Vestronidase alfa API Manufacturers

General Description:

Vestronidase alfa, identified by CAS number 1638194-78-1, is a notable compound with significant therapeutic applications. Vestronidase alfa, or vestronidase alfa-vjbk, is a recombinant human lysosomal beta glucuronidase that is a purified enzyme produced by recombinant DNA technology in a Chinese hamster ovary cell line. The enzyme is a homotetramer consisted of 4 monomers with 629 amino acids, and holds the same amino acid sequence as human beta-glucuronidase (GUS) . Vestronidase alfa is an enzyme replacement therapy for the treatment of mucopolysaccharidosis type VII (MPS VII), also known as Sly syndrome, which is an inherited, rare genetic metabolic condition that targets a small subset of population. MPS VII is a progressive condition that affects most tissues and organs due to the lack of a lysosomal enzyme called beta-glucuronidase, leading to buildup of toxic metabolites. The disorder is initiated with skeletal abnormalities, including short stature, along with other pathological conditions including enlarged liver and spleen, heart valve abnormalities, and narrowed airways which can lead to lung infections and trouble breathing. Last two conditions are leading causes of fatalities in patients with MPS VII. Some affected individuals do not survive infancy, while others may live into adolescence or adulthood and patients may experience developmental delay and progressive intellectual disability . In clinical trials, vestronidase alfa treatment demonstrated improvement and stabilization in motor symptoms by increasing the patients' ability to walk longer distances in comparison to treatment with placebo . Few patients also experienced improved pulmonary function. Vestronidase alfa was FDA-approved on November 17th, 2017 under the trade name Mepsevii as an intravenous infusion for the treatment of pediatric and adult patients.

Indications:

This drug is primarily indicated for: Indicated in pediatric and adult patients for the treatment of Mucopolysaccharidosis VII (MPS VII, Sly syndrome). Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Vestronidase alfa undergoes metabolic processing primarily in: Vestronidase alfa is eliminated by nonspecific proteolytic degradation into small peptides and amino acids . This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Vestronidase alfa are crucial for its therapeutic efficacy: Serum exposures of vestronidase alfa increases in a dose-proportional manner, from 1 mg/kg (0.25 times the approved recommended dosage) to 2 mg/kg (0.5 times the approved recommended dosage), and 4 mg/kg (the recommended dosage). After repeated dosing of 4 mg/kg every other week in patients with MPS VII, the mean ± standard deviation of maximal concentration (Cmax) was 20.0 ± 8.1 mcg/mL (range: 6.6 to 34.9 mcg/mL). The mean ± standard deviation of area under the concentration-time curve from time zero to the last measurable concentration (AUC0-t) was 3440 ± 1430 mcg x min/mL (range: 1130 to 5820 mcg x min/mL) . The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Vestronidase alfa is an important consideration for its dosing schedule: After repeated dosing of 4 mg/kg every other week in MPS VII patients, the mean ± standard deviation of the elimination half-life (t1/2) was 155 ± 37 minutes (range: 51 to 213 minutes) . This determines the duration of action and helps in formulating effective dosing regimens.

Route of Elimination:

The elimination of Vestronidase alfa from the body primarily occurs through: Vestronidase alfa-vjbk is not expected to be eliminated through renal or fecal excretion. No excretion studies have been conducted . Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Vestronidase alfa is distributed throughout the body with a volume of distribution of: After repeated dosing of 4 mg/kg every other week in MPS VII patients, the mean ± standard deviation of the total volume of distribution (Vss) was 260 ± 130 mL/kg (range: 97 to 598 mL/kg) . This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Vestronidase alfa is a critical factor in determining its safe and effective dosage: After repeated dosing of 4 mg/kg every other week in MPS VII patients, the mean ± standard deviation of the total clearance (CL) was 1.3 ± 0.7 mL/min/kg (range: 0.6 to 3.3 mL/min/kg) . It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Vestronidase alfa exerts its therapeutic effects through: In all patients evaluated, MEPSEVII treatment resulted in reduction of urinary excretion of GAGs including chondroitin sulfate and dermatan sulfate, which was sustained with continued treatment . The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Vestronidase alfa functions by: Beta-glucuronidase (GUS) is a lysosomal enzyme responsible for degradation of glucuronate-containing glycosaminoglycan (GAG) . Resulting lysosomal storage and GAG accumulation in cells from incomplete metabolic degradation of macromolecules leads to damage to multiple tissues and organs. Vestronidase alfa serves as an exogenous source of GUS enzyme for uptake into cellular lysosomes, which is facilitated by the presence of mannose-6-phosphate (M6P) residues on the oligosaccharide chains of the recombinant enzyme. The chains allow binding of the enzyme to cell surface receptors to promote cellular uptake, and targets the lysosomes to achieve catabolism of accumulated GAGs in affected tissues . This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Vestronidase 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:

Vestronidase alfa is categorized under the following therapeutic classes: Alimentary Tract and Metabolism, Enzymes, Enzymes and Coenzymes, Glycoside Hydrolases, Hydrolases, Lysosomal beta Glucuronidase. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.

Experimental Properties:

Further physical and chemical characteristics of Vestronidase alfa include:

• Molecular Weight: 72562.0