An Exploratory Clinical Trial of VGN-R08b in Patients With Type II Gaucher Disease

An Exploratory Clinical Trial to Evaluate the Tolerability and Safety of VGN-R08b Via Intracerebroventricular Injection in Patients With Type II Gaucher Disease

This exploratory trial is to prove the tolerability and safety of VGN-R08b to treat infants with type II Gaucher disease.

Study Overview

• Status: Recruiting
• Conditions: Type II Gaucher Disease
• Intervention / Treatment: Drug: VGN-R08b

Detailed Description

Gaucher disease (GD) is an autosomal recessive genetic metabolic disorder. Due to the mutation of Glucocerebrosidase gene (GBA1), the activity of glucocerebrosidase (GCase) in the lysosome of the body is reduced, causing its substrate glucocerceramide to be accumulated in macrophage lysosomes in the liver, spleen, bone, lung, brain and eyes. Type II, acute neuropathy, with extensive and severe visceral involvement, usually develops within the first year of life, and most children die before the age of 2. VGN-R08b is a kind of Gene therapy with adeno-associated virus (AAV) serotype 9 (AAV9) driven human GBA1 being injected directly into intracerebroventricular.

This is a single-center, open, dose-climbing investigator-sponsored exploratory clinical study that included a dose-climbing phase and a dose-expanding phase. The sponsor plans to explore two dose levels in dose-climbing phase (one subject each cohort), then have additional 2~4 subjects in dose-expanding phase.

This study is to give preliminary evidence for the safety and efficacy of VGN-R08b treatment for patients with type II Gaucher disease.

• Study Type: Interventional
• Enrollment (Estimated): 6
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Zhang Huiwen, Dr.; Phone Number: 18117165075; Email: zhanghuiwen@xinhuamed.com.cn

Study Locations

• China
  • Shanghai
    • Shanghai, Shanghai, China, 200097
      • Recruiting
      • Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine
      • Contact: Zhang Huiwen, Dr.; Phone Number: 18117165075; Email: zhanghuiwen@xinhuamed.com.cn

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Infants with age of ≤24 months.
2. Historical diagnosis of Gaucher disease confirmed by GCase enzyme activity test, and with GBA1 biallelic mutations.
3. Neurological signs and/or symptoms consistent with diagnosis of GD2.
4. Parent(s)/legal guardian(s) of subject must give their consent for subject to enroll in the study.
5. Parent(s)/legal guardian(s) of the subject must agree to comply with the requirements of the study, including providing disease information and support disease assessment of symptoms.

Exclusion Criteria:

1. Diagnosis of a significant CNS disease other than GD2 that may be a cause for the patient's GD symptoms or may confound study objectives.
2. Achieved independent gait.
3. Severe visceral symptoms of GD which, in the opinion of the Investigator, would pose an unacceptable risk to the patient or interfere with the patient's ability to comply with study procedures or interfere with the conduct of the study.
4. Clinically active infection (including HIV, HBV, HCV or syphilis).
5. For those receiving enzyme replacement therapy and/or substrate reduction therapy and/or ambroxol for Gaucher disease, stable treatment ≤2 months before enrollment.
6. Use of strong inhibitors or inducers of cytochrome CYP3A4 or P-glycoprotein (P-gp) medications, herbals, or over-the-counter agents.
7. Any type of prior gene or cell therapy.
8. Immunizations (live vaccines) in the prior 4 weeks.
9. Use of systemic immunosuppressant or corticosteroid therapy other than protocol-specified (topical preparations for dermatological conditions are allowed).
10. Patients with anti-AAV9 neutralizing antibody titer over 1:5.
11. Brain MRI (magnetic resonance imaging) showing clinically significant abnormality considered to prevent intracisternal injection.
12. Contraindication to sedation during surgery or imaging studies (PET).
13. Presence of other significant medical conditions that would create an unacceptable risk to the patient or interfere with the patient's ability to comply with study procedures or interfere with the conduct of the study.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: type II Gaucher disease; This is a single-center, open, dose-climbing investigator-sponsored exploratory clinical study that included a dose-climbing phase and a dose-expanding phase. The sponsor plans to explore two dose levels in dose-climbing phase (one subject each cohort), then have additional 2~4 subjects in dose-expanding phase	Drug: VGN-R08b; VGN-R08b is a kind of Gene therapy with adeno-associated virus (AAV) serotype 9 (AAV9) driven human GBA1 being injected directly into intracerebroventricular.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Adverse Events (AEs), Serious Adverse Events (SAEs)	Adverse Events (AEs), Serious Adverse Events (SAEs)	Week 52

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Long-term safety follow-up	Number of Adverse Events (AEs), Serious Adverse Events (SAEs)	Up to Year 5
Survival ratio at age of 24 months	Survival ratio at age of 24 months	Baseline until event, or reach the age of 24 months, Up to Year 5
Changes in the activity of glucose cerebroside lipase (GCase)	Pharmacodynamic indicators	Up to Year 5
Changes in the activity of glucose cerebroside (GC) levels	Pharmacodynamic indicators	Up to Year 5
Changes in the activity of glucose sphingosine (Lyso GL1) levels in peripheral blood and CSF after medication	Pharmacodynamic indicators	Up to Year 5
Immunogenicity	Number of subjects producing antibodies against AAV9 and GCase	26 weeks
Changes in the genomic level of VGN-R08b vector in peripheral blood after medication	Pharmacokinetics	26 weeks

Collaborators and Investigators

• Sponsor: Xinhua Hospital, Shanghai Jiao Tong University School of Medicine
• Collaborators: Shanghai Vitalgen BioPharma Co., Ltd.
• Investigators: Principal Investigator: Zhang Huiwen, Dr., Xinhua Hospital, Shanghai Jiao Tong University School of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2023
• Primary Completion (Estimated): January 15, 2025
• Study Completion (Estimated): February 28, 2029

Study Registration Dates

• First Submitted: July 17, 2023
• First Submitted That Met QC Criteria: February 21, 2024
• First Posted (Estimated): February 22, 2024

Study Record Updates

• Last Update Posted (Estimated): February 22, 2024
• Last Update Submitted That Met QC Criteria: February 21, 2024
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Keywords: GBA, Glucocerceramide, AAV9, CNS gene therapy
• Additional Relevant MeSH Terms: Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Metabolism, Inborn Errors; Lysosomal Storage Diseases; Lipid Metabolism Disorders; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Sphingolipidoses; Lysosomal Storage Diseases, Nervous System; Lipidoses; Lipid Metabolism, Inborn Errors; Gaucher Disease
• Other Study ID Numbers: VGN-R08b-001

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