Clinical trial NCT05747261: 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)
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Spinal Muscular Atrophy (SMA)
Lead sponsor: Biocad
Sponsor class: INDUSTRY
First posted: 2023-02-28
Enrollment: 40
Sex: ALL
Maximum age (years): 240
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: "3+3" design
Primary purpose: TREATMENT

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.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

1. Informed consent form for participation in the study signed by the subject's legal representative;
2. 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;
3. 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;
4. 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.
5. 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.
6. The ability of the subject's legal representative, in the Investigator's opinion, to perceive information and follow the Protocol procedures

Exclusion Criteria:

1. 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;
2. Unwillingness of the legal representative to use alternative feeding methods (nasogastric tube, gastrostomy) in case of swallowing disorders and a risk of aspiration;
3. 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;
4. Need for respiratory support for ≥16 hours per day or tracheostomy ;
5. 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.
6. 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.);
7. 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.
8. 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;
9. A diagnosis of acute or chronic hepatic failure at screening;
10. A known allergy or intolerance to any components of the investigational product or pre- and post-medication drug (glucocorticoids);
11. Simultaneous participation of the subject in other clinical studies or previous participation in another clinical study using an experimental therapy.

Primary outcomes:
measure: Proportion of subjects with adverse reactions
timeFrame: 12 months
measure: Proportion of subjects with serious adverse reactions
timeFrame: 12 months
measure: Proportion of subjects with CTCAE 5.0 or DAIDS grade 3 or higher adverse reactions
timeFrame: 12 months
measure: Time from date of birth to event
timeFrame: 12 months
measure: Motor development score
timeFrame: 12 months
measure: Change in the The Hammersmith Infant Neurological Examination (HINE) score
timeFrame: 12 months
Secondary outcomes:
measure: Event occurrence
timeFrame: 12 months
measure: Documented evidence of efficacy
timeFrame: 12 months
Other outcomes:
measure: Proportion of subjects with detectable IgM and IgG to the AAV9 protein capsid
timeFrame: 12 months
measure: Proportion of subjects with detectable IgM and IgG to the SMN1 protein
timeFrame: 12 months
measure: Proportion of subjects with detectable T cells specific to the AAV9 capsid
timeFrame: 12 months
measure: Proportion of subjects with detectable T cells specific to the product of the SMN transgene
timeFrame: 12 months
measure: Presence of the AAV9 vector in various body fluids (serum, saliva, urine, feces)
timeFrame: 12 months
Locations:
city: Minsk
country: Belarus
facility: 1. State Institution Republican Scientific and Practical Center "Mother and Child"
city: Ekaterinburg
country: Russian Federation
facility: State Autonomous Healthcare Institution of the Sverdlovsk Region "Regional Children's Clinical Hospital"
city: Moscow
country: Russian Federation
facility: Federal State Autonomous Educational Institution of Higher Education "N.I. Pirogov Russian National Research Medical University", Ministry of Health of the Russian Federation
city: Moscow
country: Russian Federation
facility: Federal State Autonomous Educational Institution of Higher Education "N.I. Pirogov Russian National Research Medical University", Ministry of Health of the Russian Federation
city: Moscow
country: Russian Federation
facility: Federal State Autonomous Institution "National Medical Research Center for Children's Health", Ministry of Health of the Russian Federation
city: Saint Petersburg
country: Russian Federation
facility: Federal State Budgetary Educational Institution of Higher Education "St. Petersburg State Pediatric Medical University", Ministry of Health of the Russian Federation
city: Saint Petersburg
country: Russian Federation
facility: Federal State Budgetary Institution "V. A. Almazov National Medical Research Center" of the Ministry of Health of the Russian Federation
Study officials:
affiliation: Director of Clinical Development Department, BIOCAD
name: Arina V Zinkina-Orikhan, PhD
role: STUDY_DIRECTOR
References: