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AVEXIS, INC. filed this Form 10-K on 02/28/2018
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Patients that have SMA Type 1, the most severe type of SMA, have an onset of symptoms within six months of birth, have difficulty breathing and swallowing and will never develop the strength or muscle control to sit up independently or the ability to crawl or walk. SMA Type 1 patients frequently die in early childhood due to complications related to respiratory failure resulting from motor neuron degeneration. Although SMA Types 2, 3 and 4 are generally less severe than SMA Type 1, they still present patients with significant medical challenges. The standard of care for patients with SMA Type 1 has traditionally been limited to palliative therapies, including life‑long respiratory care, ventilator support, nutritional care, orthopedic care and physical therapy. In December 2016, the FDA approved SPINRAZATM (nusinersen), developed by Biogen and Ionis Pharmaceuticals, Inc., for the treatment of SMA. Nusinersen employs an approach for the treatment of SMA called alternative splicing, which seeks to achieve more efficient production of full‑length SMN protein from the SMN2 gene. However, we believe that there is significant interest in a gene replacement therapy for SMA that can act on the underlying defect in the primary gene (SMN1) and can provide enhanced survival and motor function benefit via a one‑time dose.

SMA is caused by a genetic defect in the SMN1 gene that codes SMN, a protein necessary for survival of motor neurons. Although individuals typically receive one copy of the SMN1 gene from each parent, only one properly functioning SMN1 gene is required to generate adequate levels of full‑length SMN protein. SMA results from the patient’s lack of a properly functioning SMN1 gene, either due to mutation or loss of the gene. SMA is a recessive trait, meaning that while both parents of an SMA patient may be healthy, they each carry and pass along to their child DNA that contains either a mutated or missing SMN1 gene which results in the disease manifesting itself in the child.

Human DNA contains a backup to the SMN1 gene, the SMN2 gene. Individuals may carry multiple copies of the SMN2 backup gene within their DNA. However, approximately 90% of SMN protein produced by the SMN2 backup gene is non‑functional, truncated SMN protein missing a polypeptide segment (coded for by exon 7) that is essential to form a functional SMN molecule. The level of functional full‑length SMN protein produced by an SMA patient’s SMN2 genes is generally insufficient to prevent loss of proper motor neuron function. As the SMN2 genes are capable of producing minimal levels of full‑length SMN protein, the number of copies of the SMN2 backup gene serves as a disease modifier, such that the more copies of the SMN2 backup gene there are, the less severe the disease. The following diagram presents the difference between a healthy person and someone afflicted by SMA.

Picture 1

SMA is typically diagnosed based on the onset of clinical symptoms along with a genetic assessment of the absence of SMN1 and the number of copies of SMN2. However, a genetic diagnosis can also be made prenatally either through amniocentesis or chorionic villus sampling.

The following table describes the general disease onset, incidence rates, survival and general characteristics for each of the different types of SMA.


















Incidence per







Number of




Live Birth











among SMA





SMA Type


of SMN2









Type 1 (Werdnig-Hoffman Disease)




Before six months


Approximately 60%


Less than 10% event free* by two years of age


Will never be able to sit without support

Type 2 (Dubowitz Syndrome)


Three or Four


6 - 18 months


Approximately 27%


68% alive at age 25


Will never be able to walk or stand without support

Type 3 (Lugelberg-Welander Disease)


Three or Four


Early childhood to early adulthood (juvenile)


Approximately 13%




Stand alone and walk but may lose ability to walk in 30s - 40s

Type 4


Four to Eight


Adulthood (20s - 30s) usually after 30


Uncommon: limited incidence information available




Same as Type 3




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