Functional Characterization of Abicipar-Pegol, an Anti-VEGF DARPin Therapeutic That Potently Inhibits Angiogenesis and Vascular Permeability

Abstract

PURPOSE. DARPin molecules are a novel class of small proteins that contain engineered ankyrin repeat domain(s) and bind to target proteins with high specificity and affinity. Abicipar-pegol (abicipar), a DARPin molecule targeting vascular endothelial growth factor-A (VEGF-A), is currently under evaluation in patients with age-related macular degeneration. The pharmacodynamic properties of abicipar were characterized using in vivo and in vitro assays. METHODS. The binding affinity of abicipar was assessed using a kinetic exclusion assay (KinExA). In vitro assays evaluated abicipar effects on VEGF-A 165-induced calcium mobilization and tube formation in human umbilical vein endothelial cells. Abicipar was tested in vivo in a mouse model of corneal neovascularization and a rabbit model of chronic retinal neovascularization. The efficacies of abicipar and ranibizumab were compared in a rabbit model of VEGF-A 165-induced retinal vasculopathy. RESULTS. Abicipar has a high affinity for the soluble isoforms of VEGF-A; binding affinities for human VEGF-A 165 are approximately 100-fold greater than those of ranibizumab and bevacizumab and are similar for rat VEGF-A 164 but approximately 20-fold lower for rabbit VEGF-A 165. Abicipar was effective in cell-based and in vivo models of angiogenesis and vascular leak, blocking neovascularization in a mouse model of corneal neovascularization and vascular permeability in a rabbit model of chronic neovascularization. In a rabbit model of VEGF-A 165-induced vasculopathy, the duration of effect of abicipar was longer than ranibizumab when the two compounds were administered at molar-equivalent doses. CONCLUSIONS. These data support the testing of abicipar as a treatment for retinal diseases characterized by neovascularization and vascular leak.

A Mechanistic and Translational Pharmacokinetic-Pharmacodynamic Model of Abicipar Pegol and Vascular Endothelial Growth Factor Inhibition

“…In addition, the 2 mg, 16week (Q16) were simulated to test the feasibility of the 4month interval. The simulated vitreous exposure was compared with in vitro and in vivo IC 50 values estimated from a HUVEC-sprouting assay (0.017 nM) (Rodrigues et al, 2018) and from AH VEGF data (6 nM) obtained from patients with DME treated with abicipar, respectively. After both a Q8 and Q12 dosing regimen, mean steadystate minimal concentrations (C min,ss ) were maintained above the upper end of the IC 50 range (Figs.…”

“…Both 1 or 2 mg of abicipar produced greater improvements in best-corrected visual acuity with fewer IVT injections administered than 0.5 mg ranibizumab (Callanan et al, 2018). In the CEDAR and SEQUOIA identical phase III studies, abicipar (2 mg 8week or quarterly dosing) demonstrated noninferiority compared with ranibizumab (0.5 mg dosed monthly) on the primary endpoint of stable vision at week 52 (Rodrigues et al, 2018). The purpose of this analysis is to develop a translational pharmacokinetic/pharmacodynamic (PK/ PD) model of abicipar to provide a quantitative understanding of the drug disposition and target engagement in the rabbit and use the model to translate to humans to explore the feasibility of longer dosing intervals in the clinic.…”

“…Abicipar pegol (abicipar), is an antiangiogenic therapy that maintains vision gain with less frequent dosing through an optimized combination of molar dose, a long vitreous half-life, and high binding affinity for VEGF-A isoforms Smithwick and Stewart, 2017). Compared with ranibizumab, the current gold standard treatment of patients with nAMD, abicipar provides higher binding affinity and longer vitreous half-life (Rodrigues et al, 2018). In a rabbit model of VEGF-induced vasculopathy, abicipar provided a longer duration of effect than ranibizumab at an equimolar dose (Rodrigues et al, 2018).…”

“…Compared with ranibizumab, the current gold standard treatment of patients with nAMD, abicipar provides higher binding affinity and longer vitreous half-life (Rodrigues et al, 2018). In a rabbit model of VEGF-induced vasculopathy, abicipar provided a longer duration of effect than ranibizumab at an equimolar dose (Rodrigues et al, 2018). In phase II and III trials, abicipar 1 and 2 mg demonstrated sustained effectiveness in patients with nAMD.…”

<p>Issues with Intravitreal Administration of Anti-VEGF Drugs</p>

“…This suggests that this new drug can also be used as a therapeutic agent with a longer duration and less frequent injections. 5,6 The number of patients in need of an anti-VEGF treatment is expected to dramatically increase in the coming years due to new indications and an aging population. 7 Recently, data from the DRCR.net Protocol S study have led to the approval of ranibizumab for the treatment of proliferative diabetic retinopathy.…”