Sebetralstat for hereditary angioedema

Last updated Jan. 29, 2025, by Margarida Maia, PhD
Fact-checked by Joana Carvalho, PhD

What is sebetralstat for hereditary angioedema?

Sebetralstat, formerly known as KVD900, is a small molecule being developed by Kalvista Pharmaceuticals for the on-demand treatment of hereditary angioedema (HAE) swelling attacks. In clinical testing, it has been given as film-coated tablets to be swallowed, or as orally disintegrating tablets that dissolve quickly in the mouth without water.

Now in Phase 3 clinical testing, sebetralstat has been granted fast track and orphan drug designations in the U.S. It also has been designated an orphan drug in Japan and in the European Union, where a pediatric investigational plan has been approved.

In the U.K., sebetralstat has been granted an innovation passport and promising innovative medicine designation. Both are designed to speed a therapy’s development.

The U.S. Food and Drug Administration (FDA) has agreed to review an application requesting approval of sebetralstat as an on-demand treatment for adults and children, ages 12 and older, with HAE. A decision from the FDA is now expected by June 17, 2025. An application requesting the therapy’s approval has also been accepted for review by European regulatory authorities, and the company has filed similar applications in other countries.

Therapy snapshot

How does sebetralstat work in hereditary angioedema?

Angioedema occurs when blood vessels leak fluid into the deeper layers of the skin or the mucous membranes lining organs or cavities in the body, resulting in repeated swelling attacks that can arise anywhere in the body.

In HAE, such attacks generally are due to genetic mutations that impair the production or function of a protein called C1 inhibitor. This causes an enzyme known as kallikrein to become overactive and trigger the production and release of large amounts of bradykinin. Too much bradykinin causes blood vessels to widen and leak fluid into tissues, resulting in swelling.

Sebetralstat is a small molecule designed to block the activity of kallikrein in the blood. This is expected to bring swelling under control, reducing the severity and duration of attacks as they occur.

How will sebetralstat be administered in hereditary angioedema?

In clinical trials involving people with HAE, sebetralstat has been given as film-coated tablets at a dose of 300 mg or 600 mg. An easier to use, orally disintegrating tablet formulation of sebetralstat, which dissolves quickly in the mouth instead of being swallowed, has been tested in healthy adults. Plans are now being made to test the therapy in HAE patients.

Sebetralstat in hereditary angioedema clinical trials

Sebetralstat has been evaluated across a range of clinical trials involving both healthy volunteers and HAE patients. The therapy is now in Phase 3 clinical testing.

Phase 1 trials

A Phase 1 clinical trial (NCT04349800) involving 84 healthy adults, ages 18 to 55, tested the safety and tolerability of capsules or film-coated tablets of sebetralstat, at single, ascending doses ranging from 5 mg to 600 mg, against a placebo. The trial also evaluated the therapy’s pharmacokinetics, or its movement into, through, and out of the body.

Sebetralstat was well tolerated at doses as high as 600 mg. At that highest dose, sebetralstat achieved sufficient concentrations in the blood in less than 20 minutes after dosing and maintained greater than 95% inhibition of kallikrein for up to 10 hours. The film-coated tablet formulation entered the bloodstream more quickly than capsules.

Results from another Phase 1 clinical trial in 36 healthy adults showed a single dose of 500 mg or 600 mg of an orally disintegrating tablet formulation of sebetralstat was processed by the body in a similar way to that of a 600 mg, film-coated tablet. Both doses of the orally disintegrating tablet formulation were safe and well tolerated.

Phase 2 trial

A two-part Phase 2 clinical trial (NCT04208412) tested the safety and efficacy of sebetralstat in 68 people, ages 19 to 68, with HAE type 1 or 2. The participants had experienced at least three swelling attacks in the three months prior to the study. In the first part, all patients received a single dose of 600 mg of sebetralstat to evaluate its pharmacokinetics. In the second part, participants were randomly assigned to receive either a 600 mg, film-coated tablet of sebetralstat or a placebo within one hour of the start of the first attack. To treat a second attack, those who had previously taken sebetralstat were given a placebo and vice versa.

The clinical trial met its main goal of reducing the use of rescue medication within 12 hours of dosing with sebetralstat relative to a placebo (15.1% vs 30.2%). In addition, sebetralstat reduced the median time to symptom relief (1.6 hours vs. nine hours with the placebo). Relief was defined as patients feeling at least a little better at two consecutive time points within 12 hours of dosing, as reported by the Patient Global Impression of Change (PGI-C) scale. Sebetralstat also helped relieve both abdominal and peripheral swelling with no serious side effects reported.

KONFIDENT Phase 3 trial

A fully enrolled and now-completed Phase 3 clinical trial dubbed KONFIDENT (NCT05259917) evaluated the safety and efficacy of sebetralstat in 136 adults and adolescents, ages 12 and older, with HAE type 1 or 2, who were recruited at more than 60 sites across 20 countries. All patients received on-demand treatment for three swelling attacks: one each with 300 mg or 600 mg of sebetralstat or a placebo, given in random order.

The trial’s main goal was to watch for changes in the time needed for the start of symptom relief, again defined as patients feeling at least a little better for two consecutive time points within 12 hours of dosing on the PGI-C scale. Other goals included evaluating time to attack resolution within 24 hours, and the proportion of attacks whose symptoms were relieved within 12 hours of dosing.

Top-line data from KONFIDENT showed patients given either dose of sebetralstat started experiencing symptom relief much faster than those given the placebo. Specifically, the median time to the beginning of symptom relief was 1.61 hours in patients given 300 mg of sebetralstat, and 1.79 hours in those treated with the 600 mg dose. In patients given the placebo, the median time to symptom relief was 6.7 hours. Swelling attacks also resolved faster in sebetralstat-treated patients than in those on the placebo.

Additional KONFIDENT data demonstrated that a single dose of sebetralstat was sufficient to kickstart symptom relief, ease severity, or completely resolve the majority of treated swelling attacks.

Ongoing trials

Patients who completed KONFIDENT were invited to enter its two-year open-label extension, called KONFIDENT-S (NCT05505916), which recruited an estimated 150 adults and adolescents, ages 12 and older. All are receiving on-demand treatment with 600 mg of sebetralstat, given as two film-coated tablets of 300 mg each. The study’s main goal is to record, for up to two years, the proportion of patients who experience at least one side effect from sebetralstat. Other goals of the KONFIDENT-S extension, expected to conclude in early 2026, include assessing the time to symptom relief or attack resolution within 12-24 hours of dosing.

Interim data from KONFIDENT-S were announced in mid-2024 for 112 patients treated for a median of five attacks. These patients received on-demand treatment with sebetralstat within a median of nine minutes of the start of an attack — sooner than the median 41 minutes in the KONFIDENT trial — and began to experience symptom relief within less than two hours of dosing. Complete resolution occurred after a median of 21 hours, or less than one day. For the 14 throat or laryngeal attacks, the median time until the beginning of symptom relief was 1.3 hours; complete resolution occurred after a median of 6.8 hours.

A subtrial (NCT05511922) also will evaluate the pharmacokinetics of 600 mg of sebetralstat for up to six hours after dosing in 12 adolescents, ages 12 to 17, enrolled into the KONFIDENT-S extension.

Another Phase 3 clinical trial,  KONFIDENT-KID (NCT06467084), is assessing the safety and efficacy of sebetralstat in children ages 2-11 with HAE type 1 or 2. The study is enrolling about 24 children, who will be treated with one of three doses (75 mg, 150 mg, or 300 mg) of an orally disintegrating tablet formulation of sebetralstat. The main goal is to record, for a period of up to one year, the proportion of patients who experience at least one side effect from sebetralstat. Other goals of KONFIDENT-KID, expected to conclude in 2027, include assessing the time to symptom relief or attack resolution within 12-24 hours of dosing.

Common side effects of sebetralstat

Side effects reported with sebetralstat during clinical testing include headache, abdominal pain, and back pain. No serious side effects were reported, and all patients tolerated sebetralstat well.

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