Sebetralstat controls swelling in long-term prophylaxis patients
Therapy being developed by Kalvista as on-demand, oral treatment
On-demand treatment with oral sebetralstat is effective for controlling swelling attacks in people with hereditary angioedema (HAE) who are on long-term preventive treatment, an interim analysis from a clinical trial shows.
The findings were presented this month at the Western Society of Allergy, Asthma and Immunology (WSAAI) 2025 Annual Meeting in Hawaii. The work was funded by Kalvista Pharmaceuticals, which is developing the treatment.
“Sebetralstat has the potential to enable early treatment of attacks, thereby halting progression at an early stage and reducing morbidity, even among patients on [long-term preventive treatment],” Paul Audhya, MD, chief medical officer of Kalvista, said in a company press release.
HAE is a genetic disorder wherein swelling attacks are driven by the overproduction of the signaling molecule bradykinin. Sebetralstat is designed to reduce the molecule’s levels by blocking the activity of kallikrein, the enzyme that produces it.
There are two broad categories of HAE treatment: on-demand therapies to control swelling attacks when they happen and long-term prophylactic therapies taken regularly to reduce the risk of attacks. Other on-demand HAE treatments are given by injection, but Kalvista is developing sebetralstat as an oral on-demand therapy to be more convenient for patients.
“By overcoming the barriers imposed by current injectable on-demand therapies, sebetralstat could shift the treatment paradigm and become the foundation of HAE management,” Audhya said.
Oral therapy to comply with HAE treatment guidelines
Kalvista is seeking approval of sebetralstat as an on-demand HAE treatment in the U.S. the European Union, Japan, and several other countries. The applications are based in part on data from KONFIDENT-S (NCT05505916), an open-label extension study that’s collecting long-term data about on-demand sebetralstat.
In one WSAAI meeting presentation, researchers reported data from an interim analysis of KONFIDENT-S that focused on sebetralstat for managing swelling attacks on-demand in patients on long-term prophylaxis. The analysis included data on 35 people with HAE types 1 or 2 who treated 382 swelling attacks with sebetralstat while receiving long-term prophylactic treatment. The poster was titled, “Safety and Effectiveness of Sebetralstat in Patients with Hereditary Angioedema Receiving Long-Term Prophylaxis: Interim Analysis from the KONFIDENT-S Open-Label Study.”
Patients were able to take sebetralstat quickly when swelling attacks started, the results showed, with the median time from the start of each attack to starting treatment being six minutes.
“Treatment guidelines recommend that patients with HAE should consider treating all attacks regardless of [long-term prophylaxis] use and should treat attacks as early as possible,” said Marc A. Riedl, MD, a professor at the University of California, San Diego, who presented the data.
The data suggest the oral therapy is helping patients comply with treatment guidelines, the researchers said.
For most attacks, symptom relief started in under 1.5 hours after taking sebetralstat and the attack severity was reduced within a median of 4.2 hours after treatment. The median time to completely resolving attacks was 14.8 hours.
“Sebetralstat was effective in treating [HAE] attacks and provided early symptom relief (median, 1.3 hours) in participants having attacks while on [long-term prophylaxis],” the researchers wrote.
For most of the documented attacks, patients started to see symptom relief after just one dose. In about 1 in 4 attacks, patients took a second dose within 12 hours of the attack starting.
“These interim results suggest that, if approved, sebetralstat could be a safe and effective oral on-demand treatment for breakthrough attacks, regardless of severity, location, or type of [long-term prophylaxis] used,” Riedl said.
Oral on-demand treatment to accompany oral prophylaxis
The most common type of long-term prophylactic treatment used in KONFIDENT-S was the oral therapy Orladeyo (berotralstat). In a separate presentation, researchers highlighted data from the 16 patients taking Orladeyo in the study. That poster was titled, “Sebetralstat for the Treatment of HAE Attacks in Patients Receiving Berotralstat: Interim Analysis from the KONFIDENT-S Open-Label Study.”
The results were broadly consistent with the analysis. The median time to the onset of symptom relief was less than 1.5 hours and the median time to completely resolving the attack was less than 11 hours.
“These results demonstrate that sebetralstat, when used as an oral on-demand treatment for attacks occurring among patients receiving [Orladeyo] for [long-term prophylaxis], enabled rapid treatment and symptom improvement,” said Michael E. Manning, MD, allergist-immunologist at Allergy, Asthma and Immunology Associates, who presented the poster.
If sebetralstat is approved, patients would have an oral long-term preventive treatment option in Orladeyo plus an oral on-demand therapy with sebetralstat.
“If approved, sebetralstat alone, or in combination with [Orladeyo], would enable management of HAE without needles,” the researchers wrote.
Sebetralstat was generally well tolerated across the analyses, with no new safety signals observed. Reported adverse events that were considered related to treatment included headache, muscle and joint pain, nausea, and vomiting. None were serious or severe.
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