Gene therapy for treating a rare cholesterol disorder

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

This study is testing a new gene therapy to see if it can help people with a rare cholesterol disorder called homozygous familial hypercholesterolemia lower their cholesterol levels.

Quick facts

• Phase: Early Phase 1
• Study type: Interventional
• Enrollment: 12 (estimated)
• Ages: 12 Years to 55 Years
• Sex: All
• Sponsor: First Affiliated Hospital Xi'an Jiaotong University (Academic / other)
• Drugs / interventions: alirocumab, evolocumab, rituximab
• Locations: 1 site (Xi'an, Shaanxi)
• Trial ID: NCT06125847 on ClinicalTrials.gov

What this trial studies

This early phase 1 trial evaluates the safety and efficacy of NGGT006, a gene therapy using an adeno-associated viral vector, for patients with homozygous familial hypercholesterolemia (HoFH) caused by LDLR mutations. The trial involves a single intravenous infusion of NGGT006, which aims to promote the expression of the LDLR protein to enhance the clearance of low-density lipoprotein cholesterol (LDL-C) from the bloodstream. Participants will be divided into dose escalation groups and monitored for 52 weeks, followed by long-term follow-up for up to 260 weeks.

Who should consider this trial

Good fit: Ideal candidates are individuals aged 12 to 55 with genetically confirmed homozygous familial hypercholesterolemia and elevated LDL-C levels.

Not a fit: Patients with other forms of hypercholesterolemia or those who do not meet the genetic criteria for HoFH may not benefit from this therapy.

Why it matters

Potential benefit: If successful, this therapy could significantly lower cholesterol levels and reduce the risk of early coronary artery disease in patients with HoFH.

How similar studies have performed: While gene therapy for hypercholesterolemia is a novel approach, similar studies have shown promise in treating other genetic disorders, indicating potential for success.

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.

Where this trial is running

Xi'an, Shaanxi

• First Affiliated Hospital of Xian Jiaotong University — Xi'an, Shaanxi, China (Recruiting)

Study contacts

• Study coordinator: Tao Zheng, M.D.

Conditions Homozygous Familial Hypercholesterolemia; Homozygous familial hypercholesterolemia; Gene therapy; Low-density lipoprotein cholesterol