NGGT006 Gene Therapy for Homozygous Familial Hypercholesterolemia

Official title

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

Overview

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.

Interventions

• Genetic NGGT006
  Single intravenous infusion of NGGT006 at dose 1 (7.5e12vg/kg), dose 2 (1.5e13vg/kg) , dose 3 (3e13vg/kg) and dose 4 (4e13vg/kg).

Primary outcome measures

• Incidence of treatment-related adverse events (AE) and serious adverse events (SAE) [Time frame: 52 weeks]
• Absolute change and percent change in LDL-C [Time frame: 52 weeks]

Secondary outcome measures (5)

• Absolute change and percent change in apoB [Time frame: 52 weeks]
• Absolute change and percent change in TC [Time frame: 52 weeks]
• Absolute change and percent change in HDL-C [Time frame: 52 weeks]
• Absolute change and percent change in TG [Time frame: 52 weeks]
• Absolute change and percent change in Lp(a) [Time frame: 52 weeks]

Eligibility criteria

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;
• 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.

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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• First Affiliated Hospital of Xian Jiaotong University — Xi'an

Publications

• Zheng T, Gao G, Xu C, Li R, Shao J, Wang X, Han X, Li J, Liu P, Xiong Y, Song L, Wang J, Wen S, Zhuo X, Wang G, Jiang L, Qu G, Chen T, She J, Luo Y, Yuan Z, Wu Y. AAV gene therapy for homozygous familial hypercholesterolemia: a phase 1 trial. Nat Med. 2026 Jun;32(6):2137-2146. doi: 10.1038/s41591-026-04441-3. Epub 2026 Jun 4. PMID 42243546

Identifiers

NCT: NCT06125847 · NGGT006-P-2301

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗