Native AT is a plasma glycoprotein that is synthesized and stored in the vascular endothelium and normally present in blood
at levels of 125 µg/mL. It is one of the most significant natural inhibitors of blood coagulation and brings about its anticlotting
effect by complexing with, and hence directly inhibiting, several blood clotting factors, most notably thrombin (factor IIa)
and factor Xa. The complex is then rapidly cleared from circulation via internalization and degradation in liver cells. In
addition to a coagulation factor binding domain, AT displays a heparin binding domain; binding of heparin greatly accelerates
the rate of complex formation. Heparin is normally co-administered with the product.
Hereditary AT deficiency can be categorized by a decrease in absolute serum AT levels or by the presence of mutated (dysfunctional)
forms. The major clinical consequence is an increase in the risk of clot formation in deep veins, pulmonary embolism, and
venous clot formation at uncommon sites (e.g., hepatic, retinal, or cerebral venous thromboembolic events). Particularly high-risk
circumstances include surgery, bed rest, and pregnancy.
The manufacture of Atryn involves initial harvest (i.e., milking the animals), followed by clarification and purification
via multiple chromatographic steps, which include specific heparin affinity, hydrophobic interaction, and ion exchange steps.
A nanofiltration step is used as a precautionary viral removal step and glycine, sodium chloride, and sodium citrate are added
as excipients. After filling into vials, the product is lyophilized.
Product administration entails infusion after reconstitution with water for injection (WFI). Limited clinical trial results
have been reported, mainly involving patients with hereditary AT deficiency in high-risk situations (surgery and pregnancy),
with incidence of deep vein thrombosis. Common side effects include haemorrhage, headache, and nausea. Atryn's active ingredient
is sourced from transgenic animals maintained by GTC biotherapeutics (Framingham, MA). Leo Pharma (Ballerup, Denmark) markets
the product in Europe.
Elaprase (idursulfase) is a recombinant form of the human lysosomal enzyme iduronate-2-sulfatase, produced in an engineered transformed
human cell line (HT-1080). The 525 amino acid enzyme displays a molecular weight of 76 kDa and harbors two disulfide bonds,
eight N-linked glycosylation sites, and a formylglycine residue at position 59 that is necessary for biological activity.
Elaprase, which is an orphan product, gained approval in the US in 2006 (and subsequently in the EU in January 2007). It is
indicated for the long-term treatment of patients with Hunter syndrome (mucopolysaccharidosis II, MPS II). MPS II is a rare,
X-linked recessive genetic lysosomal storage disease caused by a lack of functional lysosomal iduronate-2-sulfatase. This
enzyme functions naturally in the body to cleave sulphate groups from two glycosaminoglycans (GAGs)—dermatan sulphate and
heparin sulphate. GAGs are unbranched polysaccharides consisting of various uronic acids and hexosamine residues, which largely
play structure-related roles in the extracellular space, particularly those associated with connective tissue. Lack of the
enzyme results in GAG accumulation in most organs and tissues, resulting in organ or tissue dysfunction. Clinical manifestations
usually become apparent within the first 12–36 months of life and are progressive, severe, and life threatening.
Elaprase is manufactured through the initial culture of the human producer cell line, chosen for production due to its ability
to attach complex, high mannose-type oligosaccharide side chains to the enzyme's polypeptide backbone. Specifically, the presence
of mannose-6-phosphate (M6P) facilitates product binding to cell surface-M6P receptors, with subsequent cellular internalization
and delivery to lysosomes—the exact target organelle.
Product purification incorporates six chromatographic steps as well as two ultrafiltration and one viral filtration step.
Formulation entails the addition of sodium chloride (to provide an isotonic solution for subsequent administration), sodium
phosphate (a buffering agent) and polysorbate 20 (as a stabilizing agent and for protection against agitation-induced aggregation).
The final product is filter sterilized and aseptically filled into presterile vials. Each vial contains 3 mL of a 2 mg/mL
active ingredient solution. The recommended dosage regimen is once weekly intravenous infusion (after product dilution to
100 mL in saline) over a time course of 1–3 hours.
Product safety and efficacy were established by a randomized, double blind, placebo-controlled trial containing 96 MPS II
patients. Primary efficacy indications used were distance walked during a six-minute walk test and pulmonary function. The
most common adverse events were infusion-related, including life-threatening anaphylactoid reactions. Elaprase is manufactured
and marketed by Shire Human Genetic Therapies, Inc. (Danderyd, Sweden).