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M. Peraza
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P1.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 233)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.04-113 - Nonclinical Development of PF-06439535, a Potential Biosimilar to Bevacizumab (ID 1217)
09:30 - 09:30 | Author(s): M. Peraza
- Abstract
Background:
Bevacizumab is a recombinant, humanized, IgG1 monoclonal antibody that binds to and inhibits the activity of vascular endothelial growth factor (VEGF), and is approved to treat a variety of advanced solid tumors. PF‑06439535 is under development as a potential biosimilar to bevacizumab.
Methods:
Amino acid sequences of PF‑06439535 and EU‑ and US‑sourced bevacizumab (bevacizumab‑EU and bevacizumab‑US, respectively) were compared by peptide mapping; post-translational modifications and biochemical properties were analyzed by N-linked oligosaccharide profiling and imaged capillary electrophoresis. Functional analysis of PF‑06439535, bevacizumab‑EU, and bevacizumab‑US included an enzyme-linked immunosorbent assay to detect binding to the 4 major VEGF isoforms (VEGF~121~, VEGF~165~, VEGF~189~, VEGF~206~), and a cell growth inhibition assay in human umbilical vein endothelial cells (HUVEC). Toxicokinetics and potential toxicity of PF‑06439535 and bevacizumab‑EU were evaluated following intravenous (IV) administration (10 mg/kg twice weekly for 1 month, 9 doses total) in sexually- and skeletally-immature male cynomolgus monkeys; control animals received vehicle.
Results:
PF‑06439535, bevacizumab‑EU, and bevacizumab‑US had identical primary amino acid sequences and similar levels of N-linked oligosaccharides. Predominant charge isoforms were similar; charge heterogeneity was due to variations between PF‑06439535 and reference products in relative proportions of species with C-terminal lysines. Target binding to each VEGF isoform showed similar dose responses between PF‑06439535, bevacizumab‑EU, and bevacizumab‑US; comparable biological activity was observed by inhibition of VEGF-induced HUVEC proliferation. In cynomolgus monkeys, PF‑06439535 and bevacizumab‑EU (n=4 each) were well tolerated, with no PF‑06439535- or bevacizumab‑EU–related clinical, laboratory, or histopathology findings, except physeal dysplasia of the distal femur with similar incidence and severity for both molecules. Induction of anti‑drug antibodies was not observed in the PF‑06439535- or bevacizumab‑EU–dosed groups. Systemic exposure (mean area under the serum drug concentration–time curve from 0 to 72 hr ± standard deviation) was similar for PF‑06439535 and bevacizumab‑EU on Day 1 (12100 ± 876 vs 14700 ± 2260 μg·hr/mL) and Day 25 (45500 ± 5420 vs 45100 ± 3670 μg·hr/mL).
Conclusion:
Results from the analytical similarity assessments and nonclinical studies have supported the clinical development of PF‑06439535 as a potential biosimilar to bevacizumab. These data supported a randomized, double-blind phase I study (NCT02031991) in healthy human male volunteers in the United States, which assessed pharmacokinetics, safety, and immunogenicity of a single 5 mg/kg IV dose of PF‑06439535, bevacizumab‑EU, or bevacizumab‑US. A global, randomized phase III trial (NCT02364999) comparing PF‑06439535 and bevacizumab‑EU, plus paclitaxel/carboplatin, for first-line treatment of advanced non-squamous non‑small cell lung cancer is enrolling patients.
