NGGT006 Gene Therapy for Homozygous Familial Hypercholesterolemia

Xi'an Jiaotong University

Status and phase

Enrolling

Early Phase 1

Conditions

Homozygous Familial Hypercholesterolemia

Treatments

Genetic: NGGT006

Study type

Interventional

Funder types

Other

Identifiers

NCT06125847

NGGT006-P-2301

Details and patient eligibility

About

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).

Full 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). 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.

Enrollment

12 estimated patients

Sex

All

Ages

12 to 55 years old

Volunteers

No Healthy Volunteers

Inclusion criteria

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;
Serum anti-AAV conjugate antibodies titer ≤ 1:80 and anti-AAV 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.