Safety and Tolerability Study of Mesenchymal Stem Cells, HeXell-2020, in Elderly Subjects With Mild to Moderate Frailty Syndrome

Frailty Syndrome (FS) is a complex clinical phenotype characterized by increased vulnerability and reduced physiological reserve resulting from progressive decline across multiple physiological systems. Clinically, FS is manifested by reduced grip strength, exhaustion, slower walking speed, low physical activity, and unintentional weight loss. This condition is associated with elevated oxidative stress, chronic inflammation, decreased muscle mass, and organ dysfunction, which collectively contribute to an increased risk of disability, hospitalization, and mortality.

The pharmacological efficacy of MSCs has been extensively investigated including the secretion of immunomodulatory molecules, antioxidative enzymes, pro-angiogenic growth factors, and anti-apoptotic agents that collectively target multiple pathological mechanisms underlying frailty syndrome. UC-MSCs also exert potent anti-apoptotic effects by upregulating the expression of anti-apoptotic protein and simultaneously downregulating cellular senescence and apoptosis.

The investigational Drug Product (DP), HeXell-2020, consists of allogeneic umbilical cord-derived mesenchymal stem cells (UC-MSCs) isolated from human Wharton's jelly, which is intended to treat patients with FS. A GLP-compliant eleven repeated-dose (once every 7 days) toxicity study (Study Number 21005IV01), in which three does levels (1.5 × 10e6, 1.5 × 10⁷, 7.5 × 10⁷ cells/kg/dose) of HeXell-2020 or vehicle control was administered to NOD/SCID mice, was conducted to evaluate toxicity, local tolerance, and biodistribution. During the observation period, most of the survived animals appeared normal in all control and treated groups after dosing. The MTD (maximum tolerated dose) of HeXell-2020 is determined to be 1.5 × 10⁷ cells/kg/dose for 11 doses.

In current in vivo studies, rodents were administered UC-MSCs, which effectively restored skeletal muscle function by modulating extracellular matrix composition, activating muscle satellite cells, promoting autophagy, and mitigating cellular senescence through down-regulation of intracellular senescence signaling pathways. These mechanisms led to improved muscle mass, strength, and physical performance, directly addressing core symptoms of frailty. MSCs were observed to promote angiogenesis and improve tissue perfusion by secreting angiogenic factors, thereby facilitating capillary network formation and accelerating tissue regeneration.

This is a Phase I, open-label, dose-escalation study designed to evaluate the safety and tolerability of HeXell-2020 in elderly subjects with mild to moderate FS. Subjects aged 60 to 85 years will be enrolled. Up to 12 subjects will be sequentially allocated, and the study will follow a standard "3+3" dose-escalation design to determine the Maximum Feasible Dose (MFD). This study is designed to evaluate the safety of human umbilical cord-derived mesenchymal stem cells (UC-MSCs) product HeXell-2020 intravenous infusion in frail adults prior to further clinical development.

Inclusion criteria

Subjects will be eligible for enrollment in the study only if they meet ALL the following criteria at time of Screening:

• Subjects aged ≥ 60 through ≤ 85 years old.
• Subjects with clinical diagnosis of mild to moderate Frailty Syndrome as assessed by the Investigator with a Clinical Frailty Scale score between 4 to 6.
• Subject will not start any new treatment for this condition during the study.
• Subjects with body weight between 40 to 90 kg.
• Subject is willing to provide written informed consent to participate in the study after reading the informed consent form and the information provided.

Exclusion criteria

Subjects meeting ANY of the following criteria at time of Screening will be excluded from enrollment:

• Subjects unwilling or unable to perform any of the assessments required by endpoint analysis.
• Subjects who have a diagnosis of any disabling neurologic disorder including, but not limited to: Parkinson's disease, Amyotrophic Lateral Sclerosis, multiple sclerosis, stroke or dementia.
• Subjects who have a score on the Mini-Mental State Examination (MMSE) of 24 or below.
• Subjects who have a significant comorbid medical condition(s) including, but not limited to:

• Severe kidney disease requiring hemodialysis or peritoneal dialysis;
• Advanced liver disease such as severe liver cirrhosis;
• Severe congestive heart failure (NYHA class 3 and 4);
• Severe pulmonary dysfunction, including severe chronic obstructive pulmonary disease stage III or IV (Gold classification)
• Subjects who have a clinical history of malignancy within 5 years (i.e., patients with prior malignancy must be disease free for 5 years), except curatively-treated basal cell carcinoma or in situ carcinomas.
• Subjects using chronic immunosuppressant therapy, including corticosteroids (> 5 mg/day of prednisone, or equivalent), or TNF-alpha antagonists.
• Subjects on chronic immunosuppressive transplant therapy.
• Subjects who have participated in another clinical study of new investigational therapies within 6 months prior to screening.
• Subjects who have received any other stem cell therapy within 12 months prior to screening.
• Subjects with known allergy or hypersensitivity to any component of the formulation and cellular therapies (i.e., penicillin or streptomycin).
• Subjects who have a history of drug or alcohol abuse within the past 3 years.
• Subjects who are known to be infected with HIV.
• Subjects currently in hospital stay.
• Subjects who have a significant illness as judged by principal investigator (PI) including, but not limited to:

• Psychiatric illness
• Uncontrolled hypertension or hypotension
• Unstable cardiac arrhythmia
• Active Hepatitis B, Hepatitis C infections
• Subjects who have any condition that in the opinion of the Principal Investigator limits lifespan to < 1 year.
• Subjects who have any other condition that, in the opinion of the investigator, may compromise the safety or compliance of the patient or preclude successful completion of the study.