NGGT006 Gene Therapy for Homozygous Familial Hypercholesterolemia
- Conditions
- Homozygous Familial Hypercholesterolemia
- Interventions
- Genetic: NGGT006
- Registration Number
- NCT06125847
- Brief Summary
This is an early phase 1, open-label, single-center, dose-escalation, pilot trial to evaluate the safety and efficacy of an intravenous infusion of NGGT006 in homozygous familial hypercholesterolemia (HoFH) patients with LDLR mutations. NGGT006 is an adeno-associated viral (AAV) vector carrying codon-optimized human LDLR gene, driving the expression of LDLR protein with normal function and promoting the clearance of low-density lipoprotein cholesterol (LDL-C).
- Detailed Description
Homozygous familial hypercholesterolemia (HoFH) is a rare inherited disorder of lipoprotein metabolism, characterized by extreme elevations in low-density lipoprotein cholesterol (LDL-C) and leading to early onset of severe coronary artery disease. This is an early phase 1, open-label, single-center, dose-escalation, pilot trial to evaluate the safety and efficacy of a single intravenous infusion of NGGT006 in HoFH patients with LDLR mutations. NGGT006 is an adeno-associated viral (AAV) vector carrying codon-optimized human LDLR gene, driving the expression of LDLR protein with normal function and promoting the clearance of low-density lipoprotein cholesterol (LDL-C). 4-15 subjects will be enrolled and divided into 4 groups according to the principle of dose escalation, respectively administered intravenous infusion of NGGT006 at dose group 1 (7.5e12vg/kg), dose group 2 (1.5e13vg/kg) , dose group 3 (3e13vg/kg) and dose group 4 (4e13vg/kg). The researcher is allowed to extend 0-3 patients. All subjects will undergo 52 weeks of treatment observation and further 260 weeks of long-term follow-up.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 12
- Voluntarily sign informed consent form;
- Male or female, 12 ≤ age ≤ 55 years (first patient≥ 18 years), diagnosed as homozygous familial hypercholesterolemia with genetic confirmation of two mutant alleles of the LDL receptor (LDLR) gene;
- AAV8 neutralizing antibodies can be negative or reduced to negative levels through methods such as plasma exchange.
- Untreated LDL-C ≥10 mmol/L (386mg/ dL) or treated LDL-C ≥7 mmol/L (270mg/ dL) together with cutaneous or tendon xanthoma before age 18 years;
- Had been on stable medication for ≥30 days if receiving lipid-lowering therapy (or ≥60 days if receiving alirocumab or evolocumab) prior to screening and not scheduled for addition of new drugs or dose adjustments during the study;
- Agreed to follow a low-fat diet and comply with all study procedures;
- Agreed to maintain a similar exercise volume and intensity to baseline during the study period;
- Agreed to maintain good lifestyle habits;
- No history of alcohol abuse or alcohol dependence (diagnosed as F10 in ICD-10 code);
- No sexual activity for 14 days prior to administration and negative serum pregnancy test in female participants;
- Participants of childbearing potential agreed to use highly effective contraception for at least 365 days from administration of NGGT006;
- No plan of stent implantation within 3 months.
- Positive for hepatitis B surface antigen, hepatitis C, human immunodeficiency virus (HIV) or syphilis test;
- Clinically significant abnormalities in liver function test: alanine aminotransferase (ALT) ≥2 × upper limit of normal (ULN) and/or aspartate aminotransferase (AST) ≥2 × ULN;
- Baseline blood pressure ≥160/100 mmHg (1 repeat measurement is allowed);
- Uncontrolled myocardial infarction or heart failure, or had surgery plan within 1 year;
- Diabetes diagnosed within 3 months or with poor control (HbA1c ≥9%);
- Acute or chronic kidney failure;
- Hemoglobin (Hb) ≥120g/L (male), Hb ≥110 (female);
- Abnormal platelet counts or morphology;
- History or laboratory tests suggestive of thrombosis;
- Had contraindications to glucocorticoid (e.g., epilepsy, severe schizophrenia, active peptic ulcer);
- Life expectancy less than 1 year;
- With malignant tumors;
- Liver fibrosis or liver cancer;
- Previous gene therapy treatment;
- Hypersensitivity to AAV or cortisone or immunosuppressants (sirolimus, rituximab, tacrolimus);
- Participation in any other clinical trial within 3 months;
- History of stent implantation within 1 month or myocardial infarction within 3 months;
- Breastfeeding females;
- Any other condition that may not be appropriate for the study in the opinion of the Investigator.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description NGGT006 NGGT006 3 doses of NGGT006 will be administered according to the principle of dose escalation
- Primary Outcome Measures
Name Time Method Incidence of treatment-related adverse events (AE) and serious adverse events (SAE) 52 weeks Incidence of AE and SAE, as assessed by physical examinations, clinical laboratory parameters and adverse event reporting
Absolute change and percent change in LDL-C 52 weeks Change in LDL-C concentration from baseline to week 52
- Secondary Outcome Measures
Name Time Method Absolute change and percent change in apoB 52 weeks Change in lipid concentrations from baseline to week 52
Absolute change and percent change in TC 52 weeks Change in lipid concentrations from baseline to week 52
Absolute change and percent change in HDL-C 52 weeks Change in lipid concentrations from baseline to week 52
Absolute change and percent change in TG 52 weeks Change in lipid concentrations from baseline to week 52
Absolute change and percent change in Lp(a) 52 weeks Change in lipid concentrations from baseline to week 52
Trial Locations
- Locations (1)
First Affiliated Hospital of Xian Jiaotong University
🇨🇳Xi'an, Shaanxi, China