Pharmacokinetics and safety of an intravitreal humanized anti-VEGF-A monoclonal antibody (PRO-169), a biosimilar candidate to bevacizumab

Abstract

Background: PRO-169 is a biosimilar candidate to bevacizumab (BEV), a monoclonal antibody (mAb) that inhibits vascular endothelial growth factor-A (VEGF-A) developed for intravitreal use. The current study demonstrates the intraocular pharmacokinetics (PK) of PRO-169 and its safety using New Zealand white (NZW) rabbits. Methods: Intraocular concentration was evaluated in thirty-six rabbits at 1h, 1, 2, 5, 14 and 30 days after a single bilateral injection of PRO-169 or BEV (1.25 mg/0.05 mL). In a secondary experiment, safety was evaluated after three consecutive unilateral injections at 30-day intervals in twenty-four rabbits (PRO-169: 1.25 mg/0.05 mL or ranibizumab [RZB]: 0.5 mg/0.05 mL), by liver-associated enzymes (LAE), ophthalmological examination and adverse event (AE) incidence. Primary endpoints were vitreous maximum concentration (Cmax), time to attain maximum concentration (tmax), area under curve (AUC0-t), half-life (t1/ 2) and LAE. Secondary endpoints included aqueous humor (AH) and plasma pharmacoki- netics, clinical examination and AEs. Results: The Cmax in the vitreous was 593.75 ± 45.63 (PRO-169) vs 644.79 ± 62.65 µg/mL (BEV) (p= 0.136). Tmax was 0.53 ± 0.82 vs 0.85 ± 0.73 days (p= 0.330). The AUC0-t was 3837.72 ± 465.91 vs 4247.31 ± 93.99 days*µg/mL (p= 0.052) and the half-life was 4.99 ± 0.89 vs 5.18 ± 0.88 days (p= 0.711). LAEs were normal in 92% of NZW rabbits; no differences between groups were observed (p>0.05). The AH and plasma PKs were also similar. Finally, clinical examinations found no alterations. AEs were observed in 25% of PRO-169 rabbits, without differences vs RZB (p=0.399). Conclusion: PRO-169 can be efficiently diffused and distributed in ocular compartments, showing vitreous pharmacokinetics analogous to BEV. The safety experiment did not find evidence of clinical alterations from a repeated injection of PRO-169. These results provide scientific justification supporting that PRO-169 should be evaluated in future clinical trials to confirm its safety and efficacy.