Objectives:
Biopharmaceuticals are an emerging branch of therapeutic agents. Their short half-life, rapid elimination and ability to induce a specific immune response, however, may impair their applicability. These disadvantages have been overcome by chemical modification with polyethylene glycol (PEG), which has enhanced the PK and safety of several marketed proteins since the 1990s. PEGylation uses metabolically stable PEG polymers, often with a molecular size of 5-60 kDa.
PEGylated rFVIII candidates include PEG-protein-conjugates with a minimal amount of PEG attached to the protein. Baxter and Nektar are developing BAX 855, a PEGylated full-length recombinant (r) FVIII based on the FVIII molecule used for Baxter’s licensed rFVIII (ADVATE). Due to the high potency of FVIII, the absolute amount of conjugated PEG applied with PEG-FVIII is within the range of μg per kg body weight and week. PEGylation was optimized to retain functionality of the FVIII molecule and improve its pharmacokinetic properties.
PEGs ≤20 kDa are rapidly cleared mainly via the kidneys and excreted into urine. Over time, the protein portion of the PEG-FVIII conjugate is degraded by proteolysis leaving a PEG portion which is rapidly eliminated.
Methods:
Preclinical safety, toxicokinetics and formation of anti-product antibodies were assessed in rats dosed intravenously at 350 or 700U/kg BAX 855 every other day, and in macaques receiving 150, 350 or 700U/kg BAX 855 every five days, for 28 days.
Like other non- degradable entities, physiological clearance mechanisms of PEG may include liver macrophage uptake. Clearance by macrophages in mammals has been reported to cause vacuolization at high cumulative doses. Generally, vacuoles were shown to consistently resolve over time, with no cellular damage, inflammation at the vacuolization site or functional deficits of affected tissues, and are therefore regarded to not affect the safety of PEGylated therapeutics.
Summary:
No systemic adverse effects or vacuolizations were observed after 28-day intravenous administration with BAX 855. Therefore, 700 U/kg was considered the no observed adverse effect level in these studies.
Conclusions:
This favorable safety profile provides the basis for proceeding with human trials.