Velmanase alfa is a recombinant form of human alpha-mannosidase. The amino acid sequence of the monomeric protein is identical to the naturally occurring human enzyme, alpha-mannosidase. Velmanase alfa is intended to supplement or replace natural alpha-mannosidase, an enzyme that catalyses the sequential degradation of hybrid and complex high-mannose oligosaccharides in the lysosome, reducing the amount of accumulated mannose-rich oligosaccharides.
There were no apparent pharmacokinetic gender differences in patients with alpha-mannosidosis disease.
Velmanase alfa is administered through intravenous infusion. At steady-state after weekly infusion administration of 1 mg/kg of velmanase alfa, the mean maximum plasma concentration was about 8 µg/mL and was reached at 1.8 hours after the start of administration corresponding to the mean infusion duration time.
As expected for a protein of this size, the steady-state volume of distribution was low (0.27 L/kg), indicating distribution confined to plasma. The clearance of velmanase alfa from plasma (mean 6.7 mL/h/kg) is consistent with a rapid cellular uptake of velmanase alfa via mannose receptors.
The metabolic pathway of velmanase alfa is predicted to be similar to other natural occurring proteins that degrade into small peptides and finally into amino acids.
After the end of the infusion, velmanase alfa plasma concentrations fell in a biphasic fashion with a mean terminal elimination half-life of about 30 hours.
Velmanase alfa exhibited a linear (i.e. first-order) pharmacokinetic profile, and Cmax and AUC increased proportionally to the dose with doses ranging from 0.8 to 3.2 mg/kg (corresponding to 25 and 100 units/kg).
Velmanase alfa is a protein and is predicted to be metabolically degraded into amino acids. Proteins larger than 50,000 Da, such as velmanase alfa, are not eliminated renally. Consequently hepatic and renal impairment are not expected to affect the pharmacokinetic of velmanase alfa. As no patients older than 41 years have been identified across Europe, no relevant use in elderly patients is expected.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, juvenile toxicity and toxicity to reproduction and development.
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