Table of Contents
to include pre-treatment with prednisolone at 1 mg/kg/day starting one day prior to the gene transfer in order to mitigate the T-cell immune response against AAV9 and the corresponding
in LFE. As of December 31, 2015, following this protocol change, out of the remaining 14 patients in our Phase 1 clinical trial, 11 patients have not had LFEs outside of the normal
range, two patients have had Grade 1 or 2 LFEs, and one patient has experienced a Grade 4 LFE. We observed that this Grade 4 LFE patient had a concomitant viral infection and required
additional prednisolone therapy until the LFEs returned to the normal range. We believe that the pretreatment with prednisolone has generally been effective in reducing the incidence and degree of
elevated LFEs. As of December 31, 2015, all AEs and SAEs related to elevated LFEs have been clinically asymptomatic.
on the 15 patients dosed as of December 31, 2015, we have observed AVXS-101 to be generally well-tolerated. There were a total of 44 adverse events, or AEs, ten of which
were SAEs, as discussed above, and 34 of which were assessed as mild or moderate. Of the 34 mild or moderate AEs, three AEs were assessed as related to study treatment and experienced by two patients
(the Grade 1 and 2 LFEs, as discussed above). As of December 31, 2015, the most frequent adverse events not related to study treatment that were assessed as mild and moderate occurring in more
than one patient were: constipation, upper respiratory infection, fever, fracture, ear infection, skin irritation and vomiting.
Preliminary preclinical proof of concept and safety and tolerability studies of the intravenous delivery method were conducted at NCH
and in conjunction with the Mannheimer Foundation for non-human primate studies. In a mouse model of SMA Type 1, it was observed that a single intravenous injection of AVXS-101 in mice improved
body weight and motor functions, while also extending the median lifespan of the treated mice from 16 days to over 400 days, compared to untreated mice, in a dose-responsive manner. In a
preclinical study of non-human primates, it was observed that a single intravenous injection of AVXS-101 led to sustained human SMN transgene expression in the spinal cord as well as in multiple
organs and muscles, when evaluated 24 weeks after injection of AVXS-101. NCH has also conducted multiple safety and tolerability studies in mice and non-human primates and no evidence of
toxicity was observed for up to 24 weeks after injection of AVXS-101.
addition, preliminary preclinical proof of concept (efficacy and safety) studies of the intrathecal delivery method were conducted at NCH. It was observed that in mice with SMA
Type 1, a single intrathecal injection of AVXS-101 at a maximum dosage level of 3.3 × 1013 vg/kg, which was 10 times lower than the intravenous dose of 3.3 × 1014 vg/kg,
improved body weight and motor functions, and most notably extended the median lifespan from 18 days to 282 days, with one-third of the mice surviving past 400 days. In the SMA
mouse model, it was observed that a single intrathecal injection of scAAV9 containing a green fluorescent protein targeted between 21% to 41% and 46% to 72% of motor neurons in the spinal cord at the
lowest dosage level and the highest dosage level, respectively. In non-human primates, it was observed that a single intrathecal injection of scAAV9 containing green fluorescent protein at a dose of
1.0 × 1013 vg/kg targeted 29%, 53% and 73% of cervical, thoracic and lumbar motor neurons, respectively. With tilting for ten minutes in the Trendelenburg position, such targeting
increased to 55%, 62% and 80% of cervical, thoracic and lumbar motor neurons, respectively. In swine, NCH designed a small hairpin RNA that targeted
porcine SMN and left human SMN intact, which reduced expression of porcine SMN. It was observed that the administration of AVXS-101 resulted in robust production of human SMN protein and significant
increases in motor function. When delivered prior to the onset of motor function decline, AVXS-101 prevented the majority of SMA symptoms, demonstrated by motor function testing as well as
electrophysiological evaluation. When delivered at the onset of SMA symptoms, AVXS-101 halted further progression and there were improvements in motor function as well as electrophysiological
evaluation of motor units.