Ekterly (sebetralstat) for hereditary angioedema: the first FDA-approved oral on-demand therapy

Dear Editor,

Hereditary angioedema (HAE) is an infrequent disorder attributable to a deficiency or functional impairment of C1 inhibitor (C1-INH). This culminates in excessive bradykinin production, causing heightened vascular permeability and resultant edema. The condition is marked by recurrent, nonpruritic swelling involving the skin and submucosal tissues of the extremities, abdomen, genitourinary tract, face, and throat, which may be associated with abdominal pain, nausea, vomiting, diarrhea, and the risk of life-threatening airway compromise^[1^].

The therapeutic management for hereditary angioedema aspires to attain comprehensive disease control and restoration of normative quality of life. Currently, four on-demand therapeutic agents have attained regulatory approval: plasma-derived C1 esterase inhibitor (pdC1INH), recombinant C1 esterase inhibitor (rhC1INH), bradykinin B2 receptor antagonist, and plasma kallikrein inhibitor^[2^]. However, parenteral options are linked to anxiety, preparation time, storage challenges, and injection-site reactions, which reduce compliance, delay use, increase treatment burden, and impair quality of life. Therefore, oral treatments remain an unmet need^[3^].

On 7 July 2025, the FDA approved sebetralstat in the US for the treatment of acute attacks of HAE in patients of age 12 years and older. The drug has since been approved in the UK on 15 July 2025 and has received a positive opinion in the EU for the same indication^[4^]. Emerging therapies such as novel oral agents, monoclonal antibodies, and RNA-based treatments are still developing in addition to these established injectable treatments. Donidalorsen (subcutaneous antisense oligonucleotide) and garadacimab (subcutaneous anti-FXIIa monoclonal antibody) are now available for long-term attack prevention in patients of age 12 years and older. While these agents offer effective prophylaxis, they require regular subcutaneous administration and are not indicated for acute symptom control^[5^]. Sebetralstat, on the other hand, continues to be the first and only FDA-approved oral agent for on-demand usage during attacks. This is supported by a phase 2 randomized controlled trial that included 68 adult patients with HAE type 1 or type 2^[6^]. For acute attacks, patients received placebo or oral sebetralstat particularly 600 mg dose in the crossover phase. Sebetralstat treatment significantly delayed the requirement for rescue medication and accelerated symptom relief when administered within 1 hour of attack onset. Within 24 hours, patients receiving sebetralstat experienced earlier improvement and higher rates of attack resolution compared with placebo, based on time to event analysis^[6^]. Similarly, the pivotal phase 3 KONFIDENT trial, which was published in 2024, assessed the safety and effectiveness of oral sebetralstat as an on-demand treatment for HAE attacks in around 136 patients with C1 inhibitor deficiency (HAE type 1 or 2) who were at least 12 years old across 66 sites in 20 countries^[7^]. In this randomized controlled trial, participants received single oral doses of sebetralstat 300 mg, 600 mg, or placebo at the beginning of an attack. Both sebetralstat doses produced clinically meaningful and statistically significant improvements compared with placebo. The median time for symptom relief to begin was about 1.6 hours with the 300 mg dose and 1.8 hours with the 600 mg dose, which was significantly shorter with sebetralstat compared to the placebo. Moreover, both doses led to quicker reductions in the severity and duration of attacks, supporting their effectiveness based on clinically relevant measures^[7^]. In both trials^[6,7^], the safety findings of sebetralstat were favorable, there were no drug-related serious adverse events, no deaths, or treatment discontinuations reported. Most side effects that can occur are mild, temporary, and occur at rates similar to placebo. The few adverse events considered drug-related were gastrointestinal, such as abdominal discomfort or nausea. Unlike currently approved on-demand injectable therapies, which are frequently associated with injection-site reactions, sebetralstat avoided such complications, highlighting its potential as a more patient-friendly treatment option.

Overall, these data suggest that sebetralstat is an important evolution in HAE therapy as the first oral treatment that enables rapid, self-administered relief from symptoms, setting it apart from currently available injectable treatments. In contrast to newer treatments such as donidalorsen and garadacimab, which mainly focus on long-term prevention and necessitate multiple subcutaneous injections, sebetralstat offers a practical on-demand option during acute episodes. This is especially significant in clinical settings, where prompt and readily available care can minimize delays, enhance symptom management, and possibly avert attacks from escalating in severity. It addresses the major limitations of parenteral therapies by enhancing patient autonomy and reducing treatment burden. However, further long-term and real-world studies are needed to determine sustained efficacy, optimize dosage regimens, and define its place in the changing landscape of HAE treatments.

Ethical approval

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Sources of funding

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Author contributions

D.A.: conceptualization; Z.I., M.A.F., J.H.J.A.: writing – original draft preparation; Z.I., M.A.F., and J.H.J.A.: writing – review and editing. All authors have reviewed the final version of the manuscript.

Conflicts of interest disclosure

The authors declare that they have no conflicts of interest.

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Guarantor

Jaber Hamad Jaber Amin, jaberhamadjaber70@gmail.com.

Provenance and peer review

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Data availability statement

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