KalVista combines deep scientific expertise in disease mechanisms and an accomplished team in small molecule drug discovery to bring new treatments to patients.
We apply our scientific leadership in the kallikrein-kinin system (KKS) and oral drug discovery to develop small molecule protease inhibitor medicines to address the needs of patients with diseases driven by plasma kallikrein and Factor XIIa. KalVista’s innovation has resulted in the clinical development of our lead investigational product, sebetralstat. Sebetralstat is a novel, oral plasma kallikrein inhibitor that has successfully completed a pivotal Phase 3 clinical trial demonstrating its potential as a new on-demand treatment for hereditary angioedema (HAE).
Our drug discovery approach combines a deep understanding of the KKS with expertise in the design and development of orally administered small molecule protease inhibitors. To date, injectable plasma kallikrein drugs have been approved for treating HAE and injectable Factor XIIa inhibitors have shown promising clinical evidence for treating HAE. KalVista is developing oral drugs that inhibit the KKS to offer non-invasive treatment options for people with HAE and other KKS-mediated diseases.
In healthy people, the activity of the kallikrein-kinin system is controlled, but in certain diseases it can become highly activated, causing increased vascular permeability and inflammation. KKS overactivation plays an essential role in HAE and is implicated in a range of other diseases, including diabetic macular edema, idiopathic pulmonary fibrosis, thrombosis, neurodegeneration, and inflammatory disorders.
Discover how we target Factor XIIa and the KKS to advance new oral treatment options and regain control in HAE and other diseases.
Factor XIIa is the primary activator of the kallikrein-kinin system and the intrinsic coagulation cascade. Emerging research also implicates Factor XIIa in driving chronic inflammatory diseases. Factor XIIa is a serine protease generated from Factor XII following contact with triggers, such as inflammatory cells, activated platelets, and misfolded proteins. Factor XIIa cleaves prekallikrein to generate plasma kallikrein, which feeds back to amplify the generation of Factor XIIa. Plasma kallikrein and Factor XIIa mediated cleavage of their respective substrates have key roles in the KKS, intrinsic coagulation cascade, and inflammatory vascular processes.
The Intrinsic Coagulation Cascade involves the activation of a series of clotting factors, which are proteins involved in thrombosis.
Factor XIIa generated by activated platelets and medical device artificial surfaces activates the intrinsic coagulation cascade. This can lead to thrombosis, which may block normal blood flow. While Factor XIIa can increase thrombosis, it does not have a significant role in the control of bleeding.
KalVista’s oral Factor XIIa inhibitors are designed to offer a new approach to safely prevent thrombosis with reduced bleeding risk compared to conventional anticoagulants.
In the kallikrein-kinin system (KKS), the protein C1 inhibitor (C1INH) normally inhibits the activity of Factor XIIa and plasma kallikrein in blood vessels.
In people with hereditary angioedema (HAE), a mutation in the gene encoding C1INH can result in the inability to control both Factor XIIa and plasma kallikrein activity. This can cause fluid to leak through the walls of blood vessels, leading to swelling and pain.
KalVista’s oral plasma kallikrein and Factor XIIa inhibitors are designed to block this pathway that mediates HAE attacks.
A growing body of data reveals a role for Factor XIIa in inflammatory processes mediated by bradykinin receptors, the complement system, and protease activated receptors.
Activation of these pathways can contribute to chronic inflammation and vascular diseases. At KalVista, we are exploring this biology to better understand the role of Factor XIIa in these disease processes.
KalVista’s oral Factor XIIa inhibitors may offer a new approach to treating the causes and complications of chronic inflammatory diseases.
Factor XII initiates the intrinsic coagulation cascade upon its activation to Factor XIIa, caused by activated platelets and the artificial surfaces of medical devices. Factor XIIa activates Factor XI, producing Factor XIa, triggering the intrinsic coagulation cascade.
Ultimately, prothrombin is converted into thrombin, causing long strands of fibrin to form, which contributes to clot formation and thrombosis.
Inhibiting Factor XIIa may prevent formation of thrombosis with reduced bleeding risk when evaluated against conventional anti-thrombotics and Factor Xa inhibitors, although head-to-head trials have not been conducted. This therapeutic approach could be applied to a range of diseases, including venous thromboembolism, as well as thrombosis related to cancer and artificial surfaces of medical devices, especially in patients with high bleeding risk.
Activation of Protease
HAE attacks are initiated when the kallikrein-kinin system (KKS) is activated via Factor XIIa.
Release of Bradykinin
KKS activation results in the generation of plasma kallikrein which cleaves kininogen to produce a peptide called bradykinin which, in turn, binds to bradykinin receptors on the endothelium.
Bradykinin receptor binding and signaling
Bradykinin receptor signaling causes an increase in blood vessel permeability, allowing fluid to leak into body tissues.
Uncontrolled plasma kallikrein activity during HAE attacks due to insufficient control by C1INH results in further generation of bradykinin and amplification of KKS activation.
This overactivity of the KKS drives the subcutaneous or submucosal swelling that occurs during an HAE attack.
Factor XIIa is involved in pathways that promote inflammation and contribute to vascular disease and dysfunction, based on emerging research.
Factor XIIa has been shown to:
Emerging therapeutic potential for Factor XIIa
Therapeutically inhibiting Factor XIIa may be useful in treating certain chronic inflammatory and fibrotic vascular diseases. Factor XIIa and the KKS are implicated in diabetic macular edema (DME), idiopathic pulmonary fibrosis (IPF), and neuroinflammation.
KalVista continues to apply our world-class drug discovery expertise to create oral small molecule medicines that offer new treatments for patients. Our drug programs are internally developed by our team of scientists, many of whom have deep experience with KKS pharmacology and protease inhibitor medicines.
Our progress is driven by in-house capabilities in three areas: biological understanding of the KKS, medicinal chemistry expertise in protease inhibitors, and extensive experience discovering and optimizing oral medicines.
