By William Elliott, MD, FACP, and James Chan, PharmD, PhD
The U.S. Food and Drug Administration (FDA) has approved sebetralstat, the first oral, on-demand treatment for acute attacks of hereditary angioedema (HAE). Sebetralstat is a selective competitive, reversible plasma kallikrein inhibitor. It is distributed by KalVista Pharmaceuticals Inc as Ekterly.
Indications
Sebetralstat is indicated for the treatment of acute attacks of HAE in adult and pediatric patients aged 12 years and older.1
Dosage
The recommended dose is 600 mg (two tablets) orally at the earliest recognition of an HAE attack.1 A second dose (600 mg) may be taken three hours after the first dose if the response is inadequate or if symptoms worsen or recur. The maximum dose is 1,200 mg in any 24-hour period. The dose should be reduced to 300 mg in the presence of moderate cytochrome P450 3A4 (CYP3A4) inhibitors or moderate hepatic impairment.1
Potential Advantages
Unlike existing on-demand HAE treatments, which must be administered intravenously or subcutaneously, sebetralstat is administered orally, potentially enabling faster and more convenient treatment. Sebetralstat inhibits the positive feedback mechanism of the kallikrein-kinin system — plasma kallikrein reduces additional plasma kallikrein generation.1
Potential Disadvantages
Sebetralstat, primarily a CYP3A4 substrate, should not be used concomitantly with strong or moderate CYP3A4 inducers or strong CYP3A4 inhibitors.1 Acid-reducing drugs may reduce the bioavailability of sebetralstat. The most common adverse reaction is headache (3.2%).1
Comments
HAE mainly is bradykinin-mediated and usually is caused by deficiency or malfunction of C1 esterase inhibitor (C1INH), which prevents the activation of the kallikrein-kinin system.2 Sebetralstat is a competitive, reversible inhibitor of plasma kallikrein, the enzyme that cleaves kininogen to release bradykinin.1 Sebetralstat achieves greater than 90% mean inhibition of plasma kallikrein beginning 30 minutes after administration and is maintained for six hours.1 The efficacy of sebetralstat was evaluated in a double-blind, randomized, placebo-controlled, three-way crossover trial (KONFIDENT).1,2
The trial compared sebetralstat 600 mg, 300 mg (not an FDA-approved dose), and placebo to treat an eligible HAE attack. A second dose was taken if needed as determined by the study participants. The study population (n = 110) had a mean age of 38 (±15) years, 60% were female, 84% were white, 92% had HAE type 1, and 22% used background HAE prophylaxis. The primary endpoint was the time to beginning of symptom relief defined as at least “a little better” at two consecutive time points within 12 hours of first dose administration assessed using a seven-point scale — Patient-Reported Global Impressions of Change (PGI-C) — ranging from “much worse“ to “much better.” The first key secondary endpoint was the time to the first incidence of reduction in severity at two consecutive time points within 12 hours of first dose administration assessed using a five-point scale — Patient Global Impression of Severity (PGI-S) — ranging from “none” to “severe.” The second key endpoint was “time to attack resolution,” defined as a PGI-S rating of “none” within 24 hours of the first dose’s (600 mg) administration. Time to the beginning of symptom relief was significantly faster for sebetralstat compared to placebo, with 76% vs. 49% achieving the primary endpoint. The median time to beginning of relief was two hours (95% confidence interval [CI], 1.4-2.8). Fifty-three percent (vs. 31%) achieved reduction in severity within 12 hours, with a median time of 9.1 hours (95% CI, 3.8-not reached). Forty-nine percent vs. 27% of participants achieved attack resolution within 24 hours.
Clinical Implications
HAE is a rare autosomal dominant disease generally caused by mutation in the SERPING1 gene that encodes C1INH, which regulates the complement and kinin systems.3 The most common form is C1INH deficiency (type 1), and less common is dysfunctional C1INH (type 2). The disease is characterized by uncontrolled activation of the kallikrein-kinin system and unpredictable episodes of swelling mediated by bradykinin.3 Laryngeal attacks can be life-threatening. Current FDA-approved on-demand treatments include ecallantide (Kalbitor) (plasma kallikrein inhibitor), icatibant (Firazyr) (bradykinin receptor antagonist) and plasma derived or recombinant human C1INH pdC1INI (Cinryze), or rhC1INH (Ruconest). All of these require parenteral administration. In terms of long-term prophylaxis, berotalstat (Orladeyo), a plasma kallikrein inhibitor, is available as oral capsules, and lanadelumab (Takhzyro), a monoclonal antibody plasma kallikrein inhibitor, requires subcutaneous administration and the aforementioned pdC1INH. Sebetralstat is the first oral, on-demand option permitting the convenience of treating HAE earlier regardless of severity. This potentially could reduce the severity of the attack and decrease their effects on daily activities, quality of life, and reduce the need to visit a provider, emergency department, or hospital. The cost for one dose (two tablets) of sebetralstat is $16,720.
William T. Elliott, MD, FACP, is Assistant Clinical Professor of Medicine, University of California, San Francisco. James Chan, PharmD, PhD, is Associate Clinical Professor, School of Pharmacy, University of California, San Francisco.
References
- U.S. Food and Drug Administration. Ekterly prescribing information. KalVista Pharmaceuticals Inc. Revised July 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/219301s000lbl.pdf
- Riedl MA, Farkas H, Aygören-Pürsünet, et al. Oral sebetralstat for on-demand treatment of hereditary angioedema attacks. N Engl J Med. 2024;391:32-43.
- Busse PJ, Christiansen SC, Reidl MA, et al. US HAEA Medical Advisory Board 2020 guidelines for the management of hereditary angioedema. J Allergy Clin Immunol Pract. 2021;9:132-150.
The U.S. Food and Drug Administration has approved sebetralstat, the first oral, on-demand treatment for acute attacks of hereditary angioedema. Sebetralstat is a selective competitive, reversible plasma kallikrein inhibitor. It is distributed by KalVista Pharmaceuticals Inc as Ekterly.
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