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)

Study Overview
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Brief Summary
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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.

Detailed Description
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The study will be conducted in 2 stages: Stage 1: pilot efficacy and safety study of different doses to select a potentially therapeutic dose for further study. Stage 2: study of the efficacy and safety of ANB-004 at the selected potentially therapeutic dose. At the first stage, the study will have a 3+3 design and involve dose escalation in two cohorts, with the possibility of including a third cohort. Three subjects are to be included in each cohort, each of whom will receive a pre-specified cohort dose of ANB-004 as a single intravenous infusion. Subjects will be monitored for dose-limiting toxicity (DLT) events for 3 weeks after the drug infusion. In this study, DLT will include any of the CTCAE 5.0 grade 3 or higher adverse events (AEs) at least possibly related to the administration of the investigational product, except for an increase in body temperature at least possibly related to the administration of the investigational product, which will be classified as DLT starting from CTCAE 5.0 grade 4. At the first stage, in the absence of DLT events in three subjects in the same cohort, an ID will be assigned, and an infusion will be administered to the first subject in subsequent cohort. If DLT events occur in 1 of 3 subjects in the same cohort, this cohort will additionally include 3 subjects who will receive the same ANB-004 dose with which the DLT event was observed. If DLT events occur in 2 or more of 3 subjects within the same cohort, the assignment of ID/infusion in subsequent subjects/study is suspended. AT the second stage, if the IDMC judges that the potentially therapeutic dose was previously used in one of the cohorts, an additional 6 subjects will be included in this cohort.

Official Title
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An Open-Label, Non-Comparative Clinical Study of the Safety and Efficacy of an Adeno-Associated Viral Vector Carrying the SMN Gene (ANB-004 (JSC BIOCAD, Russia)) After a Single Intravenous Administration of Escalating Doses in Children With Spinal Muscular Atrophy

Conditions
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Spinal Muscular Atrophy (SMA)

Intervention / Treatment
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* Genetic: ANB-004, dose 1
* Genetic: ANB-004, dose 2
* Genetic: ANB-004, dose 3


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 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 established clinically and confirmed by molecular genetic testing (homozygous deletion of exon 7 of the SMN1 gene or heterozygous deletion of exon 7 + confirmed point mutation of the SMN1 gene) and 2 copies of the SMN2 gene, with an age of onset up to 180 days from birth; The ability of the subject's legal representative, in the Investigator's opinion, to perceive information and follow the Protocol procedures. Exclusion Criteria: A diagnosis of HIV infection, hepatitis B, hepatitis C, congenital syphilis in the study subject, as well as a documented diagnosis of HIV infection in the study subject's mother. Note: documented hepatitis B and/or hepatitis C and/or syphilis in the mother of a study subject is not an exclusion criterion in this clinical study, provided that standard breastfeeding rules are followed or the subject is not breastfed due to the low risk of transmission of hepatitis B and C viruses and Treponema pallidum from mother to child with breast milk; 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); Simultaneous participation of the subject in other clinical studies or previous participation in another clinical study using an experimental therapy.

Ages Eligible for Study
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Maximum Age: 240 Days

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: 3+3 design
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort 1<br>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<br>* Adeno-associated viral vector carrying the SMN gene single infusion at dose 1. The duration of the infusion is about 60 minutes.<br>|
| Experimental: Cohort 2<br>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<br>* Adeno-associated viral vector carrying the SMN gene single infusion at dose 2. The duration of the infusion is about 60 minutes.<br>|
| Experimental: Cohort 3<br>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<br>* Adeno-associated viral vector carrying the SMN gene single infusion at dose 3. The duration of the infusion is about 60 minutes.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event occurrence | No fatal event, no need for invasive respiratory support using tracheostomy or 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 | 
| Documented evidence of efficacy | Changes in functional and motor abilities: percentage and age of children who can turn over and sit without support for more than 5, 10, 20 and 30 seconds on video records obtained during a visit to the study center and/or by a legal representative of the study participant outside the study center. | 12 months |