Kalvista Pharmaceuticals, Inc. · NASDAQ:KALV
Kalvista Pharmaceuticals — EAACI 2022
12 slides from Kalvista Pharmaceuticals's conference presentation, Jul 1, 2022
Slide 1: Novel Oral Small Molecule FXIIa Inhibitor Blocks Contact System Activation In Vivo
Novel Oral Small Molecule FXIIa Inhibitor Blocks Contact System Activation In Vivo Allen Clermont Director, Pre-clinical Pharmacology KalVista Pharmaceuticals, Cambridge, MA USA July 1, 2022
Slide 2: Disclosure
Disclosure: E: All authors are employees of KalVista Pharmaceuticals 2
Slide 3: Introduction
Introduction • Hereditary angioedema (HAE) is a genetic disorder that causes recurrent episodes of tissue swelling in the skin and mucosal membranes with a prevalence of approximately 1:50,0001 • HAE attacks are caused by uncontrolled plasma kallikrein activity resulting in increased bradykinin (BK)
Slide 4: Purpose
Purpose This study evaluated the effects of the oral FXIIa inhibitor KV998086 in carrageenan-induced kallikrein- kinin system activation and angioedema in mice 4
Slide 5: Potency and selectivity of FXIIa inhibitor KV998086
Potency and selectivity of FXIIa inhibitor KV998086 KV998086 Enzyme IC50 nM Factor XIIa 10.0 Factor Xa >40000 Plasma >40000 Kallikrein Thrombin >40000 Plasmin >40000 Trypsin >40000 • KV998086 was selected from a portfolio of potent and selective oral FXIIa inhibitors for in vitro and in vivo preclin
Slide 6: Effects of FXIIa inhibitor KV998086 on HK cleavage and PKa generation in human plasma
Effects of FXIIa inhibitor KV998086 on dextran sulfate stimulated kininogen (HK) cleavage and plasma kallikrein (PKa) generation in human plasma Pretreatment of human plasma with KV998086 • Inhibits HK cleavage with an IC50 = 81 nM • Blocks the activation of plasma prekallikrein (PK) to PKa 6
Slide 7: Oral KV998086 pharmacokinetic profiles
Oral KV998086 pharmacokinetic profiles • KV998086 has high oral bioavailability in rat and dog (>70%) • The IC50 of KV998086 for the inhibition of HK cleavage in DXS-stimulated human plasma is indicated by the green lines 7
Slide 8: Carrageenan (CG)-induced paw edema in mice
Carrageenan (CG)-induced paw edema in mice Experimental Design • Oral KV998086 protects mice from CG induced paw edema • KV998086 is as effective as FXII gene knockout in this model 8
Slide 9: Effects of oral KV998086 on CG-induced kallikrein kinin system activation and HK cleavage
Effects of oral KV998086 on CG-induced kallikrein kinin system activation and HK cleavage in plasma Plasma KKS Immunoblot Plasma HK Oral Vehicle CG - + • Carrageenan (CG) stimulates HK cleavage and increases FXIIa and PKa • Oral KV998086 protects mice from HK cleavage in a dose responsive manner 9
Slide 10: Effects of oral KV998086 upon CG-induced generation of FXIIa and PKa
Effects of orally KV998086 upon CG-induced generation of FXIIa and PKa Plasma FXIIa Plasma PKa • KV998086 protects mice from PKa and FXIIa generation in a dose-responsive manner • Oral KV998086 is as effective as FXII gene knockout in protecting mice from CG induced kallikrein kinin system activatio
Slide 11: Summary/Conclusions
Summary/Conclusions • KV998086 is a novel potent, selective, and orally available FXIIa inhibitor ‒ FXIIa IC50 is 10nM and highly selective compared with related serine proteases ‒ The IC50 for DXS-stimulated HK cleavage in whole human plasma is 81 nM ‒ High oral bioavailability demonstrated in both
Slide 12: Thank you
Thank you Authors: Allen C Clermont1, Daniel Lee1, Nivetha Murugesan1, Hannah J Edwards2, Stephen J Pethen2, Edward J Duckworth2, Sally L Hampton2 and Edward P Feener1. KalVista Pharmaceuticals: 1Cambridge MA, USA, 2Salisbury, UK 12