Study of Intrathecal Administration of AVXS-101 for Spinal Muscular Atrophy

This is a Phase 1, single-dose administration study of infants and children with a genetic
diagnosis consistent with SMA, bi-allelic deletion of SMN1 and 3 copies of SMN2 without the
genetic modifier who are able to sit but cannot stand or walk at the time of study entry.
Patients will receive AVXS-101 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 fifteen (15) patients ≥6 months and < 24 months, and at least twelve (12) patients ≥ 24
< 60 months will be enrolled.

The first cohort will enroll three (3) patients (Cohort 1) ≥6 months and < 24 months of age
who will receive administration of 6.0 × 1013 vg of AVXS-101 (Dose A). There will be at least
a four (4) week interval between the dosing of each patient within the cohort. The
investigators will confer with the Data Safety Monitoring Board (DSMB) on all Grade III or
higher AEs within 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 (3) patients < 60 months of age
will be enrolled (Cohort 2) and will receive administration of 1.2 × 1014 vg of AVXS-101
(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. AveXis,
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. The investigators will confer with the DSMB on all Grade III or higher AEs
within 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 (6) 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 twelve (12) patients > 6 months and < 24
months and twelve (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 (3) patients < 60
months of age will receive Dose C which will be no greater than 2.4 × 1014 vg administered
intrathecally. 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 (3) 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 twelve (12) patients > 6 months and < 24
months and twelve (12) patients ≥ 24 and < 60 months that have received Dose C.

All patients in the study will be followed for a total of 12 months. The primary analyses for
efficacy will be assessed when all patients reach 12 months post-dose.

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. Seasonal vaccinations 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

- Abnormal laboratory values considered to be clinically significant (INR >1.4), GGT
>3XULN, Bilirubin ≥3.0 mg/dL, Creatinine ≥1.0 mg/dL, Hgb <8 or >18 g/Dl; WBC >20,000
per cmm) prior to study dosing

- 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