Abstract
Purpose :
Anti-VEGF therapeutics that provide both reliability of administration and durability of action are critical for patients suffering from neovascular disease. Small molecule pan-VEGFR inhibitors hold great promise to meet this unmet medical need. However, the ability to deliver small molecule VEGFR2 inhibitors to posterior ocular tissues is hindered by unfavorable solubilities and dosing limitations. These shortcomings are addressed by KPI-287, an investigational NCE that potently inhibits VEGFR family members with a superior pharmacokinetic/pharmacodynamic (PK/PD) profile relative to compounds currently undergoing clinical trials.
Methods :
In vitro kinase pharmacological profiles of KPI-287 and axitinib were evaluated against a panel of 97 kinases distributed across the kinome (Eurofins DiscoveRx, USA). IC50 for VEGFR-2 and PDGFR-β were determined in HUVEC and NIH3T3 cell lines, respectively (ProQinase, Germany). PK/PD profiles of both compounds were evaluated in Dutch-belted rabbits following topical administration and intravitreal (IVT) challenge with rhVGEF.
Results :
Both KPI-287 and axitinib demonstrate comparable inhibitory profile against VEGFR and PDGFR kinases (FLT1, KDR, FLT4, PDGFR-α and PDGFR-β). However, the two compounds exhibited differing secondary pharmacology, with KPI-287 showing activity at EGFR, ALK and TGFβ1. Despite the similar activities at VEGR subtypes, KPI-287 showed superior in vivo efficacy compared to axitinib in the rabbit rhVEGF challenge model despite more frequent dosing of axitinib. The superior efficacy of KPI-287 correlated with a greater solubility and higher tissue levels achieved in the retina and choroid of Dutch-belted rabbits compared to those for axitinib. PK/PD profiling of KPI-287 demonstrated that efficacy can be achieved at retinal concentration >250 nM, supporting administration of KPI-287 by intravitreal and suprachoroidal routes.
Conclusions :
Relative to axitinib, the most potent VEGFR2 inhibitor currently in the clinic for the treatment of wet AMD, KPI-287 demonstrated comparable in vitro potency and superior efficacy in the rabbit VEGF challenge model. The favorable efficacy profile was associated with greater solubility and ability to achieve higher tissue levels. These data support the development of KPI-287 for the treatment of choroidal neovascular disease using IVT and suprachoroidal routes of delivery.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.