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.
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.
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 ;
Sequential
ANB-004, dose 1
GeneticAdeno-associated viral vector carrying the SMN gene single infusion at dose 1. The duration of the infusion is about 60 minutes.
ANB-004, dose 2
GeneticAdeno-associated viral vector carrying the SMN gene single infusion at dose 2. The duration of the infusion is about 60 minutes.
ANB-004, dose 3
GeneticAdeno-associated viral vector carrying the SMN gene single infusion at dose 3. The duration of the infusion is about 60 minutes.
Proportion of subjects with adverse reactions
Proportion of subjects with serious adverse reactions
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.
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).
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).
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.
Proportion of subjects with detectable IgM and IgG to the AAV9 protein capsid
Proportion of subjects with detectable IgM and IgG to the SMN1 protein
Proportion of subjects with detectable T cells specific to the AAV9 capsid
Proportion of subjects with detectable T cells specific to the product of the SMN transgene
