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10831 details
Primary information
ID10831
Therapeutic IDTh1197
Protein NameSebelipase alfa
Sequence>Th1197_Sebelipase_alfa SGGKLTAVDPETNMNVSEIISYWGFPSEEYLVETEDGYILCLNRIPHGRKNHSDKGPKPVVFLQHGLLADSSNWVTNLANSSLGFILADAGFDVWMGNSRGNTWSRKHKTLSVSQDEFWAFSYDEMAKYDLPASINFILNKTGQEQVYYVGHSQGTTIGFIAFSQIPELAKRIKMFFALGPVASVAFCTSPMAKLGRLPDHLIKDLFGDKEFLPQSAFLKWLGTHVCTHVILKELCGNLCFLLCGFNERNLNMSRVDVYTTHSPAGTSVQNMLHWSQAVKFQKFQAFDWGSSAKNYFHYNQSYPPTYNVKDMLVPTAVWSGGHDWLADVYDVNILLTQITNLVFHESIPEWEHLDFIWGLDAPWRLYNKIINLMRKYQ
Molecular Weight55000
Chemical FormulaC1968H2945N507O551S15
Isoelectric PointNA
HydrophobicityNA
Melting pointNA
Half-life5.4-6.6 mins
DescriptionSebelipase alfa is a recombinant form of the enzyme lysosomal acid lipase (LAL) approved for the treatment of lysosomal acid lipase deficiency (LAL-D). The amino acid sequence for sebelipase alfa is the same as the amino acid sequence for human LAL. Sebelipase alfa is an orphan drug which is expected to cost about $310,000 for annual treatment in the United States. Sebelipase alfa is marketed under the brand name Kanumaâ„¢ by Alexion Pharmaceuticals, Inc.
Indication/DiseaseSebelipase alfa is a hydrolytic lysosomal cholesteryl ester and triacylglycerol-specific enzyme indicated for the treatment of patients with a diagnosis of Lysosomal Acid Lipase (LAL) deficiency.
PharmacodynamicsIn clinical trials, after initiation of dosing with KANUMA, breakdown of accumulated lysosomal lipid led to initial increases in LDL-c and triglycerides within the first 2 to 4 weeks of treatment. In general, following increases in LDL-c and triglycerides, these parameters decreased to below pre-treatment values within 8 weeks of treatment with KANUMA.
Mechanism of ActionLAL deficiency is an autosomal recessive lysosomal storage disorder characterized by a genetic defect resulting in a marked decrease or loss in activity of the lysosomal acid lipase (LAL) enzyme. The primary site of action of the LAL enzyme is the lysosome, where the enzyme normally causes the breakdown of lipid particles including LDL-c. Deficient LAL enzyme activity results in progressive complications due to the lysosomal accumulation of cholesteryl esters and triglycerides in multiple organs, including the liver, spleen, intestine, and the walls of blood vessels. The resulting lipid accumulation in the liver may lead to increased liver fat content and progression of liver disease, including fibrosis and cirrhosis. Lipid accumulation in the intestinal wall leads to malabsorption and growth failure. In parallel, dyslipidemia due to impaired degradation of lysosomal lipid is common with elevated LDL-c and triglycerides and low HDL-cholesterol (HDL-c). Sebelipase alfa binds to cell surface receptors via glycans expressed on the protein and is subsequently internalized into lysosomes. Sebelipase alfa catalyzes the lysosomal hydrolysis of cholesteryl esters and triglycerides to free cholesterol, glycerol and free fatty acids.
ToxicityThere are no data regarding overdose with sebelipase alfa. Patients in clinical trials were exposed to doses as high as 7.5 mg/kg once weekly with no specific adverse effects observed.[L39342]
MetabolismAs with other therapeutic proteins, the metabolism of sebelipase alfa likely occurs via catabolism to smaller peptides and amino acids.
AbsorptionIn patients 4-11 years old, the AUC and Cmax of sebelipase alfa following intravenous administration of 1 mg/kg every other week were 942 ng.hr/mL and 490 ng/mL, respectively.[L39337] In patients =12 years old, the AUC and Cmax ranged between 1454-1861 ng.hr/mL and 784-957 ng/mL, respectively.[L39337] The approximate Tmax of sebelipase alfa was similar across all age groups tested and ranged between 1.1-1.3 hours.[L39337]
In patients 4-11 years old, the central volume of distribution was approximately 3.6 L.[L39337] In patients =12 years old, the central volume of distribution ranged from approximately 5.3 to 5.4 L.[L39337]
ClearanceAcross all age groups included in pharmacokinetic testing, the mean clearance of sebelipase alpha following intravenous administration of 1 mg/kg every other week ranged from 31.1 - 38.2 L/h.[L39337]
CategoriesEnzymes
Patents NumberNA
Date of IssueNA
Date of ExpiryNA
Drug InteractionNA
TargetNA
Brand NameKanuma
CompanyAlexion Pharmaceuticals, Inc.
Brand DescriptionAlexion Pharmaceuticals, Inc.
Prescribed ForKANUMAâ„¢ is indicated for the treatment of patients with a diagnosis of Lysosomal Acid Lipase (LAL) deficiency.
Chemical NameNA
Formulation20 mg/10 mL
Physical Appearance Aqueous solution
Route of AdministrationIntravenous infusion
Recommended DosageThe recommended starting dosage is 1 mg/kg administered once weekly as an intravenous infusion. For patients who do not achieve an optimal clinical response, increase to 3 mg/kg once weekly.
ContraindicationNA
Side EffectsDiarrhea, vomiting, fever, rhinitis, anemia, cough, nasopharyngitis, urticaria.
Useful Link 1Link
Useful Link 2NA
RemarksNA