Gene Replacement Therapy Clinical Trial for Patients With Spinal Muscular Atrophy Type 1

Phase 3, open-label, single-arm, single-dose, study of AVXS-101 (gene replacement therapy) in
patients with spinal muscular atrophy (SMA) Type 1 who meet enrollment criteria and are
genetically defined by nonfunctional survival motor neuron 1 gene (SMN1) with 1 or 2 copies
of survival motor neuron 2 gene (SMN2). Fifteen (15) patients < 6 months (< 180 days) of age
at the time of gene replacement therapy (Day 1) will be enrolled.

Inclusion Criteria:

- Patients with SMA Type 1 as determined by the following features: a. Diagnosis of SMA
based on gene mutation analysis with bi-allelic SMN1 mutations (deletion or point
mutations) and 1 or 2 copies of SMN2 (inclusive of the known SMN2 gene modifier
mutation (c.859G>C))2

- The first 3 patients enrolled must meet the criteria for the Intent-To-Treat
Population

- Patients must be < 6 months (< 180 days) of age at the time of AVXS-101 infusion

- Patients must have a swallowing evaluation test performed prior to administration of
gene replacement therapy

- Up-to-date on childhood vaccinations. 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 (26)

- Parent(s)/legal guardian(s) willing and able to complete the informed consent process
and comply with study procedures and visit schedule

Exclusion Criteria:

- Previous, planned or expected scoliosis repair surgery/procedure during the study
assessment period

- Pulse oximetry < 96% saturation at screening while the patient is awake or asleep
without any supplemental oxygen or respiratory support, or for altitudes > 1000 m,
oxygen saturation < 92% awake or asleep without any supplemental oxygen or respiratory
support Pulse oximetry saturation may decrease to < 96% after screening provided that
the saturation does not decrease by ≥ 4 percentage points

- Tracheostomy or current use or requirement of non-invasive ventilatory support
averaging ≥ 6 hours daily over the 7 days prior to the screening visit; or ≥ 6
hours/day on average during the screening period or requiring ventilatory support
while awake over the 7 days prior to screening or at any point during the screening
period prior to dosing

- Patients with signs of aspiration/inability to tolerate non-thickened- liquids based
on a formal swallowing test performed as part of screening. Patients with a
gastrostomy tube who pass the swallowing test will be allowed to enroll in the study

- Patients whose weight-for-age is below the third percentile based on World Health
Organization (WHO) Child Growth Standards[25]

- Active viral infection (includes human immunodeficiency virus [HIV] or positive
serology for hepatitis B or C, or Zika virus)

- 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 within 4 weeks before administration
of gene replacement therapy or concomitant illness that creates unnecessary risks for
gene replacement therapy such as: a. Major renal or hepatic impairment b. Known
seizure disorder c. Diabetes mellitus d. Idiopathic hypocalcuria e. Symptomatic
cardiomyopathy

- Known allergy or hypersensitivity to prednisolone or other glucocorticosteroids or
their excipients

- 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, immunosuppressive
therapy within 3 months prior to gene replacement therapy

- Anti-AAV9 antibody titer > 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 (gamma glutamyl- transpeptidase
[GGT], ALT, and AST > 3 × ULN, bilirubin ≥ 3.0 mg/dL, 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

- Participation in recent SMA treatment clinical study (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 at any time prior to screening for this study. Oral β-agonists
must be discontinued at least 30 days before gene therapy 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 study assessment period

- Parent(s)/legal guardian(s) unable or unwilling to comply with study procedures or
inability to travel for repeat visits

- Parent(s)/legal guardian(s) unwilling to keep study results/observations confidential
or to refrain from posting confidential study results/observations on social media
sites

- Parent(s)/legal guardian(s) refuses to sign consent form

- Gestational age at birth < 35 weeks (245 days)