Study of Intrathecal Administration of Onasemnogene Abeparvovec-xioi for Spinal Muscular Atrophy
Condition: Spinal Muscular Atrophy
MeSH terms: Muscular Atrophy; Muscular Atrophy, Spinal; Atrophy
Intervention: Onasemnogene Abeparvovec-xioi
Intervention description: Self-complementary AAV9 carrying the SMN gene under the control of a hybrid CMV enhancer/chicken-β-actin promoter
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 32.0
Sex: All
Minimum age: 6 Months
Maximum age: 60 Months
Healthy volunteers: No
Keywords: Gene Transfer; Gene Therapy; Adeno-associated virus; Survival Motor Neuron; SMN; AAV9

Summary:

      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.
    

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