiovascular magnetic resonance imaging assessment is performed post-operatively at Day 4-6 following the CABG procedure to establish the post-surgical baseline for efficacy evaluation.

Follow-up visits are conducted at predetermined intervals throughout the study period. Key assessment time points include Week 12 and Week 26 post-surgery during the primary evaluation period, at which cardiovascular magnetic resonance imaging is performed to assess changes in myocardial ischemic burden and left ventricular function. Participants who complete the initial 26-week period continue into the extension phase, with an additional assessment at Week 52 post-surgery. Throughout the study period, participants undergo safety monitoring, clinical assessments, and imaging procedures to evaluate treatment efficacy and identify any adverse events. The end-of-study visit occurs at Week 52 for participants completing the extension period, during which final efficacy and safety assessments are conducted.

Participant involvement extends for the full 52-week duration for those completing both the primary and extension periods. Conditions that may lead to early termination from the study include withdrawal of informed consent, significant protocol violations, adverse events requiring discontinuation as determined by the investigator, pregnancy, loss to follow-up, or administrative reasons. Participants who discontinue early are encouraged to complete safety follow-up assessments as feasible. The trial specifically enrolls males and females aged 18 to 80 years with symptomatic multivessel epicardial coronary artery disease and left ventricular ejection fraction between 25% and 50% who are clinically indicated for elective, stand-alone, on-pump coronary artery bypass graft surgery and are at high risk for incomplete revascularization. Participants must have anatomical findings on coronary angiography and stress imaging that increase the likelihood of incomplete revascularization post-CABG, supplying left ventricular segments determined to be ischemic on pre-operative stress imaging. All participants capable of procreation must agree to use highly effective contraception methods for 6 months following the study procedure.

The experimental treatment consists of **XC001** (**encoberminogene rezmadenovec**), a **gene therapy** product containing adenovirus serotype 5 with coding sequences for multiple isoforms of human vascular endothelial growth factor (VEGF-A). XC001 is formulated as a **solution for injection** and is administered via **intracardiac route** at a maximum dose of **2.2 milliliters** per treatment session. The total treatment period is **1 day**, with participants receiving a single administration of the investigational medicinal product during **coronary artery bypass graft surgery**. The maximum total dose is **2.2 milliliters**. This product represents an **in vivo gene transfer** therapy and is classified as an advanced therapy medicinal product.

The control group receives **Diluent A195**, which serves as the **placebo** in this double-blind study. The placebo is administered in the same manner as the active treatment to maintain blinding of participants and investigators throughout the trial.

**Gadobutrol** is utilized as an auxiliary medicinal product for diagnostic imaging purposes. This contrast agent is formulated as a **solution for injection in pre-filled syringe** and is administered via **injection**. The maximum daily dose is **0.15 millimoles per kilogram**, with a maximum total dose of **0.6 millimoles per kilogram** over a treatment period of up to **4 days**. Gadobutrol is employed during **cardiovascular magnetic resonance imaging** procedures to assess cardiac perfusion and ischemic burden.

**Adenosine** serves as an auxiliary medicinal product used as a pharmacological stress agent during cardiac imaging. The product is formulated as a **solution for injection/infusion** and is administered via **infusion**. The maximum daily dose is **8.4 milligrams per kilogram per hour**, with a maximum total dose of **33.6 milligrams per kilogram per hour** over a period of up to **4 days**. Adenosine is used to induce coronary vasodilation during stress perfusion cardiovascular magnetic resonance imaging to evaluate myocardial ischemia.

**Regadenoson** is an alternative auxiliary medicinal product that may be used as a pharmacological stress agent. This product is formulated as a **solution for injection** and is administered via **injection**. The maximum daily dose is **400 micrograms**, with a maximum total dose of **1600 micrograms** over a treatment period of up to **4 days**. Regadenoson serves as an alternative to adenosine for inducing coronary vasodilation during stress perfusion cardiovascular magnetic resonance imaging procedures to assess residual ischemic burden and left ventricular contractile function.

Efficacy will be assessed by evaluating changes from baseline in treated myocardial segments using cardiovascular magnetic resonance imaging (CMR). The primary endpoint is the change from baseline, defined as post-coronary artery bypass graft surgery at Day 4-6, in treated segments comparing XC001 and placebo in CMR imaging parameters at Week 12 and Week 26 post-surgery. At the participant level, the primary endpoint is the proportion of qualifying segments that demonstrate improvement at Week 12 and/or Week 26 as determined by myocardial ischemic burden. Secondary endpoints include changes from baseline in treated segments comparing XC001 and placebo in CMR parameters at Week 12, Week 26, and Week 52 during the extension period. Stress perfusion CMR will be performed using adenosine or regadenoson to quantify residual ischemic burden and assess left ventricular contractile function. The baseline CMR is defined as the analysis performed at Day 4-6 post-CABG surgery.