Spinal Muscular Atrophy Type 1

Primary:Determine efficacy by demonstrating achievement of developmental milestone of sitting without support up to 18 months of age as defined by World Health Organization (WHO) Motor Developmental Milestones. Secondary:Determine efficacy based on survival at 14 months of age. Safety: Evaluate the safety of AVXS 101 in patients with SMA Type 1 and determine the safety of AVXS 101 based on the development of unacceptable toxicity

AVXS-101

AVXS-101

vial

1.1 X 10(14 )

Primary Outcome Measures :
Proportion of Participants Sitting Without Support [ Time Frame: Up to 18 Months of Age Visit (Up To 14 Days After Participant Reaches 18 Months of Age) ]
The proportion of symptomatic SMA Type 1 participants who are homozygous negative for SMN1 exon 7 and have 2 copies of SMN2 without the SMN2 genetic modifier that achieve the ability to sit without support for at least 10 seconds. 'Sitting without support' is defined by the WHO Multicentre Growth Reference Study as "a patient who sits up straight with head erect for at least 10 seconds; child does not use arms or hands to balance body or support position".

Inclusion Criteria:

Participants with SMA Type 1 as determined by diagnosis of SMA based on gene mutation analysis with biallelic SMN1 mutations (deletion or point mutations) and one or 2 copies of SMN2 [inclusive of the known SMN2 gene modifier mutation (c.859G>C)]
Participants must be < 6 months (< 180 days) of age at the time of onasemnogene abeparvovec-xioi infusion
Participants must have a swallowing evaluation test performed prior to administration of gene replacement therapy
Up-to-date on childhood vaccinations as per local health authorities.
Parent(s)/legal guardian(s) willing and able to complete the informed consent process and comply with trial procedures and visit schedule

Exclusion Criteria:

Previous, planned or expected scoliosis repair surgery/procedure prior to 18 months of age
Use of invasive ventilatory support (tracheotomy with positive pressure) or pulse oximetry < 95% saturation at screening:

Pulse oximetry saturation must not decrease ≥ 4 percentage points between screening and dosing with confirmatory oximetry reading
Participants may be put on non-invasive ventilatory support for less than 12 hours per day at the discretion of their physician or trial staff
Use or requirement of non-invasive ventilatory support for greater than or equal to 12 hours daily in the two weeks prior to dosing
Participant with signs of aspiration based on a swallowing test or whose weight-for-age falls below the 3rd percentile based on World Health Organization (WHO) Child Growth Standards and unwilling to use an alternative method to oral feeding
Active viral infection (includes human immunodeficiency virus [HIV] or positive serology for hepatitis B, C, or E, or known Zika virus infection)
Serious non-respiratory tract illness requiring systemic treatment and/or hospitalization within 2 weeks prior to screening
Upper or lower respiratory infection requiring medical attention, medical intervention, or increase in supportive care of any manner within 4 weeks prior to screening
Severe non-pulmonary/respiratory tract infection (eg, pyelonephritis, or meningitis) within 4 weeks before administration of gene replacement therapy or concomitant illness that, in the opinion of the Principal Investigator, creates unnecessary risks for gene replacement such as:

Major renal or hepatic impairment
Known seizure disorder
Diabetes mellitus
Idiopathic hypocalcuria
Symptomatic cardiomyopathy
Known allergy or hypersensitivity to prednisolone or other glucocorticosteroids or their excipients, or human, animal biological raw materials (human transferrin, human insulin, trypsin derived from porcine spleen, bovine derived protein (FBS, bovine milk-derived Benzonase, casamino acid, bovine pancreas), HEK 293 cells, Cosmic Calf Serum, HyQtase) used in manufacturing of onasemnogene abeparvovec-xioi product
Concomitant use of any of the following: drugs for treatment of myopathy or neuropathy, agents used to treat diabetes mellitus, or ongoing immunosuppressive therapy, plasmapheresis, immunomodulators such as adalimumab, or immunosuppressive therapy within 3 months prior to gene replacement therapy (e.g., corticosteroids, cyclosporine, tacrolimus, methotrexate, cyclophosphamide, IV immunoglobulin, rituximab)
Anti-AAV9 antibody titer > 1:50 as determined by Enzyme-linked Immunosorbent Assay (ELISA) binding immunoassay. Should a potential participant demonstrate Anti-AAV9 antibody titer > 1:50, he or she may receive retesting within 30 days of the screening period and will be eligible to participate if the Anti-AAV9 antibody titer upon retesting is ≤ 1:50
Clinically significant abnormal laboratory values (gamma-glutamyl transpeptidase [GGT], ALT, AST, total bilirubin > 2x the ULN, creatinine ≥ 1.0 mg/dL, hemoglobin [Hgb] < 8 or > 18 g/dL; white blood cell [WBC] > 20,000 per cmm) prior to gene replacement therapy. Patients with an elevated bilirubin level that is unequivocally the result of neonatal jaundice shall not be excluded
Participation in recent SMA treatment clinical trial (with the exception of observational cohort studies or non-interventional studies) or receipt of an investigational or commercial compound, product or therapy administered with the intent to treat SMA (e.g., nusinersen, valproic acid) at any time prior to screening for this trial. Oral beta-agonists must be discontinued at least 30 days prior to dosing. Inhaled albuterol specifically prescribed for the purposes of respiratory (bronchodilator) management is acceptable and not a contraindication at any time prior to screening for this trial
Expectation of major surgical procedures during the trial assessment period (e.g., spinal surgery or tracheostomy)
Parent(s)/legal guardian(s) unable or unwilling to comply with trial procedures or inability to travel for repeat visits
Parent(s)/legal guardian(s) unwilling to keep trial results/observations confidential or to refrain from posting confidential trial results/observations on social media sites
Parent(s)/legal guardian(s) refuses to sign consent form
Participants < 35 weeks gestational age at time of birth