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AVEXIS, INC. filed this Form 10-K on 02/28/2018
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maximum CHOP INTEND score of 64. The Finkel 2014 Study reported that patients with SMA Type 1 have an average annual decrease of 1.27 points in their CHOP INTEND score. The NeuroNEXT Study indicated a mean decline of 10.5 points in CHOP INTEND scores over a one-year period in untreated SMA Type 1 patients, highlighting the rapid loss of motor function occurring early in the disease course. All 15 patients enrolled in our Phase 1 trial experienced improvement from baseline in motor skills measured by their CHOP INTEND scores and such improvement appeared to be dose‑dependent. As of August 7, 2017, the patients in cohorts 1 and 2 had increased scores from baseline on the CHOP INTEND scale and maintained these changes during the study. Patients in cohort 2 had mean increases of 9.8 points at 1 month and 15.4 points at 3 months. At the study cutoff on August 7, 2017, patients in cohort 1 had a mean increase of 7.7 points from a mean baseline of 16.3 points, and those in cohort 2 had a mean increase of 24.6 points from a mean baseline of 28.2 points. As of August 7, 2017, 10 out of 15 patients treated had completed their 2-year follow-up after receipt of their AVXS-101 gene therapy. Based on our observations to date, we believe that increases in CHOP INTEND motor assessments appear to be age, baseline CHOP INTEND score and dose‑dependent. We believe that there may be a dose response, based on our observation of CHOP INTEND scores of patients receiving the proposed therapeutic dose as compared to patients receiving the low dose because, as a group, the patients receiving the proposed therapeutic dose appear to be demonstrating a larger average CHOP INTEND score increase.

Patients with SMA Type 1 entered the trial at different ages, stages of disease progression and levels of motor function that can result in significant variability in baseline CHOP INTEND scores from patient to patient. Additionally, month‑to‑month variability in CHOP INTEND scores can be influenced by factors that are not related to study treatment. Examples of these factors include upper respiratory tract infections and fractured limbs, which may preclude the testing of some elements of the CHOP INTEND assessment. Our observations are consistent with the Finkel 2014 Study in which baseline CHOP INTEND scores also demonstrated significant variability. While the improvements seen with AVXS‑101 in the proposed therapeutic dose cohort have never been observed in the natural history population, we believe observing change in CHOP INTEND scores over time is beneficial.

The natural history of SMA Type 1 is marked by the inability to achieve or maintain developmental motor milestones. An independent, peer‑reviewed natural history study of developmental milestones in SMA Type 1 published in Neuromuscular Disorders in 2016, or the De Sanctis 2016 Study, reported that prolongation of survival with supportive care does not impact achievement of motor milestones. As observed in the De Sanctis 2016 Study, a child with SMA Type 1 with symptom onset prior to six months of age will not reach any major milestones such as sitting, crawling, standing and walking, and the highest milestone achieved is seen in the infant’s first visit followed by a rapid decline. In contrast, patients in the proposed therapeutic‑dose cohort consistently achieved and maintained key developmental motor milestones. As of August 7, 2017, 11 of 12 patients (92%) in the proposed therapeutic‑dose cohort achieved head control, nine of 12 patients (75%) could rollover and 11 of 12 patients (92%) could sit with assistance. For the end‑of‑study assessment at January 20, 2017 and subsequent assessments, including the August 7, 2017 assessment, we evaluated three validated and well‑established measures of sitting unassisted for periods of increasing duration. At August 7, 2017, 11 of 12 patients (92%) could sit unassisted for at least five seconds, 10 of 12 patients (83%) could sit unassisted for at least 10 seconds and nine of 12 patients (75%) could sit unassisted for 30 seconds or more. Two patients could walk independently and each had achieved earlier and important developmental milestones such as standing with support, standing alone and walking with support. These milestone achievements were assessed and adjudicated by an independent, third‑party reviewer using video evidence. The results of this process are included in the chart below.



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