* At baseline, none of the patients in cohort 2 had achieved any of the listed motor milestones except for bringing a hand to the mouth. As of August 7, 2017, the majority of these patients had reached at least one major motor milestone. No patients in cohort 1 are listed, since none attained any motor milestones. NA denotes not available, and NIV noninvasive ventilation. Plus signs indicate achievement of milestone.
† Event‑free survival (the primary efficacy outcome) was defined as the age at the last follow‑up at which patients were free of ventilatory support, which was defined as the need for ventilation for at least 16 hours per day for at least 14 consecutive days.
‡ According to item 20 on the Bayley Scales of Infant and Toddler Development, rolling over is defined as movement of at least 180 degrees both left and right from a position of lying on the back.
§ Sitting unassisted for at least 5 seconds is in accordance with the criteria of item 22 on the Bayley Scales of Infant and Toddler Development gross motor subtest and surpasses the 3‑second count that is used as a basis for sitting (test item 1) on the Hammersmith Functional Motor Scale–Expanded for Spinal Muscular Atrophy (SMA). Sitting unassisted for at least 10 seconds is in accordance with the criteria used in the World Health Organization Multicentre Growth Reference Study. Sitting unassisted for at least 30 seconds defines functional independent sitting and is in accordance with the criteria of item 26 on the Bayley Scales of Infant and Toddler Development gross motor subtest.
¶ Nutritional support refers to the placement of either a gastrostomy tube or a nasogastric tube, as determined by the preference of the parents or the primary physician. Once enrolled in the study, all the patients who required nutritional support underwent gastrostomy‑tube placement, and none were removed during the study.
‖ Data are from Finkel et al.
** Data are from De Sanctis et al.
The primary outcome measure for our Phase 1 trial of AVXS‑101 was safety. As of August 7, 2017, a total of 56 serious adverse events, or SAEs, were observed in 13 patients. Of these 56 SAEs, there were two treatment‑related SAEs in two patients. There were also three treatment‑related non‑serious adverse events reported in two patients. All five treatment‑related SAEs and AEs were clinically asymptomatic liver function enzyme, or LFE, elevations.
The treatment‑related SAEs consisted of two patients that experienced elevated LFEs, which were each assessed as a Grade 4 event under the Common Terminology Criteria for Adverse Events on the basis of laboratory values. We observed the first of these treatment‑related SAEs in the first patient dosed with AVXS‑101 in our Phase 1 clinical trial. After the onset of elevated LFEs, this patient was given a prednisolone regimen starting at 2 mg/kg daily and tapering off over time as LFEs returned to normal. After the first patient, we revised our clinical protocol 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 increase in LFEs. As of August 7, 2017, following this protocol change, out of the remaining 14 patients in our Phase 1 clinical trial, 11 patients had no reported adverse events related to elevations in LFEs, two patients had Grade 1 or 2 elevations in LFEs, and one patient experienced a Grade 4 elevation in LFE on the basis of laboratory values. 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 August 7, 2017, all AEs and SAEs related to elevated LFEs were isolated elevations in serum transaminases, clinically asymptomatic and resolved with prednisolone treatment. There were no elevations in total bilirubin, gamma‑glutamyl transferase or alkaline phosphatase and the conditions that constitute Hy’s law were not met.