Phase 3, Open-Label, Single-Arm, Single-Dose Gene Replacement Therapy Clinical Trial for Patients with Spinal Muscular Atrophy Type 1 with One or Two SMN2 Copies Delivering AVXS-101 by Intravenous Infusion

Spinal muscular atrophy is a neurogenetic disorder caused by a loss or mutation
in the survival motor neuron 1 gene (SMN1) on chromosome 5q13, which leads to
reduced SMN protein levels and a selective dysfunction of motor neurons.
It is an autosomal recessive, early childhood disease with an incidence of
approximately 1:10,000 live births. Spinal muscular atrophy is the leading
cause of infant mortality due to genetic diseases.
Disease severity and clinical prognosis depends on the number of copies of
survival motor neuron 2 gene (SMN2). In its most common and severe form (Type
1), hypotonia and progressive weakness are recognized in the first few months
of life, leading to diagnosis before 6 months of age and early death due to
respiratory failure before 2 years of age.

The findings from various neurophysiological and animal studies have shown an
early loss of motor neurons in the embryonic and early post-natal periods. From
a clinical perspective, these findings emphasize the importance of first
targeting the SMA Type 1 group for gene transfer of SMN2 in hopes of rescuing
neurons at this critical stage.
Trial AVXS-101-CL-302 is a pivotal Phase 3 clinical gene therapy trial
investigating the efficacy and safety of a single intravenous (IV) infusion of
AVXS-101 in up to 30 patients with Type 1 spinal muscular atrophy (SMA) with
one or two copies of SMN2.

The survival motor neuron (SMN) gene will be transferred using
self-complementary adeno-associated virus (scAAV) Type 9 under control of the
chicken-*-actin hybrid promoter.

Pre-clinical studies have demonstrated survival of the SMN*7 mouse model for
SMA from a median of 15.5 days to over one year, following IV delivery to the
peripheral vein. Additionally, preliminary results from an ongoing Phase 1
clinical trial (AVXS-101-CL-101) of AVXS-101 in SMA Type 1 patients
demonstrates broad improvements in survival, motor function, pulmonary
function, and nutritional function.

The goal in continuing the development plan for AVXS-101 is to modify the SMA
Type 1 phenotype, which will hopefully lead to a milder disease course and
prolonged survival as seen in SMA Type 2 and Type 3 patients.

Primary
* Determine efficacy by demonstrating achievement of developmental milestone of
sitting without support up to 18 months of age as defined by WHO Motor
Developmental Milestones[22].

Secondary
* Determine efficacy based on survival at 14 months of age. Survival is
defined by the avoidance of combined endpoint of either (a) death or (b)
permanent ventilation which is defined by tracheostomy or by the requirement of
* 16 hours of respiratory assistance per day (via non invasive ventilatory
support) for * 14 consecutive days in the absence of an acute reversible
illness, excluding perioperative ventilation. Permanent ventilation, so
defined, is considered a surrogate for death.

Exploratory
Determine efficacy by demonstrating achievement of other developmental
milestones.

Safety
* Evaluate the safety of AVXS 101 in patients with SMA Type 1.
* Determine the safety of AVXS 101 based on the development of unacceptable
toxicity defined as the occurrence of any Common Terminology Criteria for
Adverse Events [25] (CTCAE) Grade 3 or higher, unanticipated, treatment-related
toxicity.

Phase 3, open-label, single-arm, single-dose, trial of AVXS 101 (gene
replacement therapy) in patients with spinal muscular atrophy (SMA) Type 1 who
meet enrollment criteria and are genetically defined by a biallelic pathogenic
mutation of the survival motor neuron 1 gene (SMN1) with one or two copies of
survival motor neuron 2 gene (SMN2). Up to 30 patients < 6 months (< 180 days)
of age at the time of gene replacement therapy (Day 1) will be enrolled.

The trial 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 complete screening
procedures to determine eligibility for trial enrollment. Patients who meet
the entry criteria will enter the in patient gene replacement therapy period
(Day *1 to Day 3). On Day *1, patients will be admitted to the hospital for
pre treatment baseline procedures.
On Day 1, patients will receive a one time intravenous (IV) infusion of AVXS
101, and will undergo in patient safety monitoring over the next 48 hours.
Patients may be discharged 48 hours after the infusion, based on Investigator
judgment. During the outpatient follow-up period (Days 4 to End of Trial at 18
months of age), patients will return at regularly scheduled intervals for
efficacy and safety assessments until the End of Trial when the patient reaches
18 months of age. After the End of Trial visit, eligible patients will be
asked to rollover into the long-term follow up trial, AVXS-101-LT-002.
All post-treatment visits will be relative to the date on which gene
replacement therapy is administered, except for the 14 and 18 months of age
visits, which will be relative to the patient*s date of birth.

In an attempt to dampen the host immune response to the adeno-associated virus
(AAV) derived therapy, all patients will receive prophylactic prednisolone at
approximately 1 mg/kg/day beginning 24 hours prior to AVXS 101 infusion until
at least 30 days post infusion. Overall management of prophylactic
prednisolone is at the discretion of the Investigator. After 30 days of
treatment, the dose of prednisolone can be tapered for patients whose alanine
aminotransferase (ALT) values and aspartate aminotransferase (AST) values are
*2 X ULN, and T-cell response are < 100 SFC/106 PBMCs in accordance with the
following treatment guideline: 1 mg/kg/day until at least 30 days
post-infusion, 0.5 mg/kg/day at Weeks 5 and 6, 0.25 mg/kg/day at Weeks 7 and 8,
and discontinued at Week 9. If the AST or ALT values are *2 X ULN, or if
T-cell response is * 100 SFC/106 PBMCs after 30 days of treatment, the dose of
prednisolone will be maintained until the AST and ALT values decrease below
threshold. If T cell response continues past Day 60, Investigator discretion
should be used considering risk benefit for maintaining prednisolone. Variance
from these recommendations will be at the discretion of the Investigator based
on potential safety issues for each patient.

Efficacy will be assessed by achievement of the key developmental milestone of
sitting without support for at least 10 seconds based on World Health
Organization [WHO] Child Growth Standards [22] at any point up to and including
the 18 months of age trial visit, and survival at 14 months of age.

Safety will be assessed through monitoring adverse events (AEs), concomitant
medication usage, physical examinations, vital sign assessments, cardiac
assessments, and laboratory evaluations. A Data Safety Monitoring Board (DSMB)
/ Data Monitoring Committee (DMC) will review safety data on a quarterly basis,
and will also convene within 48 hours should any patient experience an
unanticipated CTCAE Grade 3, or higher AE/toxicity that is possibly, probably,
or definitely related to gene replacement therapy, and is associated with
clinical symptoms and/or requires medical treatment. This includes any patient
death, important clinical laboratory finding, or any complication attributed to
administration of gene replacement therapy. In such instances, the DSMB/DMC
will review the safety information and provide its recommendation. Based upon
the DSMB/DMC*s review, the DSMB/DMC can recommend continuing enrollment,
halting enrollment, or early termination of the trial for safety reasons.

AVXS 101 will be administered as a one time IV infusion over 30-approximately
60 minutes, dependent upon volume.
Active ingredient: Survival Motor Neuron Gene by Self*Complementary Adeno
Associated Virus Serotype 9 (AAV9).

Given the devastating clinical course of Type 1 SMA, the irreversible and
progressive nature of motor neuron loss as the disease progresses, and the
urgent and substantial unmet medical need in this serious disorder, the
available data strongly support a positive benefit/risk relationship and
strongly support continued study of AVXS-101 in patients with symptomatic and
presymptomatic SMA.
Because of the limited number of patients treated with AVXS-101 to date, the
potential risks associated with AVXS-101 are not fully known at this time.
Patients could develop an immune response to the AAV9 viral vector, which could
interfere with or prevent future use of gene transfer interventions using this
vector. Elevated liver function tests have been observed in the ongoing
AVXS-101-CL-101 trial, which is believed to reflect a T-cell immune response to
the AAV9 vector. None of the liver enzyme abnormalities observed in the trial
were accompanied by clinical sequelae, and all have resolved following
treatment with prednisolone. Although no other treatment-related AEs have been
reported to date, other potential risks of treatment may exist that are not
currently known given the limited clinical experience to date, and the
benefit/risk profile will continue to become better characterized with
continued study.
Non clinical data in nonhuman primates and mouse models of SMA provide
additional support for a positive benefit/risk relationship, and support
continued clinical investigation of AVXS-101 in patients with SMA. Efficacy
studies in the SMN*7 mouse model of SMA have demonstrated significant apparent
benefits in several disease-associated phenotypes, including motor functioning,
body weight, and survival. Local vascular necrosis of the ear pinna was
observed in some treated SMN*7 mice. Because similar findings have been
reported in other studies of SMN*7 mice and have been observed in several other
SMA mouse models, it is believed this finding is unlikely to be related to
treatment. In preclinical toxicology studies conducted in wild-type mice and
cynomolgus macaques, no toxicologically significant treatment related effects
were seen on body weight or on hematology, clinical chemistry and
histopathology evaluations.
Taken together, results from the clinical and nonclinical studies to date
support continued clinical investigation of the efficacy and safety of AVXS-101
in patients with SMA Type 1, and additionally support further investigation of
intravenous and intrathecal administration of AVXS-101 in a broader population
of patients with SMA.

While there is only one dose of AVXS-101 given during the study, participation
in the study requires significant time commitment from the child*s family. In
addition to the screening visit, an in-patient hospital stay is required,
weekly clinic visits for the first month after gene replacement, and then
monthly visits until the child reaches 18 months of age. Due to protocol
required assessments, including videotaping of motor function milestones, post
treatment visits could last up to 8 hours.