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AVEXIS, INC. filed this Form S-1/A on 02/01/2016
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    A recombinant AAV9 capsid shell:  a non-replicating adeno-associated virus capsid to deliver a functional copy of a human SMN gene to the patient's own cells without modifying the existing DNA of the patient. Unlike many other capsids, the AAV9 capsid utilized in AVXS-101 crosses the blood-brain barrier, a tight protective barrier which regulates the passage of substances between the bloodstream and the brain, and into the spinal cord, thus allowing the option for intravenous administration. In addition, AAV9 has been observed in preclinical studies to efficiently target motor neuron cells when delivered via either intrathecal or intravenous administration. In AVXS-101, the DNA contained within the capsid shell is engineered to contain the other three critical elements of AVXS-101, with the removal of the viral DNA, which leads to a lack of pathogenicity and inability of the AAV9 virus to replicate in the patient's existing DNA.

    A human SMN transgene:  a stable, functioning SMN gene that is introduced into the cell's nucleus.

    Self-complementary DNA technology:  the human SMN transgene is introduced as a self-complementary double-stranded molecule. The inclusion of this technology enables rapid onset of effect. Typically, a single-stranded AAV vector must wait for cell-mediated synthesis of its complementary DNA strand to form the double-stranded DNA unit that is required for DNA replication and subsequent protein synthesis. The self-complementary modification overcomes this rate-limiting step of cell-mediated second-strand synthesis, as the two complementary halves of the scAAV genomes will associate with each other to form the required double-stranded DNA unit.

    A continuous promoter: this agent activates the transgene and is designed to allow for continuous and sustained SMN expression. The cytomegalovirus enhanced chicken beta-actin hybrid promoter that we utilize is a constitutive, or "always on" promoter that has been observed to increase transgene expression from AAV vectors compared to other promoters.

Clinical Development of AVXS-101

          We are currently developing AVXS-101 for the treatment of SMA Type 1 through intravenous administration. In April 2014, an open-label, dose-escalation Phase 1 clinical trial of AVXS-101 in patients with SMA Type 1 was initiated as an investigator-sponsored trial at NCH and under an IND held by Dr. Jerry Mendell, the principal investigator at NCH. We completed the transfer of the IND to AveXis in November 2015. The trial design allows for the enrollment of up to 15 patients across a maximum of three dosing cohorts. Key inclusion criteria include patients whose diagnosis of SMA Type 1 occurred before six months of age and have two copies of the SMN2 backup gene, as determined by genetic testing conducted by Clinical Laboratory Improvement Amendments of 1988, or CLIA, certified laboratories. Additionally, patients must have been no older than nine months of age (for the first nine patients) and six months of age (for the last six patients) at the time of vector infusion.

          The primary outcome measure of our Phase 1 clinical trial is safety and tolerability. The secondary outcome measure is an efficacy measure as defined by the time from birth to an "event," which is defined as either death or at least 16 hours per day of required ventilation support for breathing for 14 consecutive days in the absence of acute reversible illness or perioperatively. We are also assessing several exploratory objective measures in the clinical trial. These exploratory measures are included to assess additional testing protocols on patients in an effort to identify objective testing criteria for measuring the results of the therapy. These exploratory tests include administering a standard motor milestone development survey and CHOP INTEND, compound motor action potentials testing (CMAP), motor unit number estimation testing (MUNE), non-invasive


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