One-year results of a clinical trial of olipudase alfa enzyme replacement therapy in pediatric patients with acid sphingomyelinase deficiency

Abstract

Purpose: To assess olipudase alfa enzyme replacement therapy for non-central nervous system manifestations of acid sphingomyelinase deficiency (ASMD) in children.

Methods: This phase 1/2, international, multicenter, open-label trial (ASCEND-Peds/NCT02292654) administered intravenous olipudase alfa every 2 weeks with intrapatient dose escalation to 3 mg/kg. Primary outcome was safety through week 64. Secondary outcomes included pharmacokinetics, spleen and liver volumes, lung diffusing capacity (DLCO), lipid profiles, and height through week 52.

Results: Twenty patients were enrolled: four adolescents (12-17 years), nine children (6-11 years), and seven infants/early child (1-5 years). Most adverse events were mild or moderate, including infusion-associated reactions (primarily urticaria, pyrexia, and/or vomiting) in 11 patients. Three patients had serious treatment-related events: one with transient asymptomatic alanine aminotransferase increases, another with urticaria and rash (antidrug antibody positive [ADA+]), and a third with an anaphylactic reaction (ADA+) who underwent desensitization and reached the 3 mg/kg maintenance dose. Mean splenomegaly and hepatomegaly improved by >40% (p < 0.0001). Mean % predicted DLCO improved by 32.9% (p = 0.0053) in patients able to perform the test. Lipid profiles and elevated liver transaminase levels normalized. Mean height Z-scores improved by 0.56 (p < 0.0001).

Conclusion: 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.

Conflict of interest statement

George A. Diaz, Simon A. Jones, Maurizio Scarpa, K. Eugen Mengel, Roberto Giugliani, and Nathalie Guffon are principal investigators in Sanofi-Genzyme sponsored trials. George A. Diaz and Simon A. Jones have received honoraria and consulting fees from Sanofi Genzyme. K. Eugen Mengel has received research support, honoraria, and consulting fees from Sanofi Genzyme. Roberto Giugliani has received honoraria, consulting fees, speaker fees and travel reimbursement from Sanofi Genzyme. Nathalie Guffon has received honoraria and travel reimbursement from Sanofi Genzyme. Maurizio Scarpa has received honoraria, consulting fees, speaker fees and travel reimbursement from Sanofi Genzyme. Isabela Batsu, Patricia A. Fraser, Jing Li, Qi Zhang, and Catherine Ortemann-Renon are/were employees of Sanofi Genzyme.

© 2021. The Author(s).

Figures

Fig. 1. Patient Disposition in the Trial.

Patient disposition.

Fig. 2. Safety Biomarker and Pharmacodynamic Parameters.

Plasma levels of ceramide, lyso-sphingomyelin, and chitotriosidase activity during treatment with olipudase alfa. (a) Mean (±SD) plasma levels of ceramide for the overall patient population preinfusion, 24 hours and 48 hours after olipudase alfa infusions. Normal range for plasma ceramide was 1.3–3.3 mg/L. 24 hour postinfusion levels were assessed in the adolescent group only.  (b) Mean (±SD) plasma levels of lyso-sphingomyelin for the overall patient population preinfusion, 24 hours and 48 hours after olipudase alfa infusions. Upper limit of normal for lyso-sphingomyelin is 9.99 μg/L. Twenty-four hour postinfusion levels were assessed in the adolescent group only. (c) Mean (±SD) normalized plasma activity of chitotriosidase for the overall patient population. Upper limit of normal is 181 μmol/L/hr.

Fig. 3. Changes over time in efficacy assessments (hepatosplenomegaly, liver transaminases, lung diffusion capacity, plasma lipids, and height) with olipudase alfa treatment.

(a, b) Individual patient responses for spleen volumes in multiples of normal (MN) and the percent change from baseline for spleen volumes in least square mean (LSM) ± standard error of the mean (SEM), respectively at 6 months and 1 year. Cutoffs of MN for severity categories are indicated by shading. (c,d) Individual patient responses for liver volumes in MN and the percent change from baseline for spleen and liver volumes in LSM ± SEM, respectively at 6 months and 1 year. Cutoffs of MN for severity categories are indicated by shading. (e,f) Mean (±SD) preinfusion plasma levels for aspartate aminotransferase (AST) and alanine aminotransferase (ALT), respectively, for the overall patient population and the means for each age group at baseline and throughout treatment with olipudase alfa. The AST and ALT upper limit of normal (ULN) for the for the adolescent, child, and infant/early child groups is 40, 59, and 69 IU/L and 43, 34, and 34 IU/L, respectively (values the same in U/L). Ranges of ULN are indicated by gray boxes. (g, h) individual patient responses and LSM ± SEM percent change from baseline for the percent predicted DLCO adjusted for hemoglobin. Cutoffs for gas exchange impairment are indicated. (i) Plasma lipid mean (±SD) for the overall population and means for each age group for total cholesterol, low density lipid cholesterol (LDL-C), high density lipid cholesterol (HDL-C), and triglycerides (TG). Low to high ranges of normal for total cholesterol: 4.4–5.15 mmol/L ( <170–199 mg/dL). Low to high ranges of normal for LDL-C: adolescent: 1.60 to 3.52 mmol/L, child: 1.63 to 3.63 mmol/L, infant/early child: 0.98 to 3.63 mmol/L (38–140 mg/dL); for TG: adolescent: 0.36 to 1.67 mmol/L, child: 0.34 to 1.48 mmol/L, infant/early child: 0.34 to 1.24 mmol/L (32–149 mg/dL); for HDL-C: adolescent: 0.78 to 1.92 mmol/L, child: 0.93 to 1.94 mmol/L, infant/early child: not reported (30–75 mg/dL). (j) Individual patient height Z-scores (graph) and the LSM changes from baseline with p values (inset table) over time.