Based on the 15 patients dosed as of August 7, 2017, we observed AVXS‑101 to be generally well‑tolerated. As previously reported, a total of five adverse events, or AEs, in four patients were deemed treatment‑related. Of these, two were SAEs experienced by two patients, and three were non‑serious AEs experienced by two patients. All consisted of clinically asymptomatic liver enzyme elevations and were resolved with prednisolone treatment. There were no clinically significant elevations of gamma‑glutamyl transferase, alkaline phosphatase or bilirubin and, as such, the conditions that constitute Hy’s Law were not met. Other non‑treatment related AEs were expected and were associated with SMA. A cumulative total of 297 AEs (5 treatment‑related AEs and 292 non‑treatment related AEs) were reported as of August 7, 2017, following monitoring and source verification. Of these, 56 were determined to be SAEs and 241 were non‑serious AEs.
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 14 days to greater than 250 days with 30% of mice surviving over 400 days, compared to untreated mice, in a dose‑responsive manner. In these studies, a minimally effective dosage was determined to be 6.7 × 1013 vg/kg which increased median lifespan to 28 days. Escalating the dosage to 2.0 × 1014 vg/kg increased the median lifespan of the SMA mouse model greater than 250 days. Further increasing the dosage to 3.3 × 1014 vg/kg also resulted in the SMA mouse model to have a median lifespan greater than 250 days. The 2.0 × 1014 vg/kg and 3.3 × 1014 vg/kg dosages appeared to be indistinguishable, with animals showing normal motor function. 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. AVXS‑101 has also been studied in 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.
In 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, 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 and collaborators at Ohio State University 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.
Future Applications and Opportunities
Based on preclinical data and the clinical data from our Phase 1 clinical trial for SMA Type 1, we believe AVXS‑101 may also have utility in other types of SMA, which result from the same genetic defect as SMA Type 1 as it addresses the root cause of the disease. In addition to our ongoing Phase 1 clinical trial for SMA Type 2, we intend to conduct the following additional clinical trials to further evaluate AVXS-101, including in new SMA patient populations: