Sebelipase Alfa: A Review in Lysosomal Acid Lipase Deficiency

Abstract

Sebelipase alfa (Kanuma, Kanuma™), the first commercially available recombinant human lysosomal acid lipase (LAL), is approved in various countries worldwide, including those of the EU, the USA and Japan, as a long-term enzyme replacement therapy for patients diagnosed with LAL deficiency (LAL-D), an ultra-rare, autosomal recessive, progressive metabolic liver disease. In an ongoing study in nine infants presenting with early-onset LAL-D (Wolman disease), open-label treatment with sebelipase alfa significantly improved 1-year survival compared with historical controls. A substantial mortality benefit was maintained at 2 years of age, as was a reduction in disease-related activity. In an ongoing study of 66 children and adults with late-onset LAL-D (cholesteryl ester storage disease), 20 weeks' double-blind treatment with sebelipase alfa significantly reduced multiple disease-related hepatic and lipid abnormalities compared with placebo. Sustained improvements in markers of liver damage and dyslipidaemia were seen after 76 weeks' open-label treatment in an extension of this trial and, similarly, after 2 years' open-label treatment in an extension of another study in nine adults with late-onset LAL-D. Sebelipase alfa therapy has thus far been generally well tolerated, with signs and symptoms consistent with anaphylaxis being the most serious adverse reactions experienced by patients receiving the drug in clinical trials. Due to the rarity of the disease, these studies have enrolled a limited number of patients. Nonetheless, the available data indicate that sebelipase alfa is an effective disease-specific therapy for individuals with LAL-D who have historically been managed using supportive therapies (e.g. cholesterol reduction, hematopoietic stem cell transplantation, and liver transplantation).

Molecular switching system using glycosylphosphatidylinositol to select cells highly expressing recombinant proteins

“…Mutations in the LIPA gene cause lysosomal storage diseases such as Wolman disease and cholesteryl ester storage disease 30 . For treatment of LIPA deficiency, Kanuma (Sebelipase alfa), which is a recombinant LIPA produced by transgenic chicken egg, was approved for use in 2015 in the USA and EU 31 . We constructed vectors carrying His6-Flag-tagged LIPA (sHF-LIPA) or sHF-LIPA fused with a GPI-attachment signal (sHF-LIPA-GPI), which were stably expressed in cells (Fig.…”

An unusual case of hypercholesterolaemia with liver dysfunction

“…Analysis of the pharmacoeconomics associated with the cost-effectiveness of a treatment such as ERT would thus be of interest. 10 A recent study in the United Kingdom evaluated the costs of managing children and adults with LAL deficiency in a tertiary centre, and found these to be staggering. In light of this, consideration needs to be given to rare diseases in policy and budgetary decision-making.…”

Persistent dyslipidemia in treatment of lysosomal acid lipase deficiency

“…Treatment for LALD was historically supportive until 2015 with Food and Drug Administration (FDA) approval of enzyme replacement therapy (ERT). The recombinant enzyme, sebelipase alfa, is given once every 2 weeks as an intravenous infusion and is taken up by target tissues, predominantly the liver, via the mannose-6-phosphate receptor [6]. A Phase III trial of biweekly enzyme replacement for 52 weeks demonstrated dramatic clinical and biochemical improvement, including normalization or near-normalization of alanine aminotransferase (ALT) levels, improved lipid parameters including reduction in low-density lipoprotein cholesterol (LDL-C) and triglycerides and increased high-density lipoprotein cholesterol (HDL-C) levels, and decreased hepatic fat content [7].…”