Biomedical Engineering Reference
In-Depth Information
Box 4.2
Preclinical assessment of Myozyme
Myozyme (tradename) is a recombinant form of the human lysosomal enzyme acid
α-glucosidase (GAA) produced in a CHO cell line. It catalyses the degradation of lysosomal
glycogen and it is approved for the treatment of Pompe disease (glycogen storage disease
type II), an inherited disorder of glycogen metabolism caused by the absence or marked
defi ciency of lysosomal GAA. The product is administered by i.v. infusion at a dosage rate
of 20 mg per kilogram body weight once every 2 weeks. The enzyme is taken up by vari-
ous cells via endocytosis, triggered by binding of its carbohydrate component to cell surface
sugar receptors. Internalization of endocytotic vesicles is followed by fusion with (and hence
delivery to) lysosomes.
During product development, many of the initial non-clinical studies were undertaken in
GAA knockout mice (i.e. mice devoid of a functional GAA gene), which serves as an animal
model for Pompe's disease. The mice proved useful in assessing the pharmacodynamic effect
of Myozyme on glycogen depletion and helped establish appropriate dosage regimens. The
mice were also used to evaluate pharmacokinetics and biodistribution of GAA following its
administration at clinically relevant doses.
Initial safety tests were carried out in beagle dogs and subsequently in cynomolgus monkeys.
Single bolus i.v. doses of up to 100 mg kg 1 were used and were found to exert no negative ef-
fect upon general condition, blood pressure, heart or cardiovascular parameters, respiration
rate or body temperature. No safety tests evaluating potential product effects upon the central
nervous system were undertaken, as the protein is considered unlikely to cross the blood-brain
barrier.
Repeat dose pharmacokinetic studies were undertaken in Sprague-Dawley rats and in mon-
keys. Biodistribution studies were carried out in both normal and knockout mice, with the ma-
jority of product distributed to the liver. No specifi c studies on product metabolism or excretion
were undertaken, as the protein is almost certainly degraded via normal protein degradation
mechanisms.
Toxicity was evaluated in mice, rats, dogs and monkeys following both acute and chronic
product administration at various dosage levels (1-200 mg kg 1 range), with a proportion of
animals displaying hypersensitivity/anaphylactic-like responses at high dosage levels.
Genotoxicity studies were not undertaken; this is normal practice for protein-based biophar-
maceuticals, as proteins are unlikely to have mutagenic potential. No carcinogenicity studies
were undertaken. Such studies are not normally required for therapeutic proteins unless there
is some specifi c concern about carcinogenic potential. Reproductive toxicity studies evaluating
product effect upon embryo-foetal development were undertaken in mice and revealed no con-
cerns. Product antigenicity was evaluated, mainly as part of chronic toxicity studies. Antibody
production against product was evaluated over a 26-week repeat administration period in mon-
keys. An enzyme-linked immunosorbent assay (ELISA)-based immunoassay (Chapter 7) was
used to detect and quantify anti-product antibodies, with all monkey studies developing such
antibodies.
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