Pre-Symptomatic Study of Intravenous AVXS-101 in Spinal Muscular Atrophy (SMA) for Patients With Multiple Copies of SMN2

Phase 3, open-label, single-arm study of a single, one-time dose of AVXS-101 (gene
replacement therapy) in patients with spinal muscular atrophy who meet enrollment criteria
and are genetically defined by bi-allelic deletion of survival motor neuron 1 gene (SMN1)
with 2 or 3 copies of survival motor neuron 2 gene (SMN2). Patients with SMN1 point mutations
or the SMN2 gene modifier mutation (c.859G>C) may enroll but will not be included in the
efficacy analysis sets.

The study includes a screening period, a gene replacement therapy period, and a follow-up
period. During the screening period (Days -30 to -2), patients whose parent(s)/legal
guardian(s) provide informed consent will undergo screening procedures to determine
eligibility for study enrollment. Patients who meet the entry criteria will enter the
in-patient gene replacement therapy period (Day -1 to Day 2). On Day -1, patients will be
admitted to the hospital for pre-treatment baseline procedures. On Day 1, patients will
receive a single, one-time intravenous (IV) infusion of AVXS-101, and will undergo in-patient
safety monitoring for a minimum of 24 hours post infusion. Patients may be discharged 24
hours after the infusion, based on Investigator judgment. During the outpatient follow-up
period (Days 3 to End of Study at 18 or 24 of age, dependent upon respective SMN2 copy
number), patients will return at regularly scheduled intervals for efficacy and safety
assessments until the End of Study when the patient reaches 18 months of age (SMN2 = 2) or 24
months of age (SMN2 = 3). After the End of Study visit, eligible patients will be asked to
rollover into a long-term follow up study.

Inclusion Criteria:

- Age ≤6 weeks (≤42 days) at time of dose

- Ability to tolerate thin liquids as demonstrated through a formal bedside swallowing
test

- Compound muscle action potential (CMAP) ≥2mV at Baseline; centralized review of CMAP
data will be conducted

- Gestational age of 35 to 42 weeks

- Patients with pre-symptomatic SMA Type 1 as determined by the following features:

− 2 copies of SMN2 Patients with 2 copies of SMN2 (n ≥12)

- Patients with pre-symptomatic SMA Type 2 as determined by the following features:

- 3 copies of SMN2

Exclusion Criteria:

- Weight at screening visit <2 kg

- Hypoxemia (oxygen saturation <96% awake or asleep without any supplemental oxygen or
respiratory support) at the screening visit or for altitudes >1000 m, oxygen
saturation <92% awake or asleep without any supplemental oxygen or respiratory support
at the screening visit

- Any clinical signs or symptoms at screening or immediately prior to dosing that are,
in the opinion of the Investigator, strongly suggestive of SMA

- Tracheostomy or current prophylactic use or requirement of noninvasive ventilatory
support at any time and for any duration prior to screening or during the screening
period

- Patients with signs of aspiration/inability to tolerate nonthickened liquids based on
a formal swallowing test performed as part of screening or patients receiving any
non-oral feeding method

- Clinically significant abnormalities in hematology or clinical chemistry parameters as
determined by investigator or medical monitor

- Treatment with an investigational or commercial product, including nusinersen, given
for the treatment of SMA. This includes any history of gene therapy, prior antisense
oligonucleotide treatment, or cell transplantation.

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

- Biological mother with active viral infection as determined by screening laboratory
samples (includes human immunodeficiency virus [HIV] or positive serology for
hepatitis B or C)

• Biological mothers with clinical suspicion of Zika virus that meet Centers for
Disease Control and Prevention (CDC) Zika virus epidemiological criteria including
history of residence in or travel to a geographic region with active Zika transmission
at the time of travel will be tested for Zika virus RNA. Positive results warrant
confirmed negative Zika virus RNA testing in the patient prior to enrollment.

- Serious nonrespiratory 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
dosing

- Severe nonpulmonary/respiratory tract infection within 4 Weeks before administration
of gene replacement therapy or concomitant illness that, in the opinion of the
Investigator or Sponsor medical monitor, creates unnecessary risks for gene
replacement therapy such as:

- Major renal or hepatic impairment

- Known seizure disorder

- Diabetes mellitus

- Idiopathic hypocalciuria

- Symptomatic cardiomyopathy

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

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

- 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 4 Weeks prior to gene replacement therapy

- AntiAAV9 antibody titer >1:50 as determined by Enzyme-linked Immunosorbent Assay
(ELISA) binding immunoassay

• Should a potential patient demonstrate AntiAAV9 antibody titer >1:50, he or she may
receive retesting inside the 30-Day screening period and will be eligible to
participate if the AntiAAV9 antibody titer upon retesting is ≤1:50, provided the <6
Week age requirement at the time of dosing is still met

- Biological mother involved with the care of the child refuses anti-AAV9 antibody
testing prior to dosing