Detailed description page of ThPDB2
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Th1661 details |
| Primary information | |
|---|---|
| ID | 16002 |
| Therapeutic ID | Th1661 |
| Protein Name | Avalglucosidase alfa |
| Sequence | >Th1661_Avalglucosidase_alfa QQGASRPGPRDAQAHPGRPRAVPTQCDVPPNSRFDCAPDKAITQEQCEARGCCYIPAKQGLQGAQMGQPWCFFPPSYPSYKLENLSSSEMGYTATLTRTTPTFFPKDILTLRLDVMMETENRLHFTIKDPANRRYEVPLETPRVHSRAPSPLYSVEFSEEPFGVIVHRQLDGRVLLNTTVAPLFFADQFLQLSTSLPSQYITGLAEHLSPLMLSTSWTRITLWNRDLAPTPGANLYGSHPFYLALEDGGSAHGVFLLNSNAMDVVLQPSPALSWRSTGGILDVYIFLGPEPKSVVQQYLDVVGYPFMPPYWGLGFHLCRWGYSSTAITRQVVENMTRAHFPLDVQWNDLDYMDSRRDFTFNKDGFRDFPAMVQELHQGGRRYMMIVDPAISSSGPAGSYRPYDEGLRRGVFITNETGQPLIGKVWPGSTAFPDFTNPTALAWWEDMVAEFHDQVPFDGMWIDMNEPSNFIRGSEDGCPNNELENPPYVPGVVGGTLQAATICASSHQFLSTHYNLHNLYGLTEAIASHRALVKARGTRPFVISRSTFAGHGRYAGHWTGDVWSSWEQLASSVPEILQFNLLGVPLVGADVCGFLGNTSEELCVRWTQLGAFYPFMRNHNSLLSLPQEPYSFSEPAQQAMRKALTLRYALLPHLYTLFHQAHVAGETVARPLFLEFPKDSSTWTVDHQLLWGEALLITPVLQAGKAEVTGYFPLGTWYDLQTVPIEALGSLPPPPAAPREPAIHSEGQWVTLPAPLDTINVHLRAGYIIPLQGPGLTTTESRQQPMALAVALTKGGEARGELFWDDGESLEVLERGAYTQVIFLARNNTIVNELVRVTSEGAGLQLQKVTVLGVATAPQQVLSNGVPVSNFTYSPDTKVLDICVSLLMGEQFLVSWC |
| Molecular Weight | 124000 |
| Chemical Formula | C4490H6818N1197O1299S32 |
| Isoelectric Point | NA |
| Hydrophobicity | NA |
| Melting point | NA |
| Half-life | The mean avalglucosidase alfa-ngpt plasma elimination half-life was 1.6 hours in patients with late-onset Pompe disease.[L35155] |
| Description | Avalglucosidase alfa, or NeoGAA, is a drug for enzyme replacement therapy specifically designed for Pompe disease, a rare inherited neuromuscular disorder caused by the deficiency of the alpha-glucosidase (GAA) enzyme. GAA is an essential enzyme that hydrolyzes glycogen into free glucose for use in cellular functions. In Pompe disease, the GAA enzyme is missing and patients are unable to properly break down glycogen, resulting in the accumulation of glycogen within lysosomes and progressive disruption of cellular function, especially in smooth, cardiac, and skeletal muscle cells. Pompe disease is characterized by progressive muscle weakness and loss of motor function, including respiratory muscle weakness, which leads to premature death and debilitating effects on people’s lives.[A232955] Avalglucosidase alfa is a recombinant form of GAA that restores deficient enzyme levels. First developed by Sanofi Genzyme, avalglucosidase alfa is a chemically modified version of [alglucosidase alfa], where synthetic bis-phosphorylated oligosaccharides were attached to the structure to improve cellular uptake of the drug and better muscle targeting.[A232960] On August 6, 2021, avalglucosidase alfa-ngpt was approved under the market name Nexviazyme to treat patients one year of age and older with late-onset Pompe disease.[L35160] Late-onset Pompe disease is associated with a range of debilitating physical symptoms, such as progressive muscle weakness, including respiratory muscle weakness, and loss of motor function.[A232955] In clinical trials, avalglucosidase alfa improved lung function in patients with Pompe disease.[L35160] Avalglucosidase alfa was approved by Health Canada on November 15, 2021 for the treatment of patients older than 6 months of age with late-onset Pompe disease.[L39205] |
| Indication/Disease | Avalglucosidase alfa is a hydrolytic lysosomal glycogen-specific enzyme indicated for the treatment of patients one year of age and older with late-onset Pompe disease (lysosomal acid alpha-glucosidase [GAA] deficiency).[L35155] It is approved for the same indication in Canada for pediatric patients six months and older.[L39357] |
| Pharmacodynamics | Avalglucosidase alfa is a recombinant alpha-glucosidase (GAA) enzyme that catalyzes hydrolysis of glycogen. In clinical trials, avalglucosidase alfa reduced the levels of glycogen excreted in the urine of patients with Pompe disease, indicating that it effectively cleaved excess glycogen.[L35155] Avalglucosidase alfa has significantly higher binding affinity for cation-independent mannose-6-phosphate receptor (CI-MPR) for cellular uptake and better muscle targeting than [alglucosidase alfa]. In GAA-deficient mice, avalglucosidase alfa reduced glycogen with more efficacy than alglucosidase alfa at an equivalent dose.[A232960] |
| Mechanism of Action | Pompe disease is a genetic glycogen metabolism disorder that is also referred to as acid maltase deficiency or glycogen storage disease type II (GSD II). It is caused by mutations in the GAA gene, which encodes the lysosomal hydrolase acid a-glucosidase (GAA), an enzyme that normally catalyzes hydrolysis of glycogen to release free glucose for absorption and use for cellular functions. GAA deficiency leads to accumulation of glycogen within lysosomes and progressive disruption of cellular function, especially in smooth, cardiac, and skeletal muscle cells.[A232955] Enzyme replacement therapy using avalglucosidase alfa aims to restore the missing GAA enzyme. Avalglucosidase alfa is a hydrolytic lysosomal glycogen-specific recombinant human GAA enzyme that is conjugated with multiple synthetic bis-mannose-6-phosphate (bis-M6P) tetra-mannose glycans for enhanced targeting to skeletal muscles. The M6P of avalglucosidase alfa binds to cation-independent mannose-6-phosphate receptor (CI-MPR) on the cell surface with high affinity, which allows drug uptake into cells. Avalglucosidase alfa is internalized and transported into lysosomes to undergo proteolytic cleavage. It then exerts GAA enzymatic activity to cleave glycogen.[A232955, L35155] |
| Toxicity | There is limited information on the overdose profile and LD50 values of avalglucosidase alfa. |
| Metabolism | The metabolic pathway of avalglucosidase alfa-ngpt has not been characterized. The protein portion of avalglucosidase alfa-ngpt is expected to be metabolized into small peptides and amino acids via catabolic pathways.[L35155] |
| Absorption | The avalglucosidase alfa-ngpt exposure increases in an approximately proportional manner with increasing doses over a range from 5 to 20 mg/kg. Following intravenous infusion of 20 mg/kg every two weeks in patients with late-onset Pompe disease, the mean ± SD plasma Cmax of avalglucosidase alfa-ngpt was 259 ± 72 µg/mL at week one and 242 ± 81 µg/mL at week 49. The mean ± SD plasma AUC of avalglucosidase alfa-ngpt was 1,290 ± 420 µg·h/mL at week one and 1,250 ± 433 µg·h/mL at week 49.[L35155] |
| The volume of distribution of avalglucosidase alfa-ngpt was 3.4 L in patients with late-onset Pompe disease. No accumulation was observed following every two weeks-dosing schedules.[L35155] | |
| Clearance | The mean avalglucosidase alfa-ngpt clearance was 0.9 L/hour in patients with late-onset Pompe disease.[L35155] |
| Categories | Enzyme Replacement Therapy |
| Patents Number | NA |
| Date of Issue | NA |
| Date of Expiry | NA |
| Drug Interaction | NA |
| Target | Cation-independent mannose-6-phosphate receptor |
| Brand Name | Nexviazyme |
| Company | Sanofi Aventis |
| Brand Description | Sanofi Aventis |
| Prescribed For | Intravenous |
| Chemical Name | 100 mg / vial |
| Formulation | None. |
| Physical Appearance | headache, fatigue, diarrhea, nausea, joint pain, dizziness, muscle aches, itching, vomiting, shortness of breath, skin redness, numbness and tingling, and hives. |
| Route of Administration | Nexviazyme helps replace an enzyme that is missing in people with a genetic disorder called late-onset Pompe disease, (also called GAA deficiency) in children at least 1 year old. Nexviazyme may also be used for purposes not listed in this medication guide. Warnings Tell your caregivers or get emergency... |
| Recommended Dosage | Nexviazyme is a prescription medicine used to treat the symptoms of Pompe Disease. Nexviazyme may be used alone or with other medications. |
| Contraindication | NA |
| Side Effects | Avalglucosidase alfa-ngpt is a hydrolytic lysosomal glycogen-specific recombinant human α-glucosidase enzyme conjugated with multiple synthetic bis-mannose-6-phosphate (bis-M6P)-tetra-mannose glycans resulting in approximately 15 moles of M6P per mole of enzyme (15 M6P) and is produced in Chinese hamster ovary cells (CHO). Avalglucosidase alfa-ngpt has a molecular weight of approximately 124 kDa. |
| Useful Link 1 | Link |
| Useful Link 2 | Link |
| Remarks | NA |
| Primary information | |
|---|---|
| ID | 16003 |
| Therapeutic ID | Th1661 |
| Protein Name | Avalglucosidase alfa |
| Sequence | >Th1661_Avalglucosidase_alfa QQGASRPGPRDAQAHPGRPRAVPTQCDVPPNSRFDCAPDKAITQEQCEARGCCYIPAKQGLQGAQMGQPWCFFPPSYPSYKLENLSSSEMGYTATLTRTTPTFFPKDILTLRLDVMMETENRLHFTIKDPANRRYEVPLETPRVHSRAPSPLYSVEFSEEPFGVIVHRQLDGRVLLNTTVAPLFFADQFLQLSTSLPSQYITGLAEHLSPLMLSTSWTRITLWNRDLAPTPGANLYGSHPFYLALEDGGSAHGVFLLNSNAMDVVLQPSPALSWRSTGGILDVYIFLGPEPKSVVQQYLDVVGYPFMPPYWGLGFHLCRWGYSSTAITRQVVENMTRAHFPLDVQWNDLDYMDSRRDFTFNKDGFRDFPAMVQELHQGGRRYMMIVDPAISSSGPAGSYRPYDEGLRRGVFITNETGQPLIGKVWPGSTAFPDFTNPTALAWWEDMVAEFHDQVPFDGMWIDMNEPSNFIRGSEDGCPNNELENPPYVPGVVGGTLQAATICASSHQFLSTHYNLHNLYGLTEAIASHRALVKARGTRPFVISRSTFAGHGRYAGHWTGDVWSSWEQLASSVPEILQFNLLGVPLVGADVCGFLGNTSEELCVRWTQLGAFYPFMRNHNSLLSLPQEPYSFSEPAQQAMRKALTLRYALLPHLYTLFHQAHVAGETVARPLFLEFPKDSSTWTVDHQLLWGEALLITPVLQAGKAEVTGYFPLGTWYDLQTVPIEALGSLPPPPAAPREPAIHSEGQWVTLPAPLDTINVHLRAGYIIPLQGPGLTTTESRQQPMALAVALTKGGEARGELFWDDGESLEVLERGAYTQVIFLARNNTIVNELVRVTSEGAGLQLQKVTVLGVATAPQQVLSNGVPVSNFTYSPDTKVLDICVSLLMGEQFLVSWC |
| Molecular Weight | 124000 |
| Chemical Formula | C4490H6818N1197O1299S32 |
| Isoelectric Point | NA |
| Hydrophobicity | NA |
| Melting point | NA |
| Half-life | The mean avalglucosidase alfa-ngpt plasma elimination half-life was 1.6 hours in patients with late-onset Pompe disease.[L35155] |
| Description | Avalglucosidase alfa, or NeoGAA, is a drug for enzyme replacement therapy specifically designed for Pompe disease, a rare inherited neuromuscular disorder caused by the deficiency of the alpha-glucosidase (GAA) enzyme. GAA is an essential enzyme that hydrolyzes glycogen into free glucose for use in cellular functions. In Pompe disease, the GAA enzyme is missing and patients are unable to properly break down glycogen, resulting in the accumulation of glycogen within lysosomes and progressive disruption of cellular function, especially in smooth, cardiac, and skeletal muscle cells. Pompe disease is characterized by progressive muscle weakness and loss of motor function, including respiratory muscle weakness, which leads to premature death and debilitating effects on people’s lives.[A232955] Avalglucosidase alfa is a recombinant form of GAA that restores deficient enzyme levels. First developed by Sanofi Genzyme, avalglucosidase alfa is a chemically modified version of [alglucosidase alfa], where synthetic bis-phosphorylated oligosaccharides were attached to the structure to improve cellular uptake of the drug and better muscle targeting.[A232960] On August 6, 2021, avalglucosidase alfa-ngpt was approved under the market name Nexviazyme to treat patients one year of age and older with late-onset Pompe disease.[L35160] Late-onset Pompe disease is associated with a range of debilitating physical symptoms, such as progressive muscle weakness, including respiratory muscle weakness, and loss of motor function.[A232955] In clinical trials, avalglucosidase alfa improved lung function in patients with Pompe disease.[L35160] Avalglucosidase alfa was approved by Health Canada on November 15, 2021 for the treatment of patients older than 6 months of age with late-onset Pompe disease.[L39205] |
| Indication/Disease | Avalglucosidase alfa is a hydrolytic lysosomal glycogen-specific enzyme indicated for the treatment of patients one year of age and older with late-onset Pompe disease (lysosomal acid alpha-glucosidase [GAA] deficiency).[L35155] It is approved for the same indication in Canada for pediatric patients six months and older.[L39357] |
| Pharmacodynamics | Avalglucosidase alfa is a recombinant alpha-glucosidase (GAA) enzyme that catalyzes hydrolysis of glycogen. In clinical trials, avalglucosidase alfa reduced the levels of glycogen excreted in the urine of patients with Pompe disease, indicating that it effectively cleaved excess glycogen.[L35155] Avalglucosidase alfa has significantly higher binding affinity for cation-independent mannose-6-phosphate receptor (CI-MPR) for cellular uptake and better muscle targeting than [alglucosidase alfa]. In GAA-deficient mice, avalglucosidase alfa reduced glycogen with more efficacy than alglucosidase alfa at an equivalent dose.[A232960] |
| Mechanism of Action | Pompe disease is a genetic glycogen metabolism disorder that is also referred to as acid maltase deficiency or glycogen storage disease type II (GSD II). It is caused by mutations in the GAA gene, which encodes the lysosomal hydrolase acid a-glucosidase (GAA), an enzyme that normally catalyzes hydrolysis of glycogen to release free glucose for absorption and use for cellular functions. GAA deficiency leads to accumulation of glycogen within lysosomes and progressive disruption of cellular function, especially in smooth, cardiac, and skeletal muscle cells.[A232955] Enzyme replacement therapy using avalglucosidase alfa aims to restore the missing GAA enzyme. Avalglucosidase alfa is a hydrolytic lysosomal glycogen-specific recombinant human GAA enzyme that is conjugated with multiple synthetic bis-mannose-6-phosphate (bis-M6P) tetra-mannose glycans for enhanced targeting to skeletal muscles. The M6P of avalglucosidase alfa binds to cation-independent mannose-6-phosphate receptor (CI-MPR) on the cell surface with high affinity, which allows drug uptake into cells. Avalglucosidase alfa is internalized and transported into lysosomes to undergo proteolytic cleavage. It then exerts GAA enzymatic activity to cleave glycogen.[A232955, L35155] |
| Toxicity | There is limited information on the overdose profile and LD50 values of avalglucosidase alfa. |
| Metabolism | The metabolic pathway of avalglucosidase alfa-ngpt has not been characterized. The protein portion of avalglucosidase alfa-ngpt is expected to be metabolized into small peptides and amino acids via catabolic pathways.[L35155] |
| Absorption | The avalglucosidase alfa-ngpt exposure increases in an approximately proportional manner with increasing doses over a range from 5 to 20 mg/kg. Following intravenous infusion of 20 mg/kg every two weeks in patients with late-onset Pompe disease, the mean ± SD plasma Cmax of avalglucosidase alfa-ngpt was 259 ± 72 µg/mL at week one and 242 ± 81 µg/mL at week 49. The mean ± SD plasma AUC of avalglucosidase alfa-ngpt was 1,290 ± 420 µg·h/mL at week one and 1,250 ± 433 µg·h/mL at week 49.[L35155] |
| The volume of distribution of avalglucosidase alfa-ngpt was 3.4 L in patients with late-onset Pompe disease. No accumulation was observed following every two weeks-dosing schedules.[L35155] | |
| Clearance | The mean avalglucosidase alfa-ngpt clearance was 0.9 L/hour in patients with late-onset Pompe disease.[L35155] |
| Categories | Hydrolytic Lysosomal Glycogen-specific Enzyme |
| Patents Number | NA |
| Date of Issue | NA |
| Date of Expiry | NA |
| Drug Interaction | NA |
| Target | Cation-independent mannose-6-phosphate receptor |
| Brand Name | Nexviazyme ngpt |
| Company | Genzyme Corporation |
| Brand Description | Genzyme Corporation |
| Prescribed For | Intravenous |
| Chemical Name | 100 mg/10mL |
| Formulation | NA |
| Physical Appearance | Back pain bluish lips or skin blurred vision chest discomfort or tightness chills confusion cough diarrhea difficulty swallowing dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position fast, pounding, or irregular heartbeat or pulse feeling of warmth fever general feeling of discomfort or illness headache hives, itching, skin rash joint pain loss of appetite muscle aches and pains nausea nervousness pounding in the ears puffiness or swelling of the eyelids or around the eyes, face, lips, or tongue redness of the face, neck, arms, and occasionally, upper chest runny nose shakiness in the legs, arms, hands, or feet shivering slow or fast heartbeat sore throat sweating trembling or shaking of the hands or feet trouble breathing trouble sleeping unusual tiredness or weakness vomiting |
| Route of Administration | NA |
| Recommended Dosage | NA |
| Contraindication | NA |
| Side Effects | NA |
| Useful Link 1 | Link |
| Useful Link 2 | Link |
| Remarks | NA |