PEGylated coagulation proteins for haemophilia A and B are under development with the goal of prolonging the circulation half-life and thereby offering extended protection from bleeding.

Bleeding events in haemophilia A are currently treated with on demand or frequent prophylactic infusions (up to three times per week or every other day) with recombinant or plasma-derived FVIII [15]. Prolongation of half-life by DAPT modification of recombinant FVIII (rFVIII), resulting in less frequent infusions can provide significant benefits and improve the quality of life of persons with haemophilia. To address these needs, a long-acting rFVIII was developed by covalently linking a single 60 kDa PEG molecule to one amino acid in rFVIII [16]. The 60 kDa PEG size was selected over smaller PEG molecules size of 12, 20 and 30 kDa, as it provided the best half-life prolongation,

as observed in preclinical studies. This PEGylated rFVIII molecule (BAY 94–9027, PLX3397 Bayer HealthCare, Berkeley, CA, USA) showed prolonged protection from bleeding, improved pharmacokinetics and no toxicity in preclinical studies [16]. Recently, a phase I study in humans using this PEG-60-rFVIII (BAY 94–9027) was completed, and showed that the drug was well tolerated, efficacious and had no serious adverse events (manuscript in preparation). A phase II/III clinical study with BAY 94–9027 is ongoing. The following review provides an assessment of the safety information of PEGylated proteins containing high molecular weight PEG (PEG 30 kDa and larger) with the focus on PEG-related safety for long-term (chronic) use in haemophilia. A review of literature of preclinical safety and toxicity, as well as clinical studies

of large PEG molecules using keywords [Medline keywords: haemophilia PEGylation (six articles), PEG preclinical safety (17), PEGylated protein in vivo review (33); Toxline keywords: PEGylated protein safety (49)] and publically available Summary Basis of Approval documents selleck inhibitor from the US Food and Drug Administration (FDA) and European Public Assessment Reports (EPAR) drug approval information from the European Medicinal Agency (EMA) was carried out searching for PEGylated proteins and PEG safety (accessed January 2012) [17, 18]. The search strategy was broad to minimize the possibility of overlooking articles relevant to high molecular weight (≥30 kDa) PEG. Studies that looked at currently available marketed high molecular PEG products were reviewed for chronic administration, side-effects and adverse event profiles with specific determination to see if the adverse events reported were due to PEG. To search for safety information on PEGylated coagulation factors, the following search terms and their combination were used: PEGylated FVII, VIII or IX drugs; and coagulation factors VII, VIII, or IX with PEGylation terms (Biomedical Core Database).