Safety and Preliminary Efficacy of NXL-001 in Patients with Ischemic Stroke

Safety and Preliminary Efficacy of NXL-001 in Patients with Ischemic Stroke

This is a single-arm, open-label, single center, dose-escalation exploratory clinical study to evaluate the safety and tolerability of a single intracerebral injection of NXL-001, a NeuroD1 base gene therapy, in patients with chronic neuronal deficits from ischemic stroke.

The death of neurons after stroke is the direct cause of brain function loss, and the difficulty of neurons to regenerate themselves in the adult brain is an important reason for the lack of effective treatment for stroke. Replacing the lost neurons and then reconstructing the functional connectivity between neurons is the key to improving stroke symptoms. NXL-001 is a gene therapy, using an AAV9 (adeno-associated virus 9) vector to deliver and express the neurodevelopmental transcription factor NeuroD1 to directly convert astrocytes into functional neurons. NXL-001 has been shown to regenerate neurons and improve motor function when administered in animal models of stroke. The primary objective of this single-arm, open-label, single center, dose-escalation study is to evaluate the safety and tolerability of intracerebral stereotactic injection of NXL-001. The secondary objective is to preliminarily evaluate the efficacy of NXL-001 in patients with chronic neuronal deficits from ischemic stroke and to determine its safe and effective dose range. This dose escalation study involves three cohorts, with 3 subjects in each group to receive a single stereo-tactically intracerebral injection of NXL-001 at escalating doses.

Inclusion Criteria:

• Age 40-75 years, inclusive, gender is not limited.
• Clinical diagnosis of ischemic stroke confirmed by neuro-imaging（CT , MRI，et al）.
• 2-4 months after the onset of ischemic stroke.
• MRI scan shows that the stroke lesion is 20-80ml in size, with cerebral motor cortex injury, and DTI shows corticospinal tract injury.
• Persisting moderate to severe motor function impairment due to stroke after standardized and guide-recommended rehabilitation therapy, characterized by baseline NIHSS score of 6-20 points, and a motor score of 3-4 on the affected upper or lower limb.
• Expected survival ≥ 12 months.
• The patient or his/her legal representative clearly understands, voluntarily participates in the study and signs the informed consent form.
• The subject is willing and able to return for follow-up visits as required by the trial protocol.
• Able to undergo rehabilitation training and treatment;
• Male and female subjects participating in the clinical study must agree to use an adequate birth control method for at least 6 months after administration

Exclusion Criteria:

• Motor deficit due to ischemic stroke of posterior circulation.
• Motor deficit due to any other causes.
• History of epilepsy.
• History of encephalitis, meningitis, multiple sclerosis or other central nervous system infections.
• History of intracranial hemorrhage and subarachnoid hemorrhage.
• History of severe head trauma within the past 5 years.
• Any contraindications to MRI scanning (such as implanted pacemaker, infusion pump etc.).
• Serum anti-AAV9 antibody titers ≥ 1:100
• History of malignant tumors within 5 years before screening (except for adequately treated cervical carcinoma in situ, papillary thyroid cancer, basal cell or squamous epithelial cell skin cancer, localized prostate cancer after radical surgery, and breast ductal carcinoma in situ).
• Active infections, including but not limited to human immunodeficiency virus (HIV), hepatitis A, B or C, syphilis, etc.
• Received any investigational drugs within 3 months (or 5 half-lives of the investigational drug, whichever is longer) of initial screening.
• Received any other cell and/or gene therapy for stroke.
• Requirement for anticoagulants.
• Intermittent use of oral anti-spasticity medications (stop/start date from 1-month prior-to and 3-month post- NXL-001 administration). Use of oral anti-spasticity medications are acceptable if they have been taken regularly for at least one month prior to NXL-001 administration).
• Pregnant or lactating female subjects.
• Insufficient reserved functions of liver, kidney and bone marrow: Neutrophil count <1,500/mm 3 ; platelets <100, 000/mm 3 ; hemoglobin <9.0 g/dL; serum creatinine >1.5 times the upper limit of normal range (ULN) ; renal function eGFR < 60mL/min/ 1.73m2 ; Bilirubin, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) >2.5 times ULN; activated partial prothrombin time ( APTT ) or international normalized ratio ( INR ) >1.3 times ULN.
• Poorly controlled illness judged by the investigator at screening, including cardiovascular system (decompensated heart failure (NYHA classification III and IV), unstable angina, acute myocardial infarction), Respiratory system, digestive system, endocrine metabolic system, neuropsychiatric system, blood system and immune system diseases, etc.
• Based on medical history and investigator's judgment, the subject is at significant risk of suicide.
• In the investigator's judgment, the subject has any other factors deemed inappropriate for participation in this trial.