KVD900, KalVista’s Investigational Therapy for HAE, Fares Well in Phase 1 Trial

Joana Carvalho, PhD avatar

by Joana Carvalho, PhD |

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KalVista Pharmaceuticals‘ investigational therapy KVD900 for the treatment of hereditary angioedema (HAE) rapidly reduces the activity of plasma kallikrein, one of the drivers of HAE attacks.

That promising result comes from the first-in-human Phase 1 clinical trial of KVD900, and was shared at the 11th C1 Inhibitor Deficiency and Angioedema Workshop in Budapest, Hungary, in oral and poster presentations.

The oral presentation, “KVD900, a new oral on-demand treatment of hereditary angioedema attacks achieves complete plasma kallikrein suppression: safety, tolerability, pharmacokinetic and pharmacodynamic results from a phase 1 first-in-human study” (abstract#O-25) was given by Andreas Maetzel, MD, PhD, senior vice president of medical at KalVista.

The poster, “High plasma exposures of KVD900 achieved in First in Human study markedly inhibit plasma prekallikrein activation; early blockade of plasma kallikrein (PKa) may halt attacks in hereditary angioedema (HAE) by reducing contact system activation” (abstract#P-35), was presented by Edward Duckworth, research biochemist at KalVista.

HAE is a rare genetic disorder characterized by sudden and recurrent episodes of swelling of tissues, markedly affecting the face, tongue, hands, feet, gastrointestinal tract, genitalia, and upper airways.

The disease is caused by lack of functional C1-inhibitor (C1-INH) protein, resulting in the continuous production of an enzyme called kallikrein. Increased levels of kallikrein raise the levels of bradykinin, a small protein that regulates blood pressure and inflammation by dilating blood vessels. So, acute swelling occurring during HAE attacks is caused by the overproduction of bradykinin.

KVD900 is a small molecule inhibitor of plasma kallikrein that prevents these molecular events, reducing the chances of an ensuing HAE attack. The compound has already completed its first Phase 1 trial, which was designed to assess the therapy’s safety and tolerability, as well as its metabolism, stability, and degradation in the body (pharmacokinetics), in a group of 68 healthy volunteers.

Participants received ascending doses of KVD900, ranging from 5 mg up to a maximum of 600 mg.

Results showed that within 10 minutes after being administered, the therapy successfully inhibited the activity of plasma kallikrein in all tested doses, and within 20 minutes it already had blocked its activity by 95% when used in the highest dosage. In addition, these protective effects lasted for up to 10 hours after the initial administration.

In general, KVD900 was well-tolerated, including among individuals treated with the highest dose of 600 mg. No gastrointestinal adverse events (side effects) were reported during the study, and the majority of adverse events reported were mild in severity.

Further analyses showed that the investigational candidate KVD900 holds greater therapeutic potential to prevent kallikrein activity when compared to Berinert, an approved acute C1 inhibitor, the company reported.

“KVD900 is an oral, novel, potent and selective inhibitor of plasma kallikrein, a validated target in HAE,” Andrew Crockett, CEO of KalVista, said in a press release. “We believe KVD900 represents a new therapeutic opportunity to rapidly halt HAE attacks at their earliest sign and we look forward to seeing the Phase 2 data late this year.”

Researchers are currently exploring KVD900’s potential in an ongoing Phase 2 trial (2018-004489-32) in approximately 50 HAE patients at 10-15 sites in the U.K., Germany, and several other European countries. This trial will evaluate the effectiveness of the therapy to prevent HAE attacks compared to a placebo.