Spinal Muscular Atrophy

Objectives: Safety: • Evaluate the safety of AVXS-101 through incidence of adverse events (AEs) and/or serious adverse events (SAEs) • Evaluate the safety of AVXS-101 based on the change from baseline in clinical laboratory parameters Efficacy objectives will be assessed independently for each cohort. Efficacy for patients with bi-allelic SMN1 deletions and 2 copies of SMN2: Primary: • Assess the efficacy of AVXS-101 by demonstrating functional independent sitting for at least 30 seconds up to 18 months of age Secondary: • Determine the efficacy of AVXS-101 based on survival, defined as avoidance of death or the requirement of permanent ventilation in the absence of acute illness or perioperatively as assessed at 14 months of age • Assess efficacy of AVXS-101 by demonstrating the ability to maintain weight at or above the third percentile without need for non-oral/mechanical feeding support at any visit up to 18 months of age

AVXS-101

Pregabalin
scAAV9.CB.SMN

oral solution
Vial

20mg
1.1 x 10(14)

Primary Outcome Measures :
Percentage of participants achieving functional independent sitting for at least 30 seconds at any visit [ Time Frame: 18 months ]
Participants with bi-allelic SMN1 deletions and 2 copies of SMN2

Percentage of participants achieving the ability to stand without support for at least 3 seconds at any visit [ Time Frame: 24 months ]
Participants with bi-allelic SMN1 deletions and 3 copies of SMN2


Secondary Outcome Measures :
Percentage of participants surviving without permanent ventilation in the absence of acute reversible illness and perioperatively [ Time Frame: 14 months ]
Participants with bi-allelic SMN1 deletions and 2 copies of SMN2

Percentage of participants achieving the ability to maintain weight at or above the 3rd percentile without non-oral/mechanical feeding support at any visit [ Time Frame: 18 months ]
Participants with bi-allelic SMN1 deletions and 2 copies of SMN2

Percentage of participants demonstrating the ability to walk alone at any visit [ Time Frame: 24 months ]
Participants with bi-allelic SMN1 deletions and 3 copies of SMN2. Ability to walk alone is defined as the ability to take at least 5 steps independently displaying coordination and balance.

Inclusion Criteria:
All patients:
• 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) ≥2 mV at Baseline; centralized review of CMAP data
will be conducted
• Gestational age of 35 to 42 weeks
• 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 the guidance of local health authorities.
• Able and willing to follow the Consensus Statement for Standard of Care in Spinal Muscular
Atrophy (J Child Neurol.2007;22[29]:1027-1049).
• Parent(s)/legal guardian(s) willing and able to complete the informed consent process and comply
with study procedures and visit schedule
• Genetic diagnosis as described below, obtained from an acceptable newborn or pre-natal screening
test method
Patients with 2 copies of SMN2 (n ≥15)
• Patients with pre-symptomatic SMA Type 1 as determined by the following features:
• 2 copies of SMN2
Patients with 3 copies of SMN2 (n ≥12)
• Patients with pre-symptomatic SMA Type 2 as determined by the following features:
• 3 copies of SMN2
Patients with 4 copies of SMN2 (n≥17)
• Patients with pre-symptomatic SMA Type 3 as determined by the following features:
• 4 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 (e.g., tongue fasciculation, hypotonia, areflexia)
• Tracheostomy or current prophylactic use or requirement of non-invasive 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 non-thickened 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 the 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 [25]
• 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 ribonucleic acid (RNA) testing in the patient prior to enrollment
• 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 dosing
• Severe non-pulmonary/respiratory tract infection (e.g., pyelonephritis, or meningitis) 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 hypocalcuria
• 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 (e.g., corticosteroids, cyclosporine, tacrolimus, methotrexate,
cyclophosphamide, IV immunoglobulin, rituximab)
• 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 inside the 30-day screening period and will be eligible to participate if the
Anti-AAV9 antibody titer upon retesting is ≤1:50, provided patient is still <6 week of age at
the time of dosing
• Biological mother involved with the care of the child refuses anti-AAV9 antibody testing prior to
dosing
• 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