NGGT006 Gene Therapy for Homozygous Familial Hypercholesterolemia

NCT ID: NCT06125847

Last Updated: 2024-12-09

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: EARLY_PHASE1
• Total Enrollment: 12 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-10-29
• Study Completion Date: 2028-11-30

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.

Conditions

Homozygous Familial Hypercholesterolemia

Keywords

Homozygous familial hypercholesterolemia; Gene therapy; Low-density lipoprotein cholesterol

Study Design

• Allocation Method: NA
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

NGGT006

4 doses of NGGT006 will be administered according to the principle of dose escalation

Group Type: EXPERIMENTAL

NGGT006

Intervention Type: GENETIC

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).

Interventions

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).

Intervention Type: GENETIC

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.

• Minimum Eligible Age: 12 Years
• Maximum Eligible Age: 55 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

First Affiliated Hospital Xi'an Jiaotong University

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Zuyi Yuan, M.D.

Role: STUDY_CHAIR

First Affiliated Hospital of Xian Jiaotong University

Locations

First Affiliated Hospital of Xian Jiaotong University

Xi'an, Shaanxi, China

Site Status: RECRUITING

Countries

China

Central Contacts

Tao Zheng, M.D.

Role: CONTACT

Phone: 086-15229218127

Email: zhengtao900305@163.com

Ge Gao, M.M.

Role: CONTACT

Phone: 086-18229068097

Email: gaoge1030@163.com

Facility Contacts

Tao Zheng, MD

Role: primary

Yue Wu, MD

Role: backup

Other Identifiers

NGGT006-P-2301

Identifier Type: -

Identifier Source: org_study_id