The term PEGylation describes the attachment of polyethylene glycol (PEG) — a non-toxic and non-immunogenic polymer — to a biomolecule. It is a well-established technology used to formulate drugs that treat a variety of clinical disorders.
Several PEGylated clotting factors are under development for hemophilia A and B with the goal of prolonging the half-life, or the time it takes to reduce by half, of factors VIII and IX. In other words, the aim is to ensure that the factor stays in circulation longer, reducing the frequency of injecting patients with factor concentrates. That, in turn, increases patients’ compliance with treatment and improves their quality of life.
How PEGylation works
PEGylation involves the covalent attachment of PEG to a protein, peptide or small molecule drug to improve its pharmacokinetics, or how it moves through the body, as well as its pharmacodynamics, or effect on the body, and its immunological profiles. That enhances its therapeutic effect.
Benefits of PEGylation of clotting factors
PEGylation improves the drug’s solubility and decreases immunogenicity, or its ability to trigger an immune response.
It also increases the drug’s stability and retention time in the blood, as well as its size and molecular weight. That reduces breakdown and excretion from the kidneys, allowing a reduced dosing frequency from three times a week or more to only twice a week. As a result, many more bleeds may be treatable at home. This, in turn, may save patients the expense of hospitalization and absence from work and school, as well as speed up recovery time from bleeds.
Pharmacokinetic studies of PEG-factor VIII conducted in mouse models of hemophilia demonstrated that the half-life of PEGylated factors is more than double (4.9 hours) that of non-PEGylated full-length recombinant factor VIII (1.9 hours). Long-term use of currently available PEGylated products in animal models or patients has been shown to be safe, paving the way for regular use by people with hemophilia.
PEGylated clotting factors
Several PEGylated factor products are either approved (BAX 855 or Adynovate) or are in clinical trials (NCT01736475, NCT01480180, NCT01580293). The three PEGylated factor VIII products are BAX 855 (Adynovate), N8-GP, and BAY 94-9027, and one PEGylated factor IX product, Refixia.
BAX 855 or rurioctocog alfa pegol (Adynovate) is a full-length recombinant factor VIII with a 20 kDa branched PEG covalently bound to the B-domain region of factor VIII. The drug has already been approved for the treatment of hemophilia A. Studies with BAX 855 report a half-life that is 1.4 times longer than the half-life of non-PEGylated recombinant factor VIII (Advate).
BAY 94-9027 is another B-domain truncated factor VIII that has a 60 kDa PEG attached to an engineered cysteine residue. The half-life of this product is reported to be 19 hours.
The only PEGylated recombinant factor IX is Refixia (N9-GP or nonacog beta pegol), which was developed by Novo Nordisk. It is produced in CHO cells and a 40 kDa-PEG is added to the activation peptide, which is cleaved upon physiological activation, leaving behind the activated recombinant factor IX.
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