Phase 1 Trial Testing Fast-melting Sebetralstat as HAE Treatment

Data show disintegrating tablets processed in body like film-coated ones

Vanda Pinto, PhD avatar

by Vanda Pinto, PhD |

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An orally disintegrating tablet (ODT) formulation of sebetralstat, an investigational on-demand treatment for swelling attacks in hereditary angioedema (HAE) patients, is processed by the body in a similar way to its film-coated tablets, according to data from a Phase 1 clinical trial.

Researchers are investigating these ODT tablets as a potentially easier-to-use formulation of the small molecule therapy.

Sebetralstat’s film-coated tablets are currently being tested against a placebo in adults and adolescents with HAE in the Phase 3 KONFIDENT clinical trial (NCT05259917). Recruitment for that trial, slated to run through October 2023, is ongoing at sites in 20 countries around the world, mostly in Europe and the U.S.

KONFIDENT results are expected in the second half of 2023. If positive, KalVista Pharmaceuticals, the therapy’s developer, will use them to support the filing of a regulatory application seeking sebetralstat’s approval in the U.S. as a treatment for HAE attacks. That application likely would be submitted in the first half of 2024.

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Orally disintegrating tablets, which quickly dissolve in the mouth without water, “are a standard in other disease areas such as migraine and would be of benefit to many people with HAE, particularly younger patients,” Andrew Crockett, CEO of KalVista, said in a company press release.

“This new ODT formulation reflects a next step in our constant efforts to provide people with HAE more options to help them manage this disease,” he added.

Should the film-coated tablets be approved for HAE attacks, KalVista would “expect this formulation to become available in the US and rest of the world following [that] initial launch,” Crockett said.

In HAE, an enzyme called kallikrein is overactive, causing the excessive release of the pro-inflammatory molecule bradykinin. This leads to sudden and severe episodes of tissue swelling.

Given as an oral tablet, sebetralstat (previously called KVD900) works by blocking kallikrein; it is intended to be taken at the start of a swelling attack to prevent it from worsening.

A previous Phase 2 trial (NCT04208412) in 68 HAE adults who regularly experienced swelling attacks showed that on-demand treatment with sebetralstat resulted in the rapid relief of swelling attacks.

The Phase 3 KONFIDENT trial is investigating the safety and effectiveness of two doses of sebetralstat film-coated tablets (300 or 600 mg) against a placebo tablet in up to 114 adults and adolescents, ages 12 and older, with HAE types 1 and 2.

Researchers will assess three separate swelling attacks in each patient, with each attack being treated with either 300 mg or 600 mg of sebetralstat or a placebo, in a random order.

The trial’s main goal is to assess time to beginning of symptom relief, while secondary goals include time to both first symptom reduction and HAE attack resolution.

Earlier this year, KalVista launched a two-year open-label extension study, called KONFIDENT-S (NCT05505916), to test the long-term safety of sebetralstat as an HAE treatment.

Now, the company has released results from a Phase 1 trial that compared the pharmacokinetics of sebetralstat’s ODTs versus film-coated tablets in 36 healthy adults. Pharmacokinetics are how a treatment moves into, through, and out of the body.

All participants received each formulation, at different time points and in a random order.

Trial findings revealed that the ODT formulation had similar pharmacokinetics to film-coated tablets. Therefore, KalVista intends to continue to develop the formulation to make it available as soon as possible after the potential approval and launch of sebetralstat for HAE attacks.

Other therapies under investigation by KalVista include the kallikrein inhibitor KVD001, and KV998086, an oral small molecule blocker of activated factor XII (FXIIa), which is designed to prevent HAE attacks. KVD001 is being developed for diabetic macular edema (DME), a form of angioedema that affects the eyes.