Safety and Efficacy Study of NGGT006 in Refractory Hypercholesterolemia Patients

Prior treatment

• Use of other drugs or nutritional products that may affect blood lipids (such as fibrates) within 6 weeks;
• Have received low-density lipoprotein apheresis (LDL apheresis) within the past 2 months;
• Abnormal thyroid function, or those using thyroid hormone replacement therapy but poorly controlled (TSH within the normal range for \<12 weeks);
• Used systemic glucocorticoid treatment within 6 weeks before enrollment;
• Previous gene therapy treatment;

Other illness

• Positive for hepatitis B surface antigen, hepatitis C, human immunodeficiency virus (HIV)，syphilis test or other infections (such as Epstein-Barr virus, Mycoplasma pneumoniae, tuberculosis virus, HPV, Chlamydia pneumoniae, respiratory syncytial virus, Adenovirus and coxsackievirus group B, etc.);
• Uncontrollable myocardial infarction or heart failure, and those planning surgery within one year; or new acute coronary syndrome in the past six months;
• Acute or chronic renal insufficiency;
• Had contraindications to glucocorticoid (e.g., epilepsy, severe schizophrenia, active peptic ulcer)；
• Suffering from malignant tumors such as liver cancer; liver fibrosis;
• Hypersensitivity to AAV preparations (for example trehalose) or cortisone or immunosuppressants (sirolimus, rituximab, tacrolimus);
• Suffering from immunodeficiency disease
• Any other condition that may not be appropriate for the study in the opinion of the Investigator.

Lab values

• Clinically significant abnormalities in liver function test: alanine aminotransferase (ALT) \>2 × upper limit of normal (ULN) and/or aspartate aminotransferase (AST) \>2 × ULN;
• Diabetes diagnosed within 3 months or with poor control (HbA1c \>9%);
• Hemoglobin (Hb) \< 120g/L (male), Hb \< 110 (female);
• Abnormal platelet counts or morphology;
• History or laboratory tests suggestive of thrombosis;

Other

• Secondary hyperlipidemia;
• Large weight fluctuations (≥5kg) in the past 2 months;
• RR at the baseline \>160/100mmHg (one repeated measurement is allowed);
• Life expectancy less than 1 year;
• Participation in any other clinical trial within 3 months;
• Breastfeeding females;

• 18 ≤ age ≤ 55 years old;
• A patient with a clear diagnosis of refractory hypercholesterolemia and confirmed by genetic testing to be familial hypercholesterolemia;
• AAV binding antibody titer ≤1:80 and AAV neutralizing antibody ≤1:5;
• 18≤BMI (body mass index)≤35;
• During the screening period, the subjects have received stable maximum tolerated dose of lipid-lowering drug treatment, but LDL-C was still ≥70mg/dL with clinical atherosclerotic cardiovascular disease; or LDL-C level was ≥ 100 mg/dL without clinical atherosclerotic cardiovascular disease: the highest tolerated dose refers to (the following must be met at the same time):
  • ① Moderate to high doses of statins for ≥4 weeks, whether used alone or in combination with other lipid-lowering drugs; exceptions: subjects cannot tolerate statins; or subjects cannot receive statin treatment due to other reasons, such as low BMI, etc.;
  • ② Ezetimibe ≥ 4 weeks;
  • ③ Alirocumab 150mg Q2W or 300mg Q4W; evolocumab 140mg Q2W or 420mg Q4W; ≥8 weeks; And during the clinical trial process, any adjustment involving the type and dosage of lipid-lowering drugs must be approved by the researcher;
• Stable healthy diet for ≥12 weeks, and can adhere to a healthy diet throughout the entire clinical trial;
• Voluntarily sign the informed consent form and be willing to comply with the trial visit plan;
• Willing to maintain a similar amount and intensity of exercise during the study period as during the baseline period;
• Maintain good living habits, have no history of alcoholism or alcohol dependence (ICD-10 diagnosis is F10)
• No new or recurring cardiovascular events (myocardial infarction, cerebral infarction, etc.) within half a year;
• No stent implantation plan within three months;
• Female subjects have not had sexual intercourse for 14 days before administration, and their blood tests indicate that they are not pregnant;
• Subjects of childbearing age agree to use highly effective contraceptive measures for at least 365 days from the time of NGGT006 administration.