|
| Primary information |
|---|
| ID | 10831 |
| Therapeutic ID | Th1197 |
| Protein Name | Sebelipase alfa |
| Sequence | >Th1197_Sebelipase_alfa
SGGKLTAVDPETNMNVSEIISYWGFPSEEYLVETEDGYILCLNRIPHGRKNHSDKGPKPVVFLQHGLLADSSNWVTNLANSSLGFILADAGFDVWMGNSRGNTWSRKHKTLSVSQDEFWAFSYDEMAKYDLPASINFILNKTGQEQVYYVGHSQGTTIGFIAFSQIPELAKRIKMFFALGPVASVAFCTSPMAKLGRLPDHLIKDLFGDKEFLPQSAFLKWLGTHVCTHVILKELCGNLCFLLCGFNERNLNMSRVDVYTTHSPAGTSVQNMLHWSQAVKFQKFQAFDWGSSAKNYFHYNQSYPPTYNVKDMLVPTAVWSGGHDWLADVYDVNILLTQITNLVFHESIPEWEHLDFIWGLDAPWRLYNKIINLMRKYQ
|
| Molecular Weight | 55000 |
| Chemical Formula | C1968H2945N507O551S15 |
| Isoelectric Point | NA |
| Hydrophobicity | NA |
| Melting point | NA |
| Half-life | 5.4-6.6 mins |
| Description | Sebelipase 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/Disease | Sebelipase 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. |
| Pharmacodynamics | In 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 Action | LAL 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. |
| Toxicity | There 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] |
| Metabolism | As with other therapeutic proteins, the metabolism of sebelipase alfa likely occurs via catabolism to smaller peptides and amino acids. |
| Absorption | In 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] |
| Clearance | Across 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] |
| Categories | Enzymes |
| Patents Number | NA |
| Date of Issue | NA |
| Date of Expiry | NA |
| Drug Interaction | NA |
| Target | NA |
| Brand Name | Kanuma |
| Company | Alexion Pharmaceuticals, Inc. |
| Brand Description | Alexion Pharmaceuticals, Inc. |
| Prescribed For | KANUMAâ„¢ is indicated for the treatment of patients with a diagnosis of Lysosomal Acid Lipase (LAL) deficiency. |
| Chemical Name | NA |
| Formulation | 20 mg/10 mL |
| Physical Appearance | Aqueous solution |
| Route of Administration | Intravenous infusion |
| Recommended Dosage | The 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. |
| Contraindication | NA |
| Side Effects | Diarrhea, vomiting, fever, rhinitis, anemia, cough, nasopharyngitis, urticaria. |
| Useful Link 1 | Link |
| Useful Link 2 | NA |
| Remarks | NA |