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VE-4840, an oral plasma kallikrein inhibitor, decreases human plasma kallikrein and VEGF-induced retinal thickening and vascular permeability

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Posterboard#: B0256

Abstract Number: 2725 - B0256

AuthorBlock: Melissa A. Calton1, Jeffrey A. Ma1, Lev Igoudin1, Sivan Sizikov1, Eric Chang1, Matthew Rienzo1, Stephanie Chang1, Elaine E. To1, Piotr J. Zalicki1, Samuel Keutzer1, M. Angels Estiarte1, Timothy P. Shiau1, Mohan Sivaraja1, Anirban Datta1, David B. Kita1
1Verseon Co., Fremont, California, United States;

DisclosureBlock: Melissa A. Calton, Verseon Co. Code E (Employment), Jeffrey A. Ma, Verseon Co. Code E (Employment), Lev Igoudin, Verseon Co. Code E (Employment), Verseon Co. Code I (Personal Financial Interest), Sivan Sizikov, Verseon Co. Code E (Employment), Eric Chang, Verseon Co. Code E (Employment), Matthew Rienzo, Verseon Co. Code E (Employment), Stephanie Chang, Verseon Co. Code E (Employment), Elaine E. To, Verseon Co. Code E (Employment), Piotr J. Zalicki, Verseon Co. Code E (Employment), Samuel Keutzer, Verseon Co. Code E (Employment), M. Angels Estiarte, Verseon Co. Code E (Employment), Verseon Co. Code P (Patent), Verseon Co. Code I (Personal Financial Interest), Timothy P. Shiau, Verseon Co. Code E (Employment), Verseon Co. Code P (Patent), Mohan Sivaraja, Verseon Co. Code E (Employment), Verseon Co. Code I (Personal Financial Interest), Anirban Datta, Verseon Co. Code E (Employment), Verseon Co. Code I (Personal Financial Interest), David B. Kita, Verseon Co. Code E (Employment), Verseon Co. Code I (Personal Financial Interest), Verseon Co. Code S (Non-remunerative)

Purpose
This study investigates the effects of an orally dosed plasma kallikrein inhibitor on human plasma kallikrein (hPK) and VEGF-induced models of retinal thickening and vascular permeability, two proteins contributing to retinal vascular dysfunction in diabetic retinopathy.

Methods
Enzyme inhibition: Enzyme activity of plasma kallikrein and related serine proteases were monitored by fluorescent peptide substrates. Inhibition kinetics was determined by pre-incubating the compound with plasma kallikrein and then measuring enzyme activity.
Pharmacokinetics: Male Sprague Dawley rats were treated by the parent VE-4839 (1mg/kg) intravenously or the prodrug VE-4840 orally (5mg/kg) and plasma concentrations were determined by LC-MS/MS.
In vivo assays: Retinal thickening was induced by intravitreal injection (IVT) of hPK (50ng/eye) or VEGF (100ng/eye) in male Brown Norway rats treated orally with VE-4840 (35mg/kg or 105mg/kg) or vehicle. Retinal thickness was measured by OCT before and 24hrs after IVT. Fluorescein angiography was performed on VEGF IVT eyes and retinal vascular permeability (RVP) was quantified computationally; a higher value equates to less observed RVP. Results are expressed as mean ±SD.

Results
VE-4839 has a 13nM IC50 for hPK. Selectivity over related serine proteases is >150 fold. Kinetic data is consistent with a reversible covalent mechanism of inhibition. The oral bioavailability of prodrug VE-4840 is 14.7%. Oral dosing 35mg/kg of VE-4840 reduced hPK-induced retinal thickening (22.7 ± 13.8 µm; n=6) compared to vehicle treatment (64.7 ± 21.6 µm; n=4; p= 0.0053). VE-4840 (105mg/kg) also reduced VEGF-induced retinal thickening (48.6 ± 13.2 µm; n= 8) compared to vehicle treatment (70.2 ± 5.6 µm; n= 5; p= 0.0055). Further, oral dosing with VE-4840 significantly reduced VEGF-induced RVP (39.58 ± 7.48 a.u.) compared to vehicle treatment (26.59 ± 9.27 a.u.; p= 0.0250).

Conclusions
Our results demonstrate that inhibition of the activated plasma kallikrein-kinin system with a potent plasma kallikrein inhibitor can decrease plasma kallikrein and VEGF mediated retinopathy. A reversible covalent mechanism of action may yield beneficial pharmacodynamic properties. Orally dosing VE-4840 significantly decreases retinal thickening and retinal vascular permeability.

Layman Abstract (optional): Provide a 50-200 word description of your work that non-scientists can understand. Describe the big picture and the implications of your findings, not the study itself and the associated details.
Diabetic retinopathy is a leading cause of blindness in diabetic adults. In addition to VEGF, the plasma kalllikrein-kinin system is activated, thereby contributing to retinal vascular dysfunction. This study reports that orally dosing a plasma kallikrein inhibitor significantly decreases retinal thickening and retinal vascular permeability in a plasma kallikrein model and VEGF model of retinopathy.