Pegylation of Abicipar Increases Vitreal Half-Life, Supporting a Potential for up to 3 Month Duration of Action in the Clinic

Abstract

Purpose : Intravitreal (IVT) delivery of anti-VEGF therapies is widely accepted as a safe and effective treatment for retinal neovascular diseases. However, a drawback of existing therapies is the need for frequent injections. The purpose of these studies was to evaluate the impact of pegylation on the rabbit vitreal T_1/2 of a designed ankyrin repeat protein therapeutic, a novel, highly potent VEGF inhibitor, and through modeling and simulation (M&S) guide dose regimen selection for the lead candidate, abicipar pegol, in the clinic.

Methods : Rabbits received a single bilateral IVT injection of study drug (Dutch belted, 1 mg abicipar pegol; Fauve de Bourgogne, 500 µg non-pegylated or pegylated (PEG20) His-tagged precursor of abicipar pegol). Vitreous humor (VH), aqueous humor (AH), choroid, retina, and serum were collected up to 30 days postdose. A 6 compartment in silico physiologically based pharmacokinetic (PBPK) model was used to fit abicipar pegol rabbit data. Simulations were performed by scaling volume of distribution to human tissue volumes. The model was validated against human serum and AH concentrations obtained from patients with diabetic macular edema (DME) and neovascular age-related macular degeneration (nAMD) receiving single IVT doses of 0.4-4.2 mg. The validated model was used to simulate potential dose regimens for the clinic.

Results : Pegylation of a His-tagged precursor of abicipar pegol with PEG20 increased the rabbit vitreal T_1/2 from 3.5 to 6.6 days. Rabbit ocular data from IVT dosing of 1 mg abicipar pegol, the lead molecule, was used to build an in silico PBPK model. After scaling to human, the model showed high predictivity when validated against human serum and AH concentrations. Simulations of a 2 mg abicipar pegol IVT dose in humans indicated vitreal concentrations were maintained above the IC₅₀ for up to 3 months.

Conclusions : These studies demonstrate pegylation of designed ankyrin repeat proteins as an effective method for extending vitreal T_1/2. Further, PBPK M&S suggests the pegylated molecule, abicipar pegol, may have a duration of efficacy of up to 3 months in humans. This extended duration of action compared to existing therapies may reduce the treatment burden for patients and would be an important advance in the treatment of retinal ischemic diseases.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.