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| Primary information |
|---|
| ID | 14367 |
| Therapeutic ID | Th1494 |
| Protein Name | Vestronidase alfa |
| Sequence | NA
|
| Molecular Weight | 72562 |
| Chemical Formula | NA |
| Isoelectric Point | NA |
| Hydrophobicity | NA |
| Melting point | NA |
| Half-life | 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) [FDA Label]. |
| Description | 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) [FDA Label]. 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 [FDA Label]. 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. |
| Indication/Disease | Indicated in pediatric and adult patients for the treatment of Mucopolysaccharidosis VII (MPS VII, Sly syndrome). |
| Pharmacodynamics | 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 [FDA Label]. |
| Mechanism of Action | Beta-glucuronidase (GUS) is a lysosomal enzyme responsible for degradation of glucuronate-containing glycosaminoglycan (GAG) [A31278]. 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 [FDA Label]. |
| Toxicity | Treatment of vestronidase alfa with doses up to 20 mg/kg administered weekly in rats did not result in adverse effect on fertility and reproductive performance of male and female rats. Studies assessing the mutagenic or carcinogenic potential of vestronidase alfa have not been performed [FDA Label]. |
| Metabolism | Vestronidase alfa is eliminated by nonspecific proteolytic degradation into small peptides and amino acids [FDA Label]. |
| Absorption | 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) [FDA Label]. |
| 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) [FDA Label]. |
| Clearance | 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) [FDA Label]. |
| Categories | Enzymes and Coenzymes |
| Patents Number | NA |
| Date of Issue | NA |
| Date of Expiry | NA |
| Drug Interaction | NA |
| Target | NA |
| Brand Name | NA |
| Company | NA |
| Brand Description | NA |
| Prescribed For | NA |
| Chemical Name | NA |
| Formulation | NA |
| Physical Appearance | NA |
| Route of Administration | NA |
| Recommended Dosage | NA |
| Contraindication | NA |
| Side Effects | NA |
| Useful Link 1 | Link |
| Useful Link 2 | NA |
| Remarks | NA |