PEGylated therapeutic proteins for haemophilia treatment: a review for haemophilia caregivers

Abstract

Summary. PEGylation is the technology involving the covalent attachment of polyethylene glycol (PEG) to a protein-, peptide-or small-molecule drug to improve their pharmacokinetic, pharmacodynamic and immunological profiles, and thus, enhance the therapeutic effect. Today, PEGylation of proteins is a well-established technology and is being used in the treatment of a variety of clinical disorders. Several PEGylated coagulation proteins for haemophilia A and B are under development with the goal of prolonging the circulation half-life of factor VIII (FVIII) or factor IX. The prolongation of half-life, resulting in less frequent injections can provide significant benefits in improving the quality of life of subjects with haemophilia and improvement in adherence to treatment. A review of published literature on PEGylated therapeutic products currently approved for human use and a discussion of a PEGylated recombinant FVIII molecule (BAY 94-9027, Bayer HealthCare, Berkeley, CA, USA) currently being investigated in the pivotal clinical trial prior to registration is provided. Available safety information of PEGylated proteins containing high molecular weight PEG does not indicate any safety concerns to date, following long-term (chronic) use in animal models or patients. Chronic use of currently available PEGylated products has been shown to be safe, paving the way for chronic use of PEGylated coagulation products in persons with haemophilia.

Long-lasting recombinant factor VIII proteins for hemophilia A

“…24 The use of PEG creates a hydrophilic cloud around FVIII and inhibits its proteolytic degradation while allowing its normal function of binding to VWF and participation in coagulation once activated. FVIII clearance is partly attributed to specific binding to the low-density lipoprotein receptor-related protein (LRP1), a hepatic clearance receptor with broad specificity.…”

“…24 Clinical trials with these agents appear to retain desired FVIII properties including binding to VWF while not raising specific clinical concerns. The clearance of PEG, once injected, especially on a regular basis as required for prophylaxis in hemophilia A, has generated discussion and analysis.…”

“…Ongoing clinical trials with a wider patient base and long-term follow-up are required; however, analyses from currently licensed products using PEG indicate a reasonable safety margin given current yearly PEG exposure estimates. 24 There is some evidence that PEG conjugation may affect antigen presentation of FVIII, resulting in deceased antigenicity; the translation of this observation to impact of inhibitor development would be significant but awaits further clinical trials. For a discussion on this topic, please refer to the chapter by Kaufman and Powell in this publication entitled "Molecular Approaches for Improved Clotting Factors for Hemophilia."…”

“…PEG molecules may be excreted mainly by the kidney, but to some extent also through bile. 24 Reprinted with permission from Ivens et al 24 Copyright 2012, Blackwell Publishing Ltd. NCT01184820); phase 3 studies are ongoing for PEGylated fulllength rFVIII (BAX 855; www.clinicaltrials.gov identifier NCT01736475) and glyco-PEGylated rFVIII (N8-GP; www. clinicaltrials.gov identifier NCT01480180).…”

“…Phase 2/3 studies are ongoing. 24 An 8-week prospective, multicenter, open-label nonrandomized phase 1 study in PTPs with severe hemophilia A without inhibitors administered 2 cohorts of 7 patients either 25 IU/kg/dose twice weekly or 60 IU/kg/dose once weekly of BAY 94-9027. The product demonstrated improved PK parameters, with a T 1 ⁄2 of ϳ 19 hours compared with the comparator non-Pegylated product, and was well tolerated without immunogenicity.…”