ID DB06720 VELAGLUCERASE ALFA CATEGORY Enzymes

DESCRIPTION Velaglucerase alfa is a gene-activated human recombinant glucocerebrosidase used for the treatment of Type 1 Gaucher disease, caused by a deficiency of the lysosomal enzyme glucocerebrosidase. Additionally, Velaglucerase alfa has also been investigated for use in Type 3 Gaucher disease. INDICATION Velaglucerase alfa is a hydrolytic lysosomal glucocerebroside-specific enzyme indicated for long-term enzyme replacement therapy for pediatric and adult patients with type 1 Gaucher disease. MECHANISM OF ACTION Velaglucerase alfa catalyzes the hydrolysis of glucocerebroside, reducing the amount of accumulated glucocerebroside.

SEQUENCE VPRIV TARGETS Glucosylceramidase HALF-LIFE = 11-12 minutes. VOLUME OF DISTRIBUTION = The mean volume of distribution at steady state ranges from 82 to 108 mL/kg (8.2% to 10.8% of body weight). CLEARANCE = Mean clearance ranges from 6.72 to 7.56 mL/min/kg. PATENT <number>7138262</number> <country>United States</country> <approved>2006-11-21</approved> <expires>2020-08-18</expires> SEQUENCE VPRIV TARGETS Glucosylceramidase

Velaglucerase alfa aka VPRIV aka Cerezyme® (Imiglucerase) IV infusion C2532H3850N672O711S16 ~63 kDa VPRIV: The active ingredient of VPRIV is velaglucerase alfa, which is produced by gene activation technology in a human fibroblast cell line. Velaglucerase alfa is a glycoprotein of 497 amino acids; with a molecular weight of approximately 63 kDa. Velaglucerase alfa has the same amino acid sequence as the naturally occurring human enzyme, glucocerebrosidase. Velaglucerase alfa contains 5 potential N-linked glycosylation sites; four of these sites are occupied by glycan chains. Velaglucerase alfa is manufactured to contain predominantly high mannose-type N-linked glycan chains. The high mannose type N-linked glycan chains are specifically recognized and internalized via the mannose receptor present on the surface on macrophages, the cells that accumulate glucocerebroside in Gaucher disease. Velaglucerase alfa catalyzes the hydrolysis of the glycolipid glucocerebroside to glucose and ceramide in the lysosome. VPRIV is dosed by Units/kg, where one Unit of enzyme activity is defined as the quantity of enzyme required to convert one micromole of p-nitrophenyl β-D-glucopyranoside to pnitrophenol per minute at 37°C.

Cerezyme®: (imiglucerase for injection) is an analogue of the human enzyme β-glucocerebrosidase, produced by recombinant DNA technology. β-Glucocerebrosidase (β-D-glucosyl-N-acylsphingosine glucohydrolase, E.C. 3.2.1.45) is a lysosomal glycoprotein enzyme which catalyzes the hydrolysis of the glycolipid glucocerebroside to glucose and ceramide. Cerezyme® (imiglucerase) is produced by recombinant DNA technology using mammalian cell culture (Chinese hamster ovary). Purified imiglucerase is a monomeric glycoprotein of 497 amino acids, containing 4 N-linked glycosylation sites (Mr = 60,430). Imiglucerase differs from placental glucocerebrosidase by one amino acid at position 495, where histidine is substituted for arginine. The oligosaccharide chains at the glycosylation sites have been modified to terminate in mannose sugars. The modified carbohydrate structures on imiglucerase are somewhat different from those on placental gluco-cerebrosidase. These mannose-terminated oligosaccharide chains of imiglucerase are specifically recognized by endocytic carbohydrate receptors on macrophages, the cells that accumulate lipid in Gaucher disease.

DOSAGE: VPRIV: 60 Units/kg Cerezyme: Initial dosages range from 2.5 U/kg of body weight 3 times a week to 60 U/kg once every 2 weeks. 60 U/kg every 2 weeks is the dosage for which the most data are available VIAL: VPRIV is supplied as a sterile, preservative free, lyophilized powder in single-use vials, each containing 400 Units Cerezyme® (imiglucerase) is supplied as a sterile, non-pyrogenic, white to off-white lyophilized product ADVERSE REACTION: Hives; difficult breathing; swelling of your face, lips, tongue, or throat VPRIV CLEARANCE: 6.72 to 7.56 mL/min/kg VPRIV HALF-LIFE: 11 to 12 minutes Cerezyme CLEARANCE: 14.5 ± 4.0 mL/min/kg Cerezyme HALF-LIFE: 3.6 to 10.4 min

Sequence ARPCIPKSFGYSSVVCVCNATYCDSFDPPTFPALGTFSRYESTRSGRRMELSMGPIQANH TGTGLLLTLQPEQKFQKVKGFGGAMTDAAALNILALSPPAQNLLLKSYFSEEGIGYNIIR VPMASCDFSIRTYTYADTPDDFQLHNFSLPEEDTKLKIPLIHRALQLAQRPVSLLASPWT SPTWLKTNGAVNGKGSLKGQPGDIYHQTWARYFVKFLDAYAEHKLQFWAVTAENEPSAGL LSGYPFQCLGFTPEHQRDFIARDLGPTLANSTHHNVRLLMLDDQRLLLPHWAKVVLTDPE AAKYVHGIAVHWYLDFLAPAKATLGETHRLFPNTMLFASEACVGSKFWEQSVRLGSWDRG MQYSHSIITNLLYHVVGWTDWNLALNPEGGPNWVRNFVDSPIIVDITKDTFYKQPMFYHL GHFSKFIPEGSQRVGLVASQKNDLDAVALMHPDGSAVVVVLNRSSKDVPLTIKDPAVGFL ETISPGYSIHTYLWRRQ http://www.ncbi.nlm.nih.gov/pubmed/24612151 http://www.ncbi.nlm.nih.gov/pubmed/24581483 http://www.ncbi.nlm.nih.gov/pubmed/24411065 http://www.ncbi.nlm.nih.gov/pubmed/24263462 http://www.ncbi.nlm.nih.gov/pubmed/24124461 VPRIV http://www.ncbi.nlm.nih.gov/pubmed/21146428 http://www.ncbi.nlm.nih.gov/pubmed/20508578 http://www.ncbi.nlm.nih.gov/pubmed/20431522

Cerezyme http://www.ncbi.nlm.nih.gov/pubmed/25303390 http://www.ncbi.nlm.nih.gov/pubmed/19953667 http://www.ncbi.nlm.nih.gov/pubmed/19804996 http://www.ncbi.nlm.nih.gov/pubmed/19195916 http://www.ncbi.nlm.nih.gov/pubmed/18312448 http://www.ncbi.nlm.nih.gov/pubmed/10656341 http://www.ncbi.nlm.nih.gov/pubmed/16502533 http://www.ncbi.nlm.nih.gov/pubmed/17539908