Infants with Wolman disease (WD)—a severe manifestation of lysosomal acid lipase deficiency (LAL-D)—may benefit from short-term intensification of their enzyme replacement therapy (ERT) regimen, according to study results presented at the 19th Annual World Symposium, held in Orlando, Florida, from February 22 to 26, 2023.
Infants with WD often present with early-onset LAL-D, rapidly progressive liver disease, and a hyperinflammatory phenotype. If the disease remains untreated, WD is fatal prior to 6 months of age. The current clinical trial reported on twice-weekly dosing with sebelipase alfa ERT in infants with WD. Sebelipase alfa is a recombinant form of the enzyme lysosomal acid.
In prior evaluations of the agent—the VITAL and CL08 studies—infants who were treated with once-weekly intravenous infusions of sebelipase alfa had survival rates of 55% and 80%, respectively. Sebelipase alfa administered at a licensed dose of 1 mg/kg to 5 mg/kg weekly has received marketing authorization in several countries.
The current analysis describes 2 infants from 2 different centers who received treatment with sebelipase alfa twice weekly. Patient 1 was diagnosed at 3.5 months of age, upon presenting with secondary hemophagocytic syndrome. The patient began treatment with an initial dose of sebelipase alfa 3 mg/kg/week. Her condition deteriorated, with respiratory distress and cytopenias reported; she required invasive ventilation and hemodiafiltration for acute kidney failure.
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In patient 2, who was diagnosed at 2.5 months of age with characteristic features of WD, treatment with sebelipase alfa 5 mg/kg/week was initiated. His condition deteriorated, with the development of ascites and respiratory distress, and he required noninvasive ventilatory support.
Following the worsening of both patients’ conditions, their ERT regimen was intensified to 5 mg/kg twice weekly. After the administration of sebelipase alfa, leukocyte sebelipase activity was maintained only for 2 or 3 additional days. Based on a pulse-chain experiment performed in patients’ fibroblasts, sebelipase activity was shown to decrease to nearly zero by 72 hours. At 24 hours following each infusion, a peak of 7-ketocholesterol was observed, which was suggestive of ongoing biologically relevant substrate storage.
Both of the patients showed rapid improvement, which permitted step-down from intensive care and eventual discharge. Their hematologic and inflammatory parameters, as well as disease-specific biomarkers, demonstrated improvement as well. No medically relevant infusion-related reactions were reported in either patient.
“We suggest that infants with advanced disease may benefit from short-term intensification of the ERT regimen,” the authors concluded.
De Castro Lopez MJ, de Frutos LL, Brammeier KL, et al. Twice weekly dosing with sebelipase alfa rescues severely ill infants with Wolman disease. Mol Genet Metab. 2023;138:106972. doi:10.1016/j.ymgme.2022.107071