Sebetralstat Becomes First and Only FDA-Approved Oral, On-Demand Treatment for HAE

The FDA approved sebetralstat (Ekterly; KalVista Pharmaceuticals) for the treatment of acute attacks of hereditary angioedema (HAE) in adults and pediatric patients 12 years and older. With this action, sebetralstat has become the first and only FDA-approved oral, on-demand treatment for this disease.¹

Sebetralstat is a novel, investigational oral plasma kallikrein inhibitor indicated for the on-demand treatment of HAE. Sebetralstat received fast track and orphan drug designations from the FDA, and the new drug application (NDA) for this indication was accepted by the FDA in September 2024.²

“The FDA approval of [sebetralstat] is a defining moment for people living with HAE. [It] enables people to treat attacks the moment symptoms begin, wherever they are. This approval affirms the strength of our science and deep commitment to the HAE community,” Ben Palleiko, CEO of KalVista, said in a news release. “[Sebetralstat] has the potential to become the foundational treatment for HAE, and our focus now is on delivering it to the people who need it.”¹

Clinical Trial Data

KONFIDENT

The NDA was initially supported by previous data from the KONFIDENT phase 3 clinical trial (NCT05259917)³ and the KONFIDENT-S open-label extension trial (NCT05505916).^2,4 KONFIDENT is a randomized, double-blind, placebo-controlled, 3-way crossover phase 3 clinical trial that assessed the efficacy and safety of 2 dose levels (300 and 600 mg) of sebetralstat as an on-demand treatment in adolescents and adults with HAE type I or II. It enrolled 136 patients 12 years and older from 66 clinical sites across 20 different countries, making it the largest clinical trial to be conducted for HAE. Patients had to have at least 2 documented HAE attacks within 90 days prior to being randomly assigned. In the trial, patients were treated for each eligible attack with up to 2 doses of their assigned study drug and treated for up to 3 attacks over the course of the study.^1-3

Sebetralstat was observed to meet its primary end point in KONFIDENT, with both 300- and 600-mg doses achieving the beginning of symptom relief significantly faster than placebo, with median times of about 1.61, 1.79, and 6.72 hours, respectively (300 mg: P < .0001; 600 mg: P = .0013). Additionally, the time to reduction in the attack severity with the 300-mg dose and the 600-mg dose was faster than with placebo (P = .004 and P = .003), with median times of 9.27, 7.75, and more than 12 hours. The time to complete resolution was also faster with the 300-mg and 600-mg doses than with placebo (P = .002 and P < .001).^1,4

Notably, the percentages of attacks with complete resolution within 24 hours were approximately 42.5%, 49.5%, and 27.4% with the 300-mg dose, 600-mg dose, and placebo, respectively. Sebetralstat and placebo had similar safety profiles, with no serious adverse events related to the trial agents being reported.^1,2,

KONFIDENT-S Extension Trial

KONFIDENT-S is the open-label, multicenter extension trial for KONFIDENT. It evaluated the long-term safety and efficacy of the 300- and 600-mg doses of sebetralstat in this patient population. The findings showed that the treatment enabled patients to treat their attacks early, with a median time from attack onset to treatment of about 9 minutes. Sebetralstat demonstrated a consistent safety and efficacy profile with KONFIDENT and included a median time to beginning of symptom relief for laryngeal attacks of about 1.3 hours.^1,2,5

“This is an important moment for patients, giving people living with HAE a treatment option that could provide greater independence and control over managing their condition,” KONFIDENT investigator Marc A. Riedl, MD, professor of medicine and clinical director of the US Hereditary Angioedema Association Center at the University of California, San Diego, said. “Until now, on-demand treatment relied on injectable subcutaneous or intravenous administration, often resulting in delayed intervention. Having an oral option empowers patients to treat attacks early, which aligns with treatment guidelines and advances our goal as physicians to reduce the overall burden of disease.”¹

REFERENCES

1. KalVista. KalVista Pharmaceuticals Announces FDA Approval of EKTERLY® (sebetralstat), First and Only Oral On-demand Treatment for Hereditary Angioedema. News release. July 7, 2025. Accessed July 7, 2025. https://ir.kalvista.com/news-releases/news-release-details/kalvista-pharmaceuticals-announces-fda-approval-ekterlyr

2. Businesswire. KalVista Announces FDA Acceptance of New Drug Application for Sebetralstat for Oral On-Demand Treatment of Hereditary Angioedema. News release. September 3, 2024. Accessed June 12, 2025. https://www.businesswire.com/news/home/20240903673442/en/KalVista-Announces-FDA-Acceptance-of-New-Drug-Application-for-Sebetralstat-for-Oral-On-Demand-Treatment-of-Hereditary-Angioedema

3. A Phase III, Crossover Trial Evaluating the Efficacy and Safety of KVD900 (Sebetralstat) for On-Demand Treatment of Angioedema Attacks in Adolescent and Adult Patients With Hereditary Angioedema (HAE). ClinicalTrials.gov identifier: NCT05259917. Updated May 2, 2025. Accessed June 12, 2025. https://clinicaltrials.gov/study/NCT05259917

4. Riedl MA, Farkas H, Aygören-Pürsün E. Oral Sebetralstat for On-Demand Treatment of Hereditary Angioedema Attacks. New Engl J Med. 2024;391(1):32-43. doi:10.1056/NEJMoa2314192

5. An Open-label Extension Trial to Evaluate the Long-term Safety of KVD900 (Sebetralstat) for On-Demand Treatment of Angioedema Attacks in Adolescent and Adult Patients With Hereditary Angioedema (HAE). ClinicalTrials.gov identifier: NCT05505916. Updated December 27, 2024. Accessed June 12, 2025. https://clinicaltrials.gov/study/NCT05505916