BAX 855, a PEGylated rFVIII product with prolonged half-life. Development, functional and structural characterisation

Area of Science:

• Biochemistry
• Pharmacology
• Biotechnology

Background:

• Patients require more convenient prophylactic therapies for hemophilia.
• Recombinant Factor VIII (rFVIII) is a standard treatment.
• Longer-acting formulations aim to improve patient adherence and outcomes.

Purpose of the Study:

• To develop and characterize BAX 855, a PEGylated rFVIII with an improved pharmacokinetic profile.
• To assess the safety, efficacy, and immunogenicity of BAX 855 in preclinical studies.

Main Methods:

• BAX 855 was produced by PEGylating Baxter's rFVIII (ADVATE™) using a novel reagent and optimized process.
• PEGylation degree was controlled to approximately 2 moles of PEG per FVIII molecule.
• HPLC and MS methods were used to identify PEGylation sites and assess lot-to-lot consistency.
• Biochemical characterization evaluated FVIII function, including LRP binding.
• Preclinical studies assessed pharmacokinetic behavior, efficacy, toxicity, and immunogenicity.

Main Results:

• BAX 855 demonstrated an improved pharmacokinetic profile and prolonged efficacy compared to ADVATE™.
• PEGylation was primarily localized to the B-domain (approx. 60%), with excellent lot-to-lot consistency.
• Reduced binding to the LRP clearance receptor was observed for BAX 855.
• No signs of toxicity or elevated immunogenicity were detected in preclinical studies.
• The preclinical data supported the initiation of a Phase 1 clinical study.

Conclusions:

• BAX 855 represents a promising longer-acting rFVIII formulation for hemophilia prophylaxis.
• Optimized PEGylation achieved improved pharmacokinetics and efficacy without compromising safety.
• Reduced LRP binding likely contributes to the prolonged circulation time of BAX 855.
• Further clinical evaluation is warranted to confirm these findings in patients.