Gene Transfer Clinical Trial for Spinal Muscular Atrophy Type 1

The study will evaluate safety and efficacy of gene therapy in spinal muscular atrophy Type 1
(SMA1) patients. SMA is caused by low levels of the survival motor neuron (SMN) protein, and
affects all muscles in the body. There is no effective treatment for SMA and current drug
therapy has been unsuccessful in stabilizing or reversing this disease. Only supportive care
is currently possible.

Open-label, dose-escalation clinical trial of AVXS-101 injected intravenously through a
peripheral limb vein. Short-term safety will be evaluated over a two year period. Patients
will be tested at baseline and return for follow up visits on days 7, 14, 21, 30, followed by
once every month through 12 months post dose, and then every three months through two (2)
years post infusion. Unscheduled visits may occur if the PI determines that they are
necessary.

The primary analysis for efficacy will be assessed when all patients reach 13.6 months of age
(a database lock will be performed at the time point at which all patients reach 13.6 months
of age). A follow-up safety analysis will be completed at the time point at which the last
patient reaches 24 months post-dose.

Upon completion of the 2-year study period, patients will be monitored annually as per
standard of care for up to 15 years.

Inclusion Criteria:

- Six or nine months of age and younger (depending on cohort) on day of vector infusion
with Type 1 SMA as defined by the following features:

- Diagnosis of SMA based on gene mutation analysis with bi-allelic SMN1 mutations
(deletion or point mutations) and 2 copies of SMN2.

- Onset of disease at birth up to 6 months of age.

- Hypotonia by clinical evaluation with delay in motor skills, poor head control,
round shoulder posture and hypermobility of joints.

Exclusion Criteria:

- Active viral infection (includes HIV or serology positive for hepatitis B or C)

- Use of invasive ventilatory support (tracheotomy with positive pressure)* or pulse
oximetry <95% saturation.

- Patients may be put on non-invasive ventilator support (BiPAP) for less than 16 hours
a day at the discretion of their physician or research staff.

- Concomitant illness that in the opinion of the PI creates unnecessary risks for gene
transfer

- Concomitant use of any of the following drugs: drugs for treatment of myopathy or
neuropathy, agents used to treat diabetes mellitus, or ongoing immunosuppressive
therapy or immunosuppressive therapy within 3 months of starting the trial (e.g.
corticosteroids, cyclosporine, tacrolimus, methotrexate, cyclophosphamide, intravenous
immunoglobulin, rituximab)

- Patients with Anti-AAV9 antibody titers >1:50 as determined by ELISA binding
immunoassay.

- Abnormal laboratory values considered clinically significant (GGT > 3XULN, bilirubin ≥
3.0 mg/dL , creatinine ≥ 1.8 mg/dL, Hgb < 8 or > 18 g/Dl; WBC > 20,000 per cmm)
Participation in a recent SMA treatment clinical trial that in the opinion of the PI
creates unnecessary risks for gene transfer.

- Family does not want to disclose patient's study participation with primary care
physician and other medical providers.

- Patient with signs of aspiration based on a swallowing test and unwilling to use an
alternative method to oral feeding.

- Patients with a single base substitution in SMN2 (c.859G>C in exon 7) will be excluded
based on predicted mild phenotype.