This is a Phase 3, open-label, single-arm, single-dose, trial of onasemnogene abeparvovec-xioi (gene replacement therapy) in participants with spinal muscular atrophy (SMA) Type 1 and who are genetically defined by a biallelic pathogenic mutation of the survival motor neuron 1 gene (SMN1) with one or two copies of survival motor neuron 2 gene (SMN2). The primary objective of the study is to evaluate the efficacy of onasemnogene abeparvovec-xioi by assessing the proportion of symptomatic SMA Type 1 participants who achieve the ability to sit unaided for at least 10 seconds up to and including the 18 months of age trial visit. At least 6 participants aged < 6 months (< 180 days) at the time of gene replacement therapy (Day 1) will be enrolled.

This is a Phase 3, open-label, single-arm, single-dose trial of onasemnogene abeparvovec-xioi (gene replacement therapy) in participants with SMA Type 1 with one or 2 copies of SMN2. At least 6 participants < 6 months (< 180 days) of age at the time of gene replacement therapy (Day 1) will be enrolled.

The trial includes 3 trial periods: screening, gene replacement therapy, and follow-up. During the screening period (Days -30 to -2), participants whose parent(s)/legal guardian(s) provide informed consent will undergo screening procedures to determine eligibility for trial enrollment. participants who meet the entry criteria will enter the in-patient gene replacement therapy period (Day -1 to Day 3). On Day -1, participants will be admitted to the hospital for pre-treatment baseline procedures. On Day 1, participants will receive a one-time intravenous (IV) infusion of the equivalent of onasemnogene abeparvovec-xioi cohort 2 dose received in the AVXS-101-CL-101 trial over approximately 60 minutes and will undergo in-patient safety monitoring over the next 48 hours. Participants may be discharged 48 hours after gene replacement therapy, based on Investigator judgment. During the outpatient follow-up period (Days 4 to End of Trial at 18 months of age), participants will return at regularly scheduled intervals for efficacy and safety assessments until the participant reaches 18 months of age.

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:

  1. Pulse oximetry saturation must not decrease ≥ 4 percentage points between screening and dosing with confirmatory oximetry reading
  2. 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:

  1. Major renal or hepatic impairment
  2. Known seizure disorder
  3. Diabetes mellitus
  4. Idiopathic hypocalcuria
  5. 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

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on https://www.clinicalstudydatarequest.com/.

From Day 1 up to 18 Months of Age Visit (total duration of approximately 12-18 months depending on age at dosing).