Sebetralstat provides early, fast relief for HAE attacks: Data
Most patients needed 1 oral dose to start experiencing symptom relief
Sebetralstat, an oral small molecule being developed by Kalvista Pharmaceuticals, provided adults and adolescents with hereditary angioedema (HAE) with early on-demand treatment for swelling attacks and offered fast symptom relief, even when swelling affected the larynx (voice box).
That’s according to interim data from KONFIDENT-S (NCT05505916), a two-year open-label extension study that’s testing how safe sebetralstat is and how well it works in more than 100 HAE patients, 12 and older, who took part in the Phase 3 KONFIDENT study (NCT05259917) or were experiencing frequent swelling attacks. The data were presented at the recent American Academy of Allergy, Asthma & Immunology/World Allergy Organization 2025 joint congress, in San Diego.
“Sebetralstat enabled early treatment and fast symptom relief from HAE attacks, regardless of age, attack location, or severity,” Ben Palleiko, CEO of Kalvista, said in a company press release. “This is especially critical for vulnerable populations, such as those experiencing laryngeal attacks or adolescents whose only approved options are injectable on-demand treatments.”
Angioedema occurs when fluid leaks out of blood vessels and accumulates in surrounding tissues, causing swelling. In HAE, this is caused by genetic mutations that lead to the excessive production and release of a signaling molecule called bradykinin, which makes blood vessels more permeable.
Swelling attacks can arise anywhere in the body, causing a range of symptoms. Swelling of the larynx, a passage that holds the vocal cords and lets air flow from the throat to the lungs, is particularly dangerous because it can block the airways, making breathing difficult. If it occurs, it’s considered to be an emergency that requires rapid, effective treatment.
Sebetralstat available as oral tablets for on-demand treatment
Sebetralstat is a small molecule designed to inhibit the activity of kallikrein, the enzyme that controls bradykinin production and is overactive in HAE. On-demand treatment with sebetralstat is expected to control swelling, reducing the severity and duration of attacks as they occur. Unlike other treatment options, which are given by into-the-vein or under-the-skin injections, sebetralstat is available as tablets to be taken by mouth.
“Sebetralstat, if approved, would be the first oral on-demand treatment for HAE attacks, with the potential to address some of the most significant unmet needs in HAE and become the foundational therapy for HAE management,” Palleiko said.
In the KONFIDENT-S study, all patients are receiving 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 side effects from sebetralstat. Other goals include assessing the time to symptom relief or attack resolution within 12-24 hours of dosing.
In a poster, titled “Effectiveness of Sebetralstat for the On-demand Treatment of Laryngeal Hereditary Angioedema Attacks: Interim Analysis from KONFIDENT-S,” Jonathan Bernstein, MD, a professor at the University of Cincinnati College of Medicine, presented data on 16 patients, median age of 44.5 years, who experienced laryngeal swelling.
Sebetralstat was used to treat 32 laryngeal attacks as of Sept. 14, 2024. Patients took sebetralstat within a median of 11.5 minutes after the onset of swelling. The treatment appeared to be effective, with symptom relief beginning within a median of 1.27 hours.
‘Sebetralstat could represent a therapeutic advance over injectables’
“In the time it takes many patients to decide whether to treat, prepare and administer an injectable on-demand treatment, most patients in KONFIDENT-S were already experiencing symptom relief,” Bernstein said. “If approved, sebetralstat could represent a therapeutic advance over injectables.”
Most patients needed a single dose of sebetralstat to start experiencing symptom relief. In fact, most (96%) of those who experienced symptom relief within 12 hours did so after taking one dose. Additionally, there were no reports of difficulty swallowing the film-coated tablet.
In a presentation, titled “On-demand Treatment of Hereditary Angioedema Attacks with Sebetralstat in Adolescents: Pooled Analysis From KONFIDENT And KONFIDENT-S,” Danny Cohn, MD, PhD, who heads the HAE clinic at Amsterdam University Medical Center, in the Netherlands, focused on data from adolescents.
In total, 149 swelling attacks in 19 adolescents with a mean age of 15.3 years were treated with sebetralstat, within a median of four minutes. Overall, data on safety and efficacy in adolescents were consistent with those seen in adults.
Symptom relief occurred within a median of 1.79 hours. In nearly all attacks (93.5%) in which patients started to feel symptom relief, this occurred before or without a second dose of sebetralstat. There were no serious side effects or side effects leading to discontinuation.
“Adolescents face considerable challenges in treating their HAE attacks, with substantially longer delays to treatment than adults,” Cohn said. “This challenge is compounded in the U.S., where the only approved treatments options require either intravenous administration or subcutaneous administration by [a healthcare professional]. The portability and ease of administration of sebetralstat, along with the elimination of injection-site reactions and associated anxiety, has the potential to bring transformative change to this underserved patient population.”
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