P.373 - AVXS-101 phase 1 gene therapy clinical trial in SMA Type 1: decreased need of ventilatory and nutritional support at End-of-Study

Abstract

Spinal muscular atrophy Type 1 (SMA1) is devastating monogenic neurodegenerative disease characterized by lower motor neuron loss. Motor neuron loss results in severe swallowing and breathing dysfunction that, without nutritional and ventilatory support, leads to malnutrition, chronic aspiration, and ultimately death via respiratory failure. According to SMA1 natural history, most SMA1 patients will require nutritional and ventilatory support. Here we report end-of-study data of SMA1 infants treated with the proposed therapeutic dose of AVXS-101, a gene replacement therapy that crosses the blood-brain-barrier. In this study, 15 patients with SMA1 with 2xSMN2 copies confirmed by genetic testing were enrolled; all patients had bi-allelic Exon 7 deletions of SMN1 and no SMN2 disease modifying mutation (predicts an extremely severe phenotype). Cohort 2 received an intravenous dose of AVXS-101 at 6.7e13vg/kg (Cohort1, n = 3, low dose) or 2.0e14vg/kg (Cohort2, n = 12, proposed therapeutic dose). At end-of-study, all patients in Cohort2 were ≥15 months (20Jan2017). At study enrollment, 10 patients did not require ventilatory support; at end-of-study, 7/10 remained free of ventilatory support. At baseline, 7 patients did not require nutritional support at baseline; at end-of-study, 6/7 remained free of nutritional support. At baseline, 7 patients were able to feed orally; at end-of-study 11 were able to feed orally; no patient lost the ability to feed orally following gene transfer. In contrast to natural history, the majority of patients in this Phase 1 trial who did not require nutritional or ventilatory support at baseline did not require either at end-of-study. Moreover, 4 patients acquired the ability to feed orally, suggesting the potential of AVXS-101 to improve swallowing function. Patients treated early in age and early in disease course have continued to avoid the need for ventilatory and/or nutritional support, in sharp contrast to the natural history of the disease.