A Trial to Evaluate Safety and Efficacy of a Product Named VGN-R09b in Severe AADC Deficiency

Aromatic L-amino Acid Decarboxylase Deficiency Clinical Trial

Official title:

An Open, Dose-escalating and Dose Confirmation Trial to Evaluate the Safety and Efficacy of VGN-R09b by Intra Putamen Injection in Patients With Severe Aromatic L-amino Acid Decarboxylase (AADC) Deficiency

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06432140
• Other study ID #: VGN-R09b-102
• Status: Not yet recruiting
• Phase: Phase 1
• Start date: May 2024
• Est. completion date: September 2030

Study information

• Verified date: May 2024
• Source: Shanghai Vitalgen BioPharma Co., Ltd.
• Contact: Xiumin Wang, MD
• Phone: +86-18017395221
• Email: GCPwxm666[@]163.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This trial includes dose-escalating part (phase 1) and dose confirming part, to prove the safety and efficacy of VGN-R09b to treat patients with severe AADC deficiency

Description:

Aromatic L-amino acid decarboxylase (AADC) is an enzyme responsible for the final step in the synthesis of neurotransmitters dopamine and serotonin. AADC deficiency is a rare genetic disorder. VGN-R09b is a kind of Gene therapy with adeno-associated virus (AAV) serotype 9 (AAV9) driven human AADC (hAADC) being injected directly into putamen. This is an open, dose-escalating and dose confirming study. The sponsor plans to explore two dose levels (6.0×1011vg and 1.28×1012vg) in dose-escalating phase (three subjects each cohort), then plans to have 10 subjects enrolled for dose confirmation phase. This study is to give evidence for the safety and efficacy of VGN-R09b treatment for patients with severe Aromatic L-amino acid decarboxylase (AADC) deficiency.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 16
• Est. completion date: September 2030
• Est. primary completion date: June 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Months to 8 Years

Eligibility

Inclusion Criteria:

1. The child patient has to be =18 months old and < 8 years old, and a head circumference big enough for surgery as judged by investigator.

2. Historical diagnosis of AADC deficiency with clinical symptoms consistency, AND with Molecular genetic confirmation of homozygous or compound heterozygous mutation point of IVS6+4A>T in DDC gene.

3. With Plasma AADC activity less than or equal to 12 pmol/min/mL.

4. Motor development at baseline <3 months (head fully uncontrollable at baseline), and Failed to benefit from standard medical therapy (dopamine agonists, monoamine oxidase inhibitor or related form of Vitamin B6) at discretion of investigators.

5. Parent(s)/legal guardian(s) with custody of subject must give their consent for subject to enroll in the study.

6. 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. Intracranial neoplasm or any structural brain abnormality or lesion (e.g., severe brain atrophy, white matter degenerative changes), which, in the opinion of the study investigators, would confer excessive risk and/or inadequate potential for benefit.

2. Presence of other significant medical or neurological conditions that would create an unacceptable operative or anesthetic risk (including congenital heart disease, respiratory disease with home oxygen requirement, history of serious anesthesia complications during previous elective procedures, history of cardiorespiratory arrest), liver or renal failure, malignancy, or HIV positive.

3. Severe coagulopathy, or need for ongoing anticoagulant therapy.

4. clinically active infection or with severe infection within 12 weeks before screening (e.g. adenovirus or herpes virus, pneumonia, sepsis, central nervous system infection).

5. Previous stereotactic neurosurgery, or any gene/cell therapy.

6. Received live vaccination within 4 weeks.

7. Contraindication to sedation during surgery or imaging studies (PET or MRI).

Related Conditions & MeSH terms

• Aromatic L-amino Acid Decarboxylase Deficiency

Intervention

Genetic:
• VGN-R09b injection
Two levels of VGN-R09b will be injected into bilateral putamen in dose-escalating phase, and one dose level will be injected in dose confirming phase

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Shanghai Vitalgen BioPharma Co., Ltd.

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Adverse Events (AEs), Serious Adverse Events (SAEs)	Vital signs, physical examination, laboratory test will be monitored after drug injection	up to Week 52
Primary	Number of subjects who achieved motor development milestones	Four milestones, including Head control, Sit independently, Stand/stepping with support, Walk with minimal assistant, would be assessed according to definition in Peabody Developmental Motor Scale 2nd edition (PDMS-2). Each milestone would be scored as 0, 1 or 2, and score 2 means achievement of the milestone.	up to 24 months
Secondary	Change in brain AADC activity	Increase in signal in the putamen and nigra on Fluorodopa-PET imaging as brain AADC activity measure	up to 5 Years
Secondary	Change in Cerebrospinal Fluid (CSF) neurotransmitter metabolite concentrations	Neurotransmitter metabolite concentrations of Homovanillic Acid/Hydroxyindoleacetic Acid (HVA/5-HIAA) would be measured	up to 5 Years
Secondary	Change from baseline in motor function	Motor function would be assessed by Peabody Developmental Motor Scale 2nd edition (PDMS-2). The score ranges from 0 to 482, and higher score means the better in motor function.	up to 5 Years
Secondary	Change in number of Clinical symptoms	Number of disease related symptoms	up to 5 Years
Secondary	Viral shedding	Concentrations of Viral genome in serum/urine would be measured	up to 1 week
Secondary	Immunogenicity after injection	Subject number with positive antibodies of AAV9/AADC/Glial Cell Line-Derived Neurotrophic Factor (GDNF) in blood would be reported	up to 26 weeks
Secondary	Number of Adverse Events (AEs), Serious Adverse Events (SAEs) in Long-term follow-up	Drug-related AEs and SAEs would be monitored as long as 5 years after injection	up to 5 Years