NGGT006 Gene Therapy for Homozygous Familial Hypercholesterolemia

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

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).

Study Overview

• Status: Recruiting
• Conditions: Homozygous Familial Hypercholesterolemia
• Intervention / Treatment: Genetic: NGGT006

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.

• Study Type: Interventional
• Enrollment (Estimated): 12
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Tao Zheng, M.D.; Phone Number: 086-15229218127; Email: zhengtao900305@163.com
• Study Contact Backup: Name: Ge Gao, M.M.; Phone Number: 086-18229068097; Email: gaoge1030@163.com

Study Locations

• China
  • Shaanxi
    • Xi'an, Shaanxi, China, 710061
      • Recruiting
      • First Affiliated Hospital of Xian Jiaotong University
      • Contact: Tao Zheng, MD; Phone Number: 086-15229218127; Email: zhengtao900305@163.com
      • Contact: Yue Wu, MD; Phone Number: 086-18092826334; Email: yue.wu@xjtu.edu.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: NGGT006; 4 doses of NGGT006 will be administered according to the principle of dose escalation	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).

What is the study measuring?

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 apoB	Change in lipid concentrations from baseline to week 52	52 weeks
Absolute change and percent change in TC	Change in lipid concentrations from baseline to week 52	52 weeks
Absolute change and percent change in HDL-C	Change in lipid concentrations from baseline to week 52	52 weeks
Absolute change and percent change in TG	Change in lipid concentrations from baseline to week 52	52 weeks
Absolute change and percent change in Lp(a)	Change in lipid concentrations from baseline to week 52	52 weeks

Collaborators and Investigators

• Sponsor: First Affiliated Hospital Xi'an Jiaotong University
• Investigators: Study Chair: Zuyi Yuan, M.D., First Affiliated Hospital of Xian Jiaotong University

Study record dates

Study Major Dates

• Study Start (Actual): October 29, 2023
• Primary Completion (Actual): November 30, 2024
• Study Completion (Estimated): November 1, 2028

Study Registration Dates

• First Submitted: October 30, 2023
• First Submitted That Met QC Criteria: November 5, 2023
• First Posted (Actual): November 9, 2023

Study Record Updates

• Last Update Posted (Estimated): December 9, 2024
• Last Update Submitted That Met QC Criteria: December 4, 2024
• Last Verified: September 1, 2024

More Information

Terms related to this study

• Keywords: Gene therapy; Low-density lipoprotein cholesterol; Homozygous familial hypercholesterolemia
• Additional Relevant MeSH Terms: Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Hyperlipidemias; Dyslipidemias; Lipid Metabolism Disorders; Lipid Metabolism, Inborn Errors; Hyperlipoproteinemias; Homozygous Familial Hypercholesterolemia; Hypercholesterolemia; Hyperlipoproteinemia Type II
• Other Study ID Numbers: NGGT006-P-2301

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No