KalVista Presents Positive Data of Sebetralstat and Oral KV998086

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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Sebetralstat, KalVista Pharmaceuticals‘ investigational on-demand treatment for swelling attacks in people with hereditary angioedema (HAE), led to a rapid and sustained suppression of kallikrein in HAE patients, according to data from a Phase 2 trial.

As previously reported, the use of sebetralstat also was associated with fast symptom relief.

Further preclinical data also supported the potential of KalVista’s KV998086, an oral small molecule inhibitor of activated factor XII (FXIIa), for the treatment of angioedema.

“The oral FXIIa inhibitors we are evaluating show great promise by blocking the earliest steps of kallikrein kinin system [KKS] activation,” Andrew Crockett, CEO of KalVista, said in a press release. “The discovery of potent, selective, and orally available FXIIa inhibitors may provide novel therapeutic opportunities to treat HAE and other KKS-mediated diseases.”

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All findings were presented across three posters at the Kinin 2022 Conference, held June 5-7 in Annecy, France.
Angioedema, a condition in which the deeper layers of the skin swell, can be triggered by a variety of factors, such as food and medications. It may also be the result of a hereditary condition, called HAE.

In the case of HAE, an enzyme called kallikrein is overly active, giving rise to excessive amounts of an inflammatory molecule called bradykinin. This molecule is the cause of the sudden and severe swelling attacks that are characteristic of the disease.

Sebetralstat, formerly known as KVD900, is a small molecule inhibitor of plasma kallikrein designed to lower bradykinin levels and therefore swelling. Unlike other approved therapies, it addresses the highest unmet need in HAE: the need for an oral therapy.

The Phase 2 trial (NCT04208412) tested sebetralstat as an on-demand treatment for HAE patients, including those with type 1 and type 2 HAE, experiencing recurrent swelling attacks.

The first part of the study was an open-label phase during which all patients — a total of 68 — received 600 mg of sebetralstat. The aim was to assess the therapy’s pharmacokinetics and pharmacodynamics. (Pharmacokinetics refers to the movement of a medicine into, through, and out of the body, while pharmacodynamics focuses on the effects a compound has in the body.)

Specifically, researchers measured the levels of sebetralstat within 15 minutes of a first dose of 600 mg dose and up to four hours.

In the second part of the study, participants were asked to treat two swelling attacks with 600 mg of sebetralstat or a placebo, in a random order.

Data from the initial portion of the study, now shared in a poster, showed sebetralstat was rapidly absorbed following a single oral 600 mg dose, reaching a concentration of 501 nanograms per milliliter (ng/mL) in the blood at 15 minutes.

A peak in its concentration — 6,080 ng/mL — was seen within one hour of dosing.

Within 15 minutes of dosing, more than 80% of plasma kallikrein was inhibited. More than 95% inhibition was achieved one hour after dosing. Notably, kallikrein inhibition was sustained for four hours.

Moreover, data from the second part of the study showed the rapid inhibition of kallikrein by sebetralstat was associated with fast symptom relief when compared to placebo: a median of 1.6 hours versus 9 hours.

Two additional posters presented data for a KalVista’s novel oral small molecule, called KV998086, that inhibits the activity of FXII. This protein is present in the bloodstream and, once activated, starts a cascade of events that cause swelling.

In a first poster, researchers tested the activity of KV998086 in a mouse model of ACE inhibitor-induced angioedema. ACE inhibitors, or angiotensin-converting enzyme inhibitors, work by blocking the breakdown of bradykinin. These medications, however, can increase blood vessel permeability (leakiness), triggering swelling.

Results showed that oral KV998086 reduced blood vessel leakage in the animal’s colon (large intestine), as well as larynx (voice box) and trachea (windpipe).

Also, when delivered as an under-the-skin continuous infusion for 48 hours using a pump, it also reduced ACEi-induced blood leakage in the colon, larynx, and trachea.

In a second poster reporting data from in vitro (lab) studies using mouse and human blood samples, KV998086 was found to act as a potent FXIIa inhibitor.