Genet Med 2021 Aug;23(8):1543-1550. doi: 10.1038/s41436-021-01156-3. Epub 2021 Apr 19.

PMID: 33875845

George A Diaz, Simon A Jones, Maurizio Scarpa

Highlights: In this study in children with chronic ASMD, olipudase alfa was generally well-tolerated with significant, comprehensive improvements in disease pathology across a range of clinically relevant endpoints.

Abstract

Purpose: The goal of this study was to assess olipudase alfa enzyme replacement therapy for non-central nervous system manifestations of acid sphingomyelinase deficiency (ASMD) in children.

Methods: In this phase 1/2, worldwide, multicenter, open-label study (ASCEND-Peds/NCT02292654), olipudase alfa was given intravenously every two weeks, with intrapatient dose escalation to 3 mg/kg. Primary outcome was safety through week 64. Pharmacokinetics, spleen and liver volumes, lung diffusing capacity (DLCO), lipid profiles, and height through week 52 were all secondary outcomes.

Results: Twenty patients were included in the study: four adolescents (12-17 years), nine children (6-11 years), and seven infants/young toddlers (1-5 years). The majority of adverse events were mild or moderate, with 11 patients experiencing infusion-related reactions (mainly urticaria, pyrexia, and/or vomiting). Three patients experienced serious treatment-related events: one experienced transient asymptomatic alanine aminotransferase increases, another experienced urticaria and rash (antidrug antibody positive [ADA+]), and a third experienced an anaphylactic reaction (ADA+) who underwent desensitization and reached the 3 mg/kg maintenance dose. Splenomegaly and hepatomegaly improved by more than 40% on average (p<0.0001). In patients who were able to conduct the test, the mean % predicted DLCO improved by 32.9% (p = 0.0053). The increased liver transaminase values and lipid profiles were normalized. The mean Z-scores for height increased by 0.56 (p<0.0001).

Conclusion: Olipudase alfa was generally well tolerated in this trial in children with chronic ASMD, with significant, comprehensive improvements in disease pathology across a variety of clinically relevant endpoints.

Keywords: Acid sphingomyelinase deficiency, Olipudase alfa, Enzyme replacement therapy