Study of Intrathecal Administration of Onasemnogene Abeparvovec-xioi for Spinal Muscular Atrophy

The purpose of this trial is to evaluate the safety and tolerability of intrathecal administration of onasemnogene abeparvovec-xioi in infants and children with Spinal Muscular Atrophy with 3 copies of SMN2 and deletion of SMN1.

This is a Phase 1, single-dose administration study of infants and children with a genetic diagnosis consistent with spinal muscular atrophy (SMA), bi-allelic deletion of survival motor neuron 1 gene (SMN1) and 3 copies of survival motor neuron 2 gene (SMN2) without the genetic modifier who are able to sit but cannot stand or walk at the time of study entry. Patients will receive onasemnogene abeparvovec-xioi in a dose comparison safety study of two (or three) potential therapeutic doses. Patients will be stratified in two groups, those ≥6 months and \< 24 months of age at time of dosing and those ≥ 24 months and \< 60 months of age at time of dosing. At least 15 patients ≥ 6 months and \< 24 months, and at least 12 patients ≥ 24 \< 60 months will be enrolled.

The first cohort will enroll three patients (Cohort 1) ≥ 6 months and \< 24 months of age who will receive administration of 6.0 × 1013 vg of onasemnogene abeparvovec-xioi (Dose A). There will be at least a four week interval between the dosing of each patient within the cohort. Novartis Gene Therapies, Inc. will confer with the Data Safety Monitoring Board (DSMB) on all Grade III or higher AEs within approximately 48 hours of awareness that are possibly, probably or definitely related to the study agent before continuing enrollment. Safety data will be reviewed by the DSMB during quarterly meetings; following enrollment of the three patients and based upon the available safety data a decision will be made whether to: a) stop due to toxicity, or b) proceed to Cohort 2 using Dose B.

Should the determination be made to advance to Dose B, three patients \< 60 months of age will be enrolled (Cohort 2) and will receive administration of 1.2 × 1014 vg of onasemnogene abeparvovec-xioi (Dose B). Again, there will be at least a four-week interval between dosing of the three patients within the cohort. Based on the available safety data from the three Cohort 2 patients and all of the Cohort 1 patients, the DSMB will decide and document during quarterly meetings whether further four-week intervals between patients dosing is necessary. Novartis Gene Therapies, Inc. will take this recommendation into consideration and will make the final determination whether to persist with four-week intervals between patients dosing going forward; the decision will be communicated to sites and Institutional Review Boards (IRBs) in a formal sponsor letter. Novartis Gene Therapies, Inc. will confer with the DSMB on all Grade III or higher AEs within approximately 48 hours of awareness that are possibly, probably or definitely related to the study agent before continuing enrollment. Safety data will be reviewed by the DSMB during quarterly meetings; following enrollment of the first six patients and based upon available safety data, a decision will be made whether to: a) stop due to toxicity, or b) continue to enroll an additional 21 patients until there are a total of 12 patients \> 6 months and \< 24 months and 12 patients ≥ 24 and \< 60 months that have all received Dose B.

Based upon an ongoing assessment of safety and efficacy data from patients treated with the 1.2 × 1014 vg dose, an option for testing of a third dose (Dose C), will be considered. If, based on all available data, this is judged to be safe and necessary, three patients \< 60 months of age will receive Dose C, 2.4 × 1014 vg administered IT. A meeting of the DSMB will be called to obtain a recommendation on the safety of escalating to a higher dose prior to proceeding. If a decision is made to proceed to testing a higher dose, there will again be a four-week interval between dosing of the first three patients receiving Dose C, as in Cohorts 1 and 2. Safety data will be reviewed by the DSMB during quarterly meetings. Following enrollment of the first three Dose C patients and based upon available safety data, the DSMB will be consulted and a decision will be made whether to: a) stop dosing Dose C due to safety concerns, or b) continue to enroll an additional 21 patients until there are a total of 12 patients \> 6 months and \< 24 months and 12 patients ≥ 24 and \< 60 months that have received Dose C.

Patients from Cohort 3 will be followed for a total of 15 months post-dose. The primary analyses for efficacy will be assessed when all patients reach 12 months post-dose and the primary analyses for safety will be assessed when the last patient of Cohort 3 reaches 15 months post-dose (and database lock will be performed after the last patient reaches 15 months post-dose).

Eligibility Criteria:
Key Inclusion Criteria

* Patients ≥6 months and up to 60 months (1800 days) of age at time of dosing following diagnostic confirmation during screening period by genotype who demonstrate the ability to sit unassisted for 10 or more seconds but cannot stand or walk
* Diagnostic confirmation by genotype includes lab documentation of homozygous absence of SMN1 exon 7; with exactly three copies of SMN2
* Negative gene testing for SMN2 gene modifier mutation (c.859G\>C)
* Onset of clinical signs and symptoms consistent with spinal muscular atrophy (SMA) at \< 12 months of age
* Able to sit independently and not standing or walking independently. Definition of sitting independently is defined by the World Health Organization Multicentre Growth Reference Study (WHO-MGRS) criteria of being able to sit up unsupported with head erect for at least 10 seconds. Child should not use arms or hands to balance body or support position (Wijnhoven 2004)
* Be up-to-date on childhood vaccines that include palivizumab prophylaxis (also known as Synagis) to prevent respiratory syncytial virus (RSV) infections are also recommended in accordance with American Academy of Pediatrics (AAP 2009)

Key Exclusion Criteria

* Current or historical ability to stand or walk independently
* Contraindications for spinal tap procedure or administration of intrathecal therapy or presence of an implanted shunt for the drainage of CSF or an implanted central venous (CNS) catheter
* Severe contractures as determined by designated Physical Therapist(s) at screening that interfere with either the ability to attain/demonstrate functional measures or interferes with ability to receive intrathecal (IT) dosing
* Severe scoliosis (defined as ≥ 50° curvature of spine) evident on X-ray examination
* Previous, planned or expected scoliosis repair surgery/procedure within 1 year of dose administration
* Use of invasive ventilatory support (tracheotomy with positive pressure) or pulse oximetry \< 95% saturation at screening while the patient is awake, or for high altitudes \> 1000 m, oxygen saturation \< 92% while the patient is awake
* Pulse oximetry saturation must not decrease ≥ four (4) percentage points between screening and highest value on day of dosing
* Use or requirement of non-invasive ventilatory support for 12 or more hours daily over the two (2) weeks prior to dosing
* Medical necessity for a gastric feeding tube, where the majority of feedings are given by non-oral methods (i.e., nasogastric tube or nasojejunal tube) or patients whose weight-for-age falls below the 3rd percentile based on WHO Child Growth Standards (Onis 2006). Placement of a permanent gastrostomy prior to screening is not an exclusion
* Use or requirement of non-invasive ventilatory support for 12 or more hours daily over the two (2) weeks prior to dosing
* Medical necessity for a gastric feeding tube, where the majority of feedings are given by non-oral methods or patients whose weight-for-age falls below the 3rd percentile based on WHO Child Growth Standards (Onis 2006). Placement of a permanent gastrostomy prior to screening is not an exclusion
* Active viral infection (includes human immunodeficiency virus (HIV) or serology positive for hepatitis B or C, or Zika virus)
* Serious non-respiratory tract illness requiring systemic treatment and/or hospitalization within two (2) weeks prior to study entry
* Respiratory infection requiring medical attention, medical intervention or increase in supportive care of any manner within four (4) weeks prior to study entry
* Severe non-pulmonary/respiratory tract infection within four (4) weeks before study dosing or concomitant illness that in the opinion of the Principal Investigator (PI) creates unnecessary risks for gene transfer such as:

  * Major renal or hepatic impairment
  * Known seizure disorder
  * Diabetes mellitus
  * Idiopathic hypocalciuria
  * Symptomatic cardiomyopathy
* History of bacterial meningitis or brain or spinal cord disease, including tumors, or abnormalities by magnetic resonance imaging (MRI) or computerized tomography (CT) that would interfere with the lumbar puncture (LP) procedures or CSF circulation
* Known allergy or hypersensitivity to prednisolone or other glucocorticosteroids or their excipients
* Known allergy or hypersensitivity to iodine or iodine-containing products
* 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 of study dosing
* Inability to withhold use of laxatives or diuretics in the 24 hours prior to dose administration
* Anti-AAV9 antibody titers \>1:50 as determined by Enzyme-linked Immunosorbent Assay (ELISA) binding immunoassay

  * Should a potential patient 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 (GGT, ALT, and AST, or total bilirubin \> 2 × 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 or receipt of an investigational or approved compound product or therapy received with the intent to treat SMA at any time prior to screening for this study

  * Oral beta agonists must be discontinued 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 study
* Expectation of major surgical procedures during the 1-year study assessment period