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General Description:

Avalglucosidase alfa, identified by CAS number 1802558-87-7, is a notable compound with significant therapeutic applications. 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. 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 , where synthetic bis-phosphorylated oligosaccharides were attached to the structure to improve cellular uptake of the drug and better muscle targeting. On August 6, 2021, avalglucosidase alfa-ngpt was approved by the FDA under the market name Nexviazyme to treat patients one year of age and older with late-onset Pompe disease. 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. In clinical trials, avalglucosidase alfa improved lung function in patients with Pompe disease. Avalglucosidase alfa was approved by Health Canada on November 15, 2021 for the treatment of patients older than six months of age with late-onset Pompe disease. The EMA approved the drug on June 24, 2022.

Indications:

This drug is primarily indicated for: Avalglucosidase alfa is a hydrolytic lysosomal glycogen-specific enzyme indicated for the treatment of patients with late-onset Pompe disease (lysosomal acid alpha-glucosidase deficiency). In the US, it is approved in patients one year of age and older. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Avalglucosidase alfa undergoes metabolic processing primarily in: 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. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Avalglucosidase alfa are crucial for its therapeutic efficacy: 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 C_max 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. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Avalglucosidase alfa is an important consideration for its dosing schedule: The mean avalglucosidase alfa-ngpt plasma elimination half-life was 1.6 hours in patients with late-onset Pompe disease. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Avalglucosidase alfa exhibits a strong affinity for binding with plasma proteins: There is limited information on drug protein binding. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Avalglucosidase alfa from the body primarily occurs through: There is limited information on drug elimination. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Avalglucosidase alfa is distributed throughout the body with a volume of distribution of: 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. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Avalglucosidase alfa is a critical factor in determining its safe and effective dosage: The mean avalglucosidase alfa-ngpt clearance was 0.9 L/hour in patients with late-onset Pompe disease. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Avalglucosidase alfa exerts its therapeutic effects through: 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. Avalglucosidase alfa has significantly higher binding affinity for cation-independent mannose-6-phosphate receptor (CI-MPR) for cellular uptake and better muscle targeting than . In GAA-deficient mice, avalglucosidase alfa reduced glycogen with more efficacy than alglucosidase alfa at an equivalent dose. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Avalglucosidase alfa functions by: 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 α-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. 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. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Avalglucosidase alfa belongs to the None, classified under the direct parent group Peptides. This compound is a part of the Organic Compounds, falling under the Organic Acids superclass, and categorized within the Carboxylic Acids and Derivatives class, specifically within the Amino Acids, Peptides, and Analogues subclass.

Categories:

Avalglucosidase alfa is categorized under the following therapeutic classes: Alimentary Tract and Metabolism, Enzyme Replacement Therapy, Enzymes, Enzymes and Coenzymes, Hydrolytic Lysosomal Glycogen-specific Enzyme. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Avalglucosidase alfa include:

• Molecular Weight: 124000.0
• Molecular Formula: C4490H6818N1197O1299S32