Pediatric Patients With ASMD Show Significant Improvement in Olipudase Alfa Trial

Findings from the single-arm, open-label ASCEND-Peds trial suggest olipudase alfa is well-tolerated and may lead to clinically meaningful improvements in patients with acid sphingomyelinase deficiency (ASMD) who do not have neurovisceral manifestations.

There are currently no approved disease-modifying therapies for acid sphingomyelinase deficiency (ASMD), also known as Niemann-Pick disease (NPD), an inherited lysosomal storage disorder. Enzyme replacement therapy with olipudase alfa has been a promising option in clinical trials, and a 1-year study showed significant improvements along with a tolerable safety profile in children with chronic ASMD without central nervous system (CNS) manifestations.

ASMD is a rare disorder caused by sequence variants in the SMPD1 gene, which encodes the lysosomal enzyme acid sphingomyelinase (ASM). The resulting buildup of sphingomyelin leads to a variety of manifestations, including hepatosplenomegaly, thrombocytopenia, hyperlipidemia, interstitial lung disease (ILD), liver dysfunction and fibrosis, and CNS damage in severe cases. ASMD phenotypes include type A, which is characterized by severe infantile onset with neurovisceral manifestations and fatality; type A/B, which has neurovisceral manifestations but is chronic; and type B, which is chronic and does not typically involve neurological symptoms.

The single-arm, phase 1/2, open-label ASCEND-Peds study (NCT02292654) included 20 pediatric patients with confirmed ASMD stratified into 3 cohorts: infants/early children (less than 6 years of age), children (6 to 11 years old), and adolescents (12 to 17 years old). Patients with low platelet counts (<60 × 109/L), levels of alanine aminotransferase (ALT) or aspartate aminotransferase (AST) above 250 IU/L, bilirubinabove 25.7 µmol/L were excluded from the study, as were those with rapidly progression neurovisceral manifestations. Patients with genotypes associated with ASMD type A were also excluded.

Participants received olipudase alfa infusions once every 2 weeks and were monitored as inpatients for minimum 24 hours post-infusion as the doses were escalated. The doses were as follows:

  • 0.03 mg/kg
  • 0.1 mg/kg
  • 2 consecutive doses of 0.3 mg/kg
  • 2 consecutive doses at 0.6 mg/kg
  • 1 mg/kg
  • 2 mg/kg
  • 3 mg/kg (maintenance dose)

All 20 patients reached the maintenance dose. A total of 7 patients, all in the children or early children cohorts, had at least 1 dose reduction or repeat dose at some point before reaching the final maintenance dose.

All patients experienced at least 1 adverse event (AE) during the study, 17% of which were considered infusion-associated reactions (IARs). Overall, 88% of IARs were categorized as mild. Pyrexia, cough, vomiting, nasopharyngitis, diarrhea, headache, nausea, rhinitis, oropharyngeal pain, ear pain, and rhinorrhea were all common AEs. A total of 5 patients experienced serious AEs, all of which were resolved. One severe anaphylactic reaction was reported, and that patient was able to continue therapy after a desensitization regimen. There were 10 total dose-limiting toxicity events in 6 patients, all of which resolved after dose reduction or repeat dosing.

Efficacy was considered exploratory in this trial, but patients experienced improvements in moderate or severe splenomegaly and hepatomegaly by an assessment at week 26 of the trial. Eleven of 12 patients with severe splenomegaly at baseline and all 10 patients with severe hepatomegaly at baseline improved to moderate levels by week 52. Overall decreases in spleen and liver volume were similar across all 3 age groups.

Five of 6 patients who showed severe ILD at baseline showed improvements to mild or moderate, and ILD was absent in 1 by week 52. Mean lipid levels were within normal limits by week 52—an improvement over baseline, when mean levels of total cholesterol, low-density lipoprotein, and triglycerides were above normal limits and high-density lipoprotein levels were abnormally low.

Although the study lacked a placebo group and included a small sample size, these findings suggest olipudase alfa is well-tolerated and may lead to clinically meaningful improvements after 6 months that are maintained through 12 months of treatment in pediatric patients with chronic ASMD.


Diaz GA, Jones SA, Scarpa M, et al. One-year results of a clinical trial of olipudase alfa enzyme replacement therapy in pediatric patients with acid sphingomyelinase deficiency. Genet Med. 2021;23(8):1543-1550. doi:10.1038/s41436-021-01156-3

Related Videos
View All
Related Content
© 2023 MJH Life Sciences
All rights reserved.