Pediatric Patients With ASMD Show Significant Improvement in Olipudase Alfa Trial

Findings from the single-arm, open-label ASCEND-Peds study suggest that olipudase alfa is well tolerated and may lead to clinically meaningful improvements in patients with acidic 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 disease. Enzyme replacement therapy with olipudase alfa was a promising option in clinical trials, and a 1-year study showed significant improvements along with an acceptable 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 codes for the lysosomal enzyme acid sphingomyelinase (ASM). The resulting accumulation of sphingomyelin leads to a variety of manifestations, including hepatosplenomegaly, thrombocytopenia, hyperlipidemia, interstitial lung disease (ILD), liver dysfunction and fibrosis, and in severe cases CNS damage. ASMD phenotypes include type A, which is characterized by severe infantile onset with neurovisceral manifestations and fatal outcome; type A/B, which has neurovisceral manifestations but is chronic; and type B, which is chronic and usually does not 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 of age) years) and adolescents (12 to 17 years). Patients with a low platelet count (<60 × 109/L), alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than 250 IU/L, bilirubin greater than 25.7 µmol/L were excluded from the study, as were patients with rapid progression of 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 an inpatient for a minimum of 24 hours post-infusion as doses were increased. The dosages were as follows:

0.03 mg/kg0.1 mg/kg2 sequential doses at 0.3 mg/kg2 sequential doses at 0.6 mg/kg1 mg/kg2 mg/kg3 mg/kg (maintenance dose)

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

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

Efficacy was considered exploratory in this study, but patients experienced improvements in moderate or severe splenomegaly and hepatomegaly by assessment at week 26 of the study. Eleven of 12 patients with severe baseline splenomegaly and all 10 patients with baseline severe hepatomegaly improved to moderate levels at Week 52. The overall decrease in spleen and liver volume was similar in all 3 age groups.

Five of 6 patients who had severe ILD at baseline showed improvements to mild or moderate, and ILD was absent in 1 at Week 52. Mean lipid levels were within normal limits at Week 52 – an improvement from baseline when the 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 did not include a placebo group and included a small sample size, these findings suggest that olipudase alfa is well tolerated and may lead to clinically meaningful improvements at 6 months that are sustained 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 alpha enzyme replacement therapy in pediatric patients with acidic sphingomyelinase deficiency. Genet Med. 2021;23(8):1543-1550. doi:10.1038/s41436-021-01156-3

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