SMA THERAPIES I: P.179AVXS-101 trial experience: CHOP-INTEND effectively quantifies early, rapid, and sustained improvements that precede subsequent milestone achievement but is not sensitive to continued advances in motor function in infants with SMA type 1

Abstract

The Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) quantifies the natural decline of motor skills in spinal muscular atrophy type 1 (SMA1) infants (maximum score=64). By 6 months of age, SMA1 infants almost never achieve a CHOP-INTEND score ≥40 points. We aimed to assess the sensitivity of the CHOP-INTEND to improvement in motor skills of infants treated with AVXS-101 gene replacement therapy. Twelve SMA1 infants (median age=3.1 months) who received a one-time, intravenous, proposed therapeutic dose of AVXS-101 (NCT02122952) underwent CHOP-INTEND assessments monthly (subsequently changed to quarterly in year 2) over a 24-month follow-up interval. Rapid response in CHOP-INTEND was observed with mean increases of 9.8 points at 1 month and 15.4 points at 3 months post-dosing; 11/12 patients achieved a score of ≥40 at a mean age of 5.3 months. Eleven of 12 sat unassisted and rolled without a commensurate change in score (August 7, 2017). Discordant with achievement of sitting unassisted at a mean of 15.9 months post-dose, the mean CHOP-INTEND score plateaued at 54 at approximately 9.9 months post-dose in the 9 children who sat unassisted for ≥5 seconds, but did not achieve the scale maximum. CHOP-INTEND identifies an early rapid treatment response in AVXS-101-treated infants, demonstrating departure from natural history. However, the CHOP-INTEND ceiling limits its sensitivity to predicting motor milestone achievement. To accurately detect further gains in motor function beyond that historically achieved by SMA1 children, additional assessment tool(s) with advanced items are necessary (eg, Bayley-III).