Sebelipase alfa enzyme replacement therapy in Wolman disease: a nationwide cohort with up to ten years of follow-up

Abstract

Background Wolman disease (WD), the rapidly progressive phenotype of lysosomal acid lipase (LAL) deficiency, presents in neonates with failure to thrive and hepatosplenomegaly, and leads to multi-organ failure and death before 12 months of age. In clinical trials, enzyme replacement therapy (ERT) with sebelipase alfa led to improved survival, growth and biological parameters in WD patients followed up to 5 years. Long-term follow-up and health-related quality of life (HRQoL) evaluation are lacking. Results We performed a nationwide, retrospective study of sebelipase alfa in WD patients. Five patients with abolished LAL activity and bi-allelic LIPA mutations were included with a median follow-up of 7 years (1–10). ERT was initiated at a median age of 1 month (0–4). Infusion tolerance was excellent on the long-term with only one patient requiring systematic pre-medication. Cholestyramine, fat-soluble vitamin supplements and a specific diet (high in medium-chain triglycerides and low in long-chain fatty acids) were prescribed. Liver function tests, plasma lipid profiles, fat-soluble vitamin levels and growth parameters improved. Three patients transiently exhibited a neuromyopathic phenotype (footdrop gait, waddling walk or muscle fatigue) but electromyography and muscle strength testing were normal. At last follow-up, all patients were alive with normal growth parameters and a satisfactory HRQoL, no patient had special education needs, and one patient required parenteral nutrition since an acute gastroenteritis. Conclusions Early ERT initiation allowed 100% survival with positive outcomes. Very long-term follow-up and hematopoietic stem cell transplantation while on ERT should be evaluated to strengthen the benefits of sebelipase alfa.

Early diagnosis and successful long-term management of a rare, severe lysosomal acid lipase deficiency/Wolman disease patient: Infancy to age five

“…Our case demonstrated bilateral echogenic adrenal glands on fetal ultrasound at gestational week 34 and postnatally, similar to another case of an infant with LAL-D (6), suggesting a potential early diagnostic feature. A diet high in MCT fat was associated with optimized growth, consistent with findings in infants with severe LAL-D who received sebelipase alfa treatment (7,8).…”

Lysosomal acid lipase deficiency: A rare inherited dyslipidemia but potential ubiquitous factor in the development of atherosclerosis and fatty liver disease

“…In WD, similar improvements in lipid and liver function parameters were observed with sebelipase alfa treatment in two studies, with trends in another study compared to baseline ( Jones et al, 2017 ; Demaret et al, 2021 ; Vijay et al, 2021 ); the smaller difference between pre and post-treatment values in the latter study may have occurred due to very early treatment initiation (median 7 weeks of age). Relief of symptoms including nausea and diarrhea, resolution of hepatosplenomegaly, and increased weight for age were also shown with treatment, as well as reduced requirement for nutritional support.…”

“…Sebelipase alfa is a recombinant human LAL protein, administered intravenously every one to 2 weeks ( CADTH Common Drug Review, 2018 ). It is typically dosed at 1 mg/kg for CESD and 3–5 mg/kg for WD patients ( Jones et al, 2017 ; Demaret et al, 2021 ; Burton et al, 2022 ). Cellular uptake of sebelipase alfa occurs via the mannose receptor, which then facilitates delivery to the lysosome ( Balwani et al, 2013 ).…”

“…Relief of symptoms including nausea and diarrhea, resolution of hepatosplenomegaly, and increased weight for age were also shown with treatment, as well as reduced requirement for nutritional support. Survival in the first 12 months increased from 11% in a historical untreated control population to 67–100% with sebelipase alfa, with 68% surviving to 5 years of age and one patient surviving 10 years ( Demaret et al, 2021 ; Vijay et al, 2021 ) ( Supplementary Table S1 ). Earlier initiation of treatment when patients are in more stable condition appears to improve outcome.…”

“…Sebelipase alfa has been shown to be safe in both short and long-term studies, for both CESD and WD patients. Mild infusion reactions occur in most patients, with infrequent severe hypersensitivity-like responses that can be resolved with diphenhydramine or epinephrine ( Balwani et al, 2013 ; Burton et al, 2015a ; Demaret et al, 2021 ; Vijay et al, 2021 ; Burton et al, 2022 ). In almost all cases, reducing the dose then slowly returning to the initial dose is effective and patients are able to continue treatment even after severe reactions.…”