Safety of PEGylated recombinant human full‐length coagulation factor VIII (BAX 855) in the overall context of PEG and PEG conjugates

Abstract

Introduction BAX 855 is a PEGylated human full‐length recombinant factor VIII (rFVIII) based on licensed rFVIII (ADVATE). The applied PEGylation technology has been optimized to retain functionality of the FVIII molecule, improve its pharmacokinetic properties and allow less frequent injections while maintaining efficacy.AimThe aim of this study was to confirm that the excellent safety profile of ADVATE remains unchanged after PEGylation.MethodsNon‐clinical safety studies with BAX 855 and its respective unbound polyethylene glycol (PEG) were conducted in several species. The distribution of a single dose of radiolabelled BAX 855 was further investigated in rats. Publically available safety data on PEG alone and PEGylated biomolecules were summarized and reviewed for specific safety findings attributable to PEG or PEGylated biopharmaceuticals.ResultsSafety pharmacology studies in rabbits and macaques and repeated dose toxicity studies in rats and macaques identified no safety issues. Results of a distribution study in rats administered radiolabelled BAX 855 showed that radioactivity was completely excreted; urine was the major elimination route. A 28‐day study in rats dosed with the unbound PEG constituent (PEG2ru20KCOOH) of BAX 855 showed no adverse or non‐adverse effects.Safety data for PEG and PEG‐protein conjugates indicate no safety concerns associated with PEG at clinically relevant dose levels. Although vacuolation of certain cell types has been reported in mammals, no such vacuolation was observed with BAX 855 or with the unbound PEG constituent.ConclusionNon‐clinical safety evaluation of PEG and BAX 855 identified no safety signals; the compound is now in clinical development for the treatment of patients with haemophilia A.

Defining extended half‐life rFVIII—A critical review of the evidence

“…With more than 25 years of accumulated experience, PEGylation is a well‐established technology for prolonging the half‐life of proteins . The technology has been used in twelve approved medicinal products since the 1990s and in more in development . In the case of rFVIII, 3 products (BAX 855, BAY 94‐9027 and N8‐GP) employ PEGylation, albeit with different size PEG molecules (Table ), to extend half‐life by disrupting interactions with the low‐density lipoprotein receptor‐related protein (LRP) 1.…”

The Mystery of Antibodies Against Polyethylene Glycol (PEG) - What do we Know?

“…Details of the ELISA platform are provided in Online supplement 1. A 20 kDa branched PEG (Nektar Therapeutics) containing both ethoxy and terminal methoxy groups as well as an active N-hydroxy succinimide (NHS) ester group (36) was covalently bound to human serum-albumin (HSA) obtained from Baxalta and used as coating antigen. Importantly, no Tween 20 or Tween 80 was used in the assays.…”

“…To further investigate the specificity of anti-PEG antibodies, different PEG species for competition were used in the ELISA platform, including linear PEGs of 200, 2000, and 20,000 Da and branched PEG of 20,000 Da. The branched 20,000 Da PEG contained terminal methoxy groups (36), the other PEGs contained none. Results presented in Table IV indicate that anti-PEG antibodies found in healthy blood donors bind to different PEG polymers independent of the presence or absence of methoxy groups.…”

A world‐wide survey and field study in clinical haemostasis laboratories to evaluate FVIII:C activity assay variability of ADYNOVATE and OBIZUR in comparison with ADVATE

“…ADYNOVATE is a human, full-length, recombinant factor VIII (rFVIII) modified with polyethylene glycol (PEG). ADYNOVATE is characterised by an extended half-life for on-demand treatment and control of bleeding episodes, and for routine prophylaxis to reduce the frequency of bleeding episodes of patients with haemophilia A. ADYNOVATE is manufactured by covalently binding a branched PEG reagent with a molecular weight of 20 kDa to fulllength rFVIII (ADVATE) [9][10][11][12]. ADVATE is expressed in Chinese hamster Ovary (CHO) cells by a plasma-and albumin-free cell culture method [13].…”