Safety and Preliminary Effectiveness Study of Mesenchymal Stem Cells, HeXell-2020, in Patients With Stable Coronary Artery Disease

Coronary artery disease (CAD) is the most common form of heart disease and a leading cause of mortality worldwide. It is a manifestation of myocardial ischemia, a condition resulting from insufficient blood flow to the myocardial tissue. CAD occurs when the coronary arteries become progressively narrowed and stiffened due to atherosclerosis-the accumulation of cholesterol, lipids, and plaque along the inner arterial walls. Narrowed blood vessels and increased shear stress may contribute to plaque destabilization, vessel outward remodeling, as well as increased pro-inflammatory cytokines production, leading to advanced atherosclerosis. As the disease advances, this narrowing impairs coronary blood flow, causing permanent heart damage. Over time, CAD can progressively weaken the heart muscle, contributing to heart failure.

Mesenchymal stem cells (MSC) become a potential therapeutic tool for treating cardiovascular diseases due to their capabilities in tissue repair, anti-oxidation, immune-modulation and anti-inflammatory. Intravenous infusion of HeXell-2020, the allogenic umbilical cord MSC, in an atherosclerotic rat model improved blood glucose tolerance, LDL cholesterol levels, and the severity of aortic arch stenosis. Additionally, results further demonstrated significant improvement in atherosclerotic lesions caused by fat deposition at the aortic arch and descending aorta after the treatment. Although the mode of actions of MSCs in CADs have not been fully elucidated, these nonclinical results, together with the established immunomodulatory and anti-inflammatory effects of MSCs, are supportive for the rationale of HeXell-2020 in treating patients with CAD.

This study is composed of two phases, Phase I and Phase IIa. In Phase I, two cohorts were designed following traditional 3+3 scheme to define recommended phae 2 dose (RP2D). In Phase IIa, 22 evaluable subjects are estimated. Safety and efficacy will be evaluated through follow-up visit over one year.

Inclusion criteria

• Subject who is able to understand the nature of this study and accepts to enter the study by signing written informed consent
• Male or female who are aged between 18 and 75 years old on date of consent
• Patient without LV thrombus or ventricular aneurysm documented by echocardiography at screening
• Patient having a diagnosis of CAD caused by ≥ 50% stenosis of at least 1 major or larger epicardial coronary artery (target vessel ≥ 2 mm in diameter without in-stent restenosis) documented by imaging studies within 12 months prior to the date of dosing. If the stenosis results are derived from CCTA, the examination time of CCTA should be at least 6 months prior to screening.
• Patient with Canadian Cardiovascular Society (CCS) Class I, II, or III angina pectoris and received optimal, stable, medical therapy (e.g., anticoagulants therapy, β-blockers, calcium channel blockers, nitrates, ranolazine) per country specific treatment guidelines for at least 4 weeks prior to the date of screening, if prescribed
• Patients with stable hemodynamic parameters and adequate pulmonary function, defined as systolic pressure ≥ 90 mmHg and < 150 mmHg, and heart rate > 50/min and <110/min on at least 2 consecutive readings, at screening and baseline (before dosing)
• Patient's medical history shows no history of organ or cell transplant rejection, or suspected contraindication to HeXell-2020 including the components (penicillin and streptomycin).
• Female subjects show negative pregnancy test results within 30 days prior to the first study treatment.
• All male patients and female patients with child-bearing potential (between puberty and 2 years after menopause) should use at least any one of the appropriate contraception methods shown below, during dosing and for at least 4 weeks after stopping study treatment.

• Total abstinence (when this is in line with the preferred and usual lifestyle of the subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
• Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy), total hysterectomy, or tubal ligation at least 6 weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment.
• Male sterilization (at least 6 months prior to screening). For female subjects on the study, the vasectomized male partner should be the sole partner for that subject.
• Combination of any two of the following listed methods: (d.1+d.2 or d.1+d.3, or d.2+d.3):

d.1. Use of oral, injected or implanted hormonal methods of contraception or other forms of hormonal contraception that have comparable efficacy (failure rate <1%), for example hormone vaginal ring or transdermal hormone contraception. Please refer to 8.2 Prohibited Treatments for detailed information.

d.2. Placement of an intrauterine device (IUD) or intrauterine system (IUS). d.3. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault caps).

Exclusion criteria

• Subject had participated in investigational drug trials and took any investigational drugs within 28 days prior to the first treatment.
• Patient is schedule to [or has received within 180 days prior to Screening Visit] undergo the following coronary revascularization throughout the study period:

• Coronary artery bypass grafting (CABG)
• Valve repair/replacement
• Cardiac resynchronization therapy (CRT) device
• Patient is scheduled to undergo percutaneous coronary intervention (PCI) during the trial before screening.
• Patient with high-risk or unstable acute coronary syndrome (e.g., myocardial infarction), major cardiovascular surgery (e.g., coronary valve replacement, or aortic aneurysm surgery), stroke, transient ischemic attack (TIA), carotid surgery, pulmonary embolism, or deep venous thrombosis in past 90 days prior to the date of screening
• Patient with evidence of medical condition as follows,

• Acute cardiac decompensation
• Congenital heart disease
• Significantly uncorrected valvular heart disease
• Malignant arrhythmia in the absence of a defibrillator
• Severe pulmonary disease
• Essential thrombocytosis
• Anti-phospholipid syndrome
• Other hypercoagulable disorders (e.g., disseminated intravascular coagulation, Factor V Leiden)
• Patient with poorly controlled diabetes mellitus (HbA1c >8%) or a known history or present evidence of conditions that may affect study assessments (e.g., currently receiving chemotherapeutic or immunosuppressant agents, or have received prior radiation therapy to the chest)
• Patient carry history of malignancy of any organ system (other than curatively treated localized basal or squamous cell carcinoma of the skin, cervical carcinoma in situ, or superficial bladder cancer) within 5 years prior to study entry.
• Subject had a history of drug abuse or alcohol abuse according to the Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-5) criteria.
• Evidence of inadequate hematopoietic, hepatic, and renal function as determined by any one of the following laboratory requirements:

• Hemoglobin <8.5 mg/dL
• Estimated glomerular filtration rate (eGFR) <45 mL/min/1.73 m2 as calculated by the Modified in Diet in Renal Disease (MDRD) formula or requiring dialysis prior to study dosing.
• Total bilirubin >2× upper limit of normal (ULN)
• Alanine aminotransferase (ALT) >3× ULN
• Patient with HIV, active HBV, or active HCV infections
• Subject who is pregnant or lactating
• Subject with underlying medical, mental or psychological conditions that would impair the treatment compliance, unable to undergo study-required tests/scans for any reason, or in the opinion of the investigator would not permit to participate in the study