IP 853. AVXS-101 Phase-1-Gene Therapy Clinical Trial in SMA Type 1: Event-Free Survival and Achievement of Developmental Milestones

Background: Spinal muscular atrophy (SMA) is a devastating, monogenic neurodegenerative disease. Children with its most severe form, SMA Type 1 (SMA1), are unable to sit unassisted or maintain head control. A natural history study of SMA1 reported that none achieved an Infant Test of Neuromuscular Disorders (CHOP-INTEND) score of ≥40 by 6 months of age (one transient exception), and 92% died or required permanent ventilation by 20 months.

Aims: The AVXS-101 phase 1 clinical trial explores safety and efficacy of a one-time intravenous administration of gene replacement therapy in SMA1. AVXS-101 delivers the survival of motor neuron (SMN) gene via the adenoassociated virus 9 viral vector, which crosses the blood–brain barrier.

Question: Does AVXS-101 appear to demonstrate both rapid improvement following intravenous administration as well as sustained response up to 2 years posttreatment?

Methods: In this phase 1 trial, 15 patients with SMA1 confirmed by genetic testing (with 2 × SMN2 copies) were enrolled. Patients received an intravenous dose of AVXS-101 at the low dose (cohort 1, n = 3) or proposed therapeutic dose (cohort 2, n = 12). The primary objective was safety and secondary objectives included survival (avoidance of death/permanent ventilation) and ability to sit unassisted (video confirmed by external independent reviewer). CHOP-INTEND scores and other motor milestones were recorded.

Results: AVXS-101 appeared to have a favorable safety profile and to improve survival (as of August 7, 2017). All 15 patients were alive and did not require permanent mechanical ventilation at 20 months of age. Patients in cohort 2 demonstrated improvements in motor function. Responses in CHOP-INTEND scores were observed with mean increases of 9.8 points at 1 month and 15.4 points at 3 months postdosing; 11/12 patients achieved a score ≥40, and a mean increase of 24.6 points from a mean baseline of 28.2 points. Eleven of 12 patients were able to sit unassisted for at least 5 seconds, 10 for at least 10 seconds, and 9 for at least 30 seconds; 11/12 achieved head control and 9 could roll over. Two patients were able to crawl, pull to stand, stand, and walk independently. Asymptomatic transient rise in serum aminotransferase levels occurred in four patients and were attenuated by prednisolone.

Conclusion: In contrast with the natural history, a one-time intravenous administration of AVXS-101 appeared to demonstrate a positive impact on the survival of both cohorts. Early improvements in motor function, as well as a dramatic, sustained impact on motor function were seen in cohort 2: CHOP-INTEND scores increased during the first and third months posttreatment, and 11/12 patients achieved CHOP-INTEND scores and motor milestones rarely or never seen in this population. No waning of effect or clinical regression in motor function was reported up to August 7, 2017, data cut. A clinical update of the 24-month safety follow-up will be given at the time of presentation.