Study of the Safety and Efficacy of an Adeno-Associated Viral Vector Carrying the SMN Gene After a Single Intravenous Administration of Escalating Doses in Children With Spinal Muscular Atrophy (BLUEBELL)

NCT05747261 | Recruiting Phase 1 DMC

• 1 other identifier: ANB-004-1
• Study Type: interventional
• Target: 40
• Locations: 2 countries
• Sites: 7

Brief Summary

The goal of this multicenter, open-label, non-comparative, cohort study is to investigate the safety, immunogenicity, and efficacy of ANB-004 in children with spinal muscular atrophy. The study will have a standard 3+3 dose-escalation design.

Conditions

Spinal Muscular Atrophy (SMA)

Outcome Measures

Primary Outcomes (6)

• Proportion of subjects with adverse reactions

  12 months

• Proportion of subjects with serious adverse reactions

  12 months

• Proportion of subjects with CTCAE 5.0 or DAIDS grade 3 or higher adverse reactions

  Since some of the severity criteria used in the CTCAE are not applicable to the pediatric population, it is proposed to use the 2017 Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events of the National Institute of Allergy and Infectious Diseases.

  12 months

• Time from date of birth to event

  Time from date of birth to onset of a fatal event or the need for invasive respiratory support using tracheostomy or the need for non-invasive respiratory support for at least 16 hours a day for ≥14 consecutive days (in the absence of acute reversible disease and excluding surgery).

  12 months

• Motor development score

  The assessment will be made using the motor development scale of a healthy child, which reflects the motor development milestones from birth to a certain age.

  12 months

• Change in the The Hammersmith Infant Neurological Examination (HINE) score

  To assess the motor skills of study subjects, Section 2 of this scale will be used; the assessment will be made in subjects aged 3 to 24 months.

  12 months

Secondary Outcomes (2)

• Event occurrence

  12 months

• Documented evidence of efficacy

  12 months

Other Outcomes (5)

• Proportion of subjects with detectable IgM and IgG to the AAV9 protein capsid

  12 months

• Proportion of subjects with detectable IgM and IgG to the SMN1 protein

  12 months

• Proportion of subjects with detectable T cells specific to the AAV9 capsid

  12 months

Study Arms (3)

Cohort 1

EXPERIMENTAL

Subjects in Cohort 1 will receive ANB-004 at a dose 1. Depending on the DLT, the cohort may include 1 to 6 subjects in the first stage and 9 to 12 in the second stage.

Genetic: ANB-004, dose 1

Cohort 2

EXPERIMENTAL

Subjects in Cohort 2 will receive ANB-004 at a dose 2. The dose for Cohort 2 will be determined at the IDMC meeting. Depending on the DLT, the cohort may include 1 to 6 subjects in the first stage and 9 to 12 in the second stage.

Genetic: ANB-004, dose 2

Cohort 3

EXPERIMENTAL

Subjects of Cohort 3, if included, will receive the drug at a dose 3. The dose for Cohort 3 will be determined at the IDMC meeting. Depending on the DLT, the cohort may include 1 to 6 subjects in the first stage and 9 to 12 in the second stage.

Genetic: ANB-004, dose 3

Interventions

ANB-004, dose 1 GENETIC

Adeno-associated viral vector carrying the SMN gene single infusion at dose 1. The duration of the infusion is about 60 minutes.

Cohort 1

ANB-004, dose 2 GENETIC

Adeno-associated viral vector carrying the SMN gene single infusion at dose 2. The duration of the infusion is about 60 minutes.

Cohort 2

ANB-004, dose 3 GENETIC

Adeno-associated viral vector carrying the SMN gene single infusion at dose 3. The duration of the infusion is about 60 minutes.

Cohort 3

Eligibility Criteria

• Age: Up to 240 Days
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Informed consent form for participation in the study signed by the subject's legal representative;
• Subjects of either sex under the age of 240 days at the time of signing the Information Sheet for the Legal Representative of the Clinical Study Subject with Informed Consent Form;
• A diagnosis of 5q-SMA (homozygous deletion of exon 7 of the SMN1 gene or heterozygous deletion of exon 7 + confirmed point mutation of the SMN1 gene) and 2 or 3 copies of the SMN2 gene established based on molecular genetic testing;
• Subjects with 2 copies of the SMN2 gene can be included in the study both at the presymptomatic stage of the disease and in the presence of SMA symptoms. If symptoms are present, the age of onset of the disease should be up to 180 days from birth.
• Subjects with 3 copies of the SMN2 gene can be included in the study if they have symptoms of SMA type 1 and the disease began before the age of 180 days.
• The ability of the subject's legal representative, in the Investigator's opinion, to perceive information and follow the Protocol procedures

You may not qualify if:

• Unwillingness of the legal representative to use alternative feeding methods (nasogastric tube, gastrostomy) in case of swallowing disorders and a risk of aspiration;
• Anti-AAV9 antibody titer \>1:50 determined by ELISA. Note: if a subject's screening anti-AAV9 antibody titer is \>1:50, the anti-AAV9 antibody titer may be determined again. Subjects with anti-AAV9 antibody titers ≤1:50 in the second test may be included in the study;
• Need for respiratory support for ≥16 hours per day or tracheostomy ;
• Treatment with nusinersen, risdiplam, branaplam, onasemnogene abeparvovec or other antisense oligonucleotides/selective SMN2 splicing modifiers or gene therapy drugs for SMN1 transduction or other AAV-based gene therapy drugs regardless of serotype used previously (from birth) or planned for the main study period, i.e., within 12 months after the administration of the investigational product.
• A need to use any medications for the treatment of myopathy or neuropathy, drugs for the treatment of diabetes, ongoing immunosuppressive therapy, or the need for immunosuppressive therapy after the start of the study (for example, glucocorticoids (except for premedication and post-medication), cyclosporine, tacrolimus, methotrexate, cyclophosphamide, intravenous immunoglobulin, rituximab, etc.);
• Subjects with the following laboratory test results at screening:
• increased activity of transaminases (ALT, AST) or GGT \>2×ULN;
• total bilirubin level ≥34 µmol/L;
• creatinine level ≥160 µmol/L;
• hemoglobin \<80 g/L and \>180 g/L;
• WBC count \>20x109/L;
• Troponin I level \> ULN.
• Any concomitant diseases that, in the Investigator's opinion, may affect the safety of ANB-004 in the subject or have a significant impact on the assessment of the outcomes of SMA therapy;
• A diagnosis of acute or chronic hepatic failure at screening;
• A known allergy or intolerance to any components of the investigational product or pre- and post-medication drug (glucocorticoids);

Sponsors & Collaborators

• Biocad: lead

Study Sites (7)

1. State Institution Republican Scientific and Practical Center "Mother and Child"

Minsk, Belarus

RECRUITING

Federal State Autonomous Educational Institution of Higher Education "N.I. Pirogov Russian National Research Medical University", Ministry of Health of the Russian Federation

Moscow, 117997, Russia

RECRUITING

Federal State Autonomous Educational Institution of Higher Education "N.I. Pirogov Russian National Research Medical University", Ministry of Health of the Russian Federation

Moscow, 117997, Russia

RECRUITING

Federal State Autonomous Institution "National Medical Research Center for Children's Health", Ministry of Health of the Russian Federation

Moscow, 119991, Russia

RECRUITING

Federal State Budgetary Educational Institution of Higher Education "St. Petersburg State Pediatric Medical University", Ministry of Health of the Russian Federation

Saint Petersburg, 194100, Russia

RECRUITING

Federal State Budgetary Institution "V. A. Almazov National Medical Research Center" of the Ministry of Health of the Russian Federation

Saint Petersburg, 197341, Russia

RECRUITING

State Autonomous Healthcare Institution of the Sverdlovsk Region "Regional Children's Clinical Hospital"

Yekaterinburg, 620149, Russia

RECRUITING

MeSH Terms

Conditions

Muscular Atrophy, Spinal

Condition Hierarchy (Ancestors)

Spinal Cord Diseases; Central Nervous System Diseases; Nervous System Diseases; Motor Neuron Disease; Neurodegenerative Diseases; Neuromuscular Diseases

Study Officials

• Arina V Zinkina-Orikhan, PhD

  Director of Clinical Development Department, BIOCAD

  STUDY DIRECTOR

Central Study Contacts

Maria Morozova, MD, PhD

CONTACT

+7 (985) 910 28 13; morozovama@biocad.ru

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: "3+3" design

Study Record Dates

• First Submitted: February 14, 2023
• First Posted: February 28, 2023
• Study Start: February 2, 2023
• Primary Completion: September 1, 2025
• Study Completion (Estimated): August 1, 2030
• Last Updated: February 22, 2024

Record last verified: 2024-02

Data Sharing

• IPD Sharing: Will not share

Locations

BE (1); RU (6)