Gene Therapy for Homozygous Familial Hypercholesterolemia

Study Overview
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Brief Summary
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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) serotype 8 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
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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) serotype 8 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). 3-12 subjects will be enrolled and divided into 3 groups according to the principle of dose escalation, respectively administered intravenous infusion of NGGT006 at low dose (7.5e12vg/kg), medium dose (1.5e13vg/kg) and high dose (3e13vg/kg). All subjects will undergo 52 weeks of treatment observation and further 260 weeks of long-term follow-up.

Official Title
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A Clinical Study for the Safety and Efficacy of Intravenous Infusion of NGGT006 in Treatment of Homozygous Familial Hypercholesterolemia With LDLR Mutations

Conditions
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Homozygous Familial Hypercholesterolemia

Intervention / Treatment
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* Genetic: NGGT006


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Voluntarily sign informed consent form; Male or female, 12 ≤ age ≤ 35 years (first patient≥ 18 years), diagnosed as homozygous familial hypercholesterolemia with genetic confirmation of two mutant alleles of the LDL receptor (LDLR) gene; Serum anti-AAV8 conjugate antibodies titer ≤ 1:80 and anti-AAV8 neutralizing antibodies titer ≤ 1:5; Untreated LDL-C >10 mmol/L (180mg/ dL) or treated LDL-C ≥7 mmol/L (126 mg/ 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. Exclusion Criteria: 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.

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 35 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: NGGT006<br>3 doses of NGGT006 will be administered according to the principle of dose escalation | Genetic: NGGT006<br>* Single intravenous infusion of NGGT006 at low dose (7.5e12vg/kg), medium dose (1.5e13vg/kg) and high dose (3e13vg/kg).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of treatment-related adverse events (AE) and serious adverse events (SAE) | Incidence of AE and SAE, as assessed by physical examinations, clinical laboratory parameters and adverse event reporting | 52 weeks | 
| Absolute change and percent change in LDL-C | Change in LDL-C concentration from baseline to week 52 | 52 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute change and percent change in lipid parameters | Change in lipid concentrations from baseline to week 52. Lipid parameters include: non-high density lipoprotein cholesterol (non-HDL-C); apolipoprotein B (apoB); total cholesterol (TC); HDL-C; triglycerides (TG); very low-density lipoprotein cholesterol (VLDL-C); lipoprotein(a) (Lp(a)); and apolipoprotein A-I (apo A-I) | 52 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Homozygous familial hypercholesterolemia, Gene therapy, Low-density lipoprotein cholesterol