Sebetralstat found effective in trial as on-demand treatment for HAE

KalVista says it plans to file for approval in US, Japan and EU this year

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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Two hands, a stethoscope, and some medications surround a clinical trial graph showing positively trending results.

On-demand treatment with the experimental oral medication sebetralstat was effective for resolving swelling attacks in people with hereditary angioedema (HAE) — meeting all endpoints, or goals, in the Phase 3 KONFIDENT trial — top-line data show.

Based on the positive findings, sebetralstat’s developer KalVista Pharmaceuticals is planning to submit an application to the U.S. Food and Drug Administration (FDA) in the coming months seeking the therapy’s approval in the U.S., according to a company press release.

KalVista also is planning to submit additional applications requesting the therapy’s approval in Japan, and in the European Union, later this year.

“We are thrilled to announce positive Phase 3 results for the KONFIDENT trial, which we believe position sebetralstat to become the first oral, on-demand therapy for the treatment of HAE,” said Andrew Crockett, CEO of KalVista.

“We look forward to submitting a new drug application for sebetralstat to the U.S. FDA in the first half of 2024 and in the EU and Japan later this year,” Crockett said.

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Despite preventive treatment, HAE patients require on-demand care

Treatment for HAE tested in trial spanning 20 countries

HAE is a genetic disorder characterized by sudden swelling attacks due to the overproduction in the body of a signaling molecule called bradykinin. The most common forms, types 1 and 2, are specifically caused by mutations in the SERPING1 gene. Sebetralstat, formerly known as KVD900, is an oral medicine that works to reduce bradykinin levels by blocking kallikrein, an enzyme that regulates its production.

A few approved treatments already are on the market for the on-demand management of swelling attacks in HAE, but they’re all given by injection. Sebetralstat is poised to become the first oral option for the on-demand treatment of HAE.

Danny Cohn, MD, PhD, the principal investigator for the KONFIDENT trial at the University of Amsterdam, in the Netherlands, said the therapy “could transform the management of HAE” if approved.

U.S. experts note that there hasn’t been an on-demand treatment for HAE approved in the country for nearly 10 years.

“With no new on-demand therapies for HAE approved for nearly a decade, having a safe and effective oral, on-demand treatment for HAE attacks could be immensely valuable in addressing unmet needs and reducing the treatment burden associated with current injectable treatments,” said Marc A. Riedl, MD, clinical director of the U.S. Hereditary Angioedema Association Center at the University of California, San Diego, and an investigator on the KONFIEDENT study.

KONFIDENT (NCT05259917), which wrapped up in late 2023, enrolled 136 people with HAE types 1 or 2, ages 12 and older, at 66 clinical sites across 20 countries. According to KalVista, it was “the largest and most representative trial ever conducted in HAE,” including adults and adolescents experiencing attacks of all degrees of severity in different locations.

“We want to thank the people living with HAE, their families, and the investigator teams around the world who supported KONFIDENT and made it the largest clinical trial ever conducted in HAE,” Crockett said.

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HAE patients can see early signs of attacks, need for prompt treatment

Most patients given sebetralstat in trial see symptom relief within 2 hours

During the trial, when participants experienced a swelling attack, they were given on-demand treatment with one of two doses of sebetralstat (300 or 600 mg) or a placebo. All patients had at least three attacks treated — one with each dose of sebetralstat and a third with the placebo.

The study’s main goal was to test whether sebetralstat would speed the time that it took for swelling to start to ease.

The results showed that most patients given sebetralstat at either dose started experiencing symptom relief within two hours. Specifically, the median time to the beginning of symptom relief was 1.61 hours at the lower dose and 1.79 hours at the higher dose. By comparison, most patients given the placebo didn’t start experiencing symptom relief for at least six hours (median time 6.7 hours).

The time to a complete resolution of symptoms also was significantly faster with sebetralstat than with placebo, according to KalVista.

“These highly encouraging Phase 3 results show that sebetralstat provided rapid symptom relief in a broad HAE population,” Cohn said, noting that the differing patient characteristics seen in the study participants “reflects my clinical practice.”

If approved, sebetralstat may offer a compelling treatment option for patients and their caregivers given the long-standing preference for an effective and safe oral therapy that provides rapid symptom relief for HAE attacks.

Sebetralstat was found to be well tolerated. There were no serious side effects related to the therapy, and the overall rates of side effects judged to be related to treatment were lower for patients given sebetralstat (2.2%-2.3%) than the placebo (4.8%).

“These clinically meaningful results represent a potentially significant advance for people living with HAE,” Crockett said.

“If approved, sebetralstat may offer a compelling treatment option for patients and their caregivers given the long-standing preference for an effective and safe oral therapy that provides rapid symptom relief for HAE attacks,” Crockett added.

KalVista plans to present detailed results from the study later this month at the annual meeting of the American Academy of Allergy Asthma and Immunology (AAAAI), taking place on Feb. 25 in Washington, D.C.

Riedl noted that trial results “are extremely encouraging for the HAE community.”