NGGT006 Gene Therapy for Homozygous Familial Hypercholesterolemia

Homozygous Familial Hypercholesterolemia Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06125847
• Other study ID #: NGGT006-P-2301
• Status: Recruiting
• Phase: Early Phase 1
• Start date: October 29, 2023
• Est. completion date: November 2028

Study information

• Verified date: November 2023
• Source: First Affiliated Hospital Xi'an Jiaotong University
• Contact: Tao Zheng, M.D.
• Phone: 086-15229218127
• Email: zhengtao900305[@]163.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 12
• Est. completion date: November 2028
• Est. primary completion date: November 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Years to 55 Years

Eligibility

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.

Related Conditions & MeSH terms

• Homozygous Familial Hypercholesterolemia
• Hypercholesterolemia
• Hyperlipoproteinemia Type II

Intervention

Genetic:
• NGGT006
Single intravenous infusion of NGGT006 at low dose (7.5e12vg/kg), medium dose (1.5e13vg/kg) and high dose (3e13vg/kg).

Locations

Country	Name	City	State
China	First Affiliated Hospital of Xian Jiaotong University	Xi'an	Shaanxi

Sponsors (1)

Lead Sponsor	Collaborator
First Affiliated Hospital Xi'an Jiaotong University

Country where clinical trial is conducted

China, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	Absolute change and percent change in LDL-C	Change in LDL-C concentration from baseline to week 52	52 weeks
Secondary	Absolute change and percent change in apoB	Change in lipid concentrations from baseline to week 52	52 weeks
Secondary	Absolute change and percent change in TC	Change in lipid concentrations from baseline to week 52	52 weeks
Secondary	Absolute change and percent change in HDL-C	Change in lipid concentrations from baseline to week 52	52 weeks
Secondary	Absolute change and percent change in TG	Change in lipid concentrations from baseline to week 52	52 weeks
Secondary	Absolute change and percent change in Lp(a)	Change in lipid concentrations from baseline to week 52	52 weeks
Secondary	Absolute change and percent change in Apo A-I	Change in lipid concentrations from baseline to week 52	52 weeks