PC3013: Improved Growth in Children with Acid Sphingomyelinase Deficiency Treated with Olipudase Alfa Enzyme Replacement Therapy

Background: Acid sphingomyelinase deficiency (ASMD) is an under-recognized and debilitating lysosomal storage disease. Deficient ASM activity results in progressive visceral, hematologic, and pulmonary dysfunction across a disease spectrum, with CNS manifestations in the most severe patients. Growth deficits and delayed puberty are common; in a prospective ASMD natural history study, mean height Z-scores were -0.9 in children aged 6-11 and -2.7 in children aged 12-17 with little catch-up growth over time. Olipudase alfa, intravenous recombinant human ASM (Sanofi), was recently approved in Japan and is being evaluated in other markets as the first and only treatment for the non-central-nervous-system manifestations of ASMD. An international open-label trial of olipudase alfa in 20 children with chronic ASMD (ASCEND-Peds, NCT02292654, primary outcome, safety at 64 weeks) demonstrated significant clinical improvements during year 1 of treatment. All 20 patients continue treatment in a long-term study (NCT02004704). We report the long-term safety, efficacy, and growth outcomes in olipudase-alfa-treated children from the ASCEND-Peds trial.

Methods: Mean efficacy data are provided as 2-year change from baseline±SD; safety data and individual patient data represent all data as of database lock (03/2021).

Results: Because enrollment spanned 3 years, time on treatment ranged from 2.5 to 5.7 years (mean 4.0±1.2). At baseline, age ranged from 1.5-17.5 years; mean spleen volume was 19.0±8.8 multiples of normal (MN); mean liver volume was 2.7±0.7 MN; mean percent-predicted hemoglobin-adjusted carbon monoxide diffusing capacity (DLCO; n=9 children able to perform test) was 54.8±14.2%; mean height Z-score was -2.1±0.8 (min-max: -3.8 to -1.0). Spleen and liver volume decreased over time on treatment in all patients (mean 2-year percent decrease in MN: 60.9%±8.7% and 49.0%±10.1%, respectively, p< 0.0001). Mean percent change in percent-predicted DLCO improved (mean 2-year increase: 46.6%±25.5%, p< 0.0001). Lung imaging studies, lipid profiles, liver function tests, and plasma disease biomarkers also improved. Height Z-score (Figure 1) and height percentiles relative to CDC norms (Figure 2) improved over time in all patients (mean 2-year increase in Z-score: 1.17±0.50, p< 0.0001). At baseline, 10/20 patients had Z-scores ≤-2 (definition of short stature); after olipudase alfa treatment, just one patient remained below this threshold (Figure 1). The difference between actual age and bone age (by hand x-ray) improved from a mean of -24.4±18.4 months at baseline to -17.0±16.0 months at 2 years. Olipudase alfa was well-tolerated; >99% of adverse events were mild or moderate. Four patients had seven treatment-related serious adverse events, none led to treatment discontinuation. An anaphylactic reaction was reported in one infant who was successfully desensitized and reached target dose.

Conclusion: In addition to improvements in organomegaly, pulmonary function, and dyslipidemia, all 20 children with ASMD from the ASCEND-Peds trial of olipudase alfa showed significant catch-up growth, with improvements in height Z-scores and CDC percentiles.
Funded by Sanofi