Updated international guidance reinforces early self-administered on-demand therapy and integrates newer kallikrein-targeted agents into routine HAE management.
New international guidance on
For clinicians managing pediatric HAE, the update formalizes a shift that has been evolving over the past decade: from reactive, injection-based rescue treatment toward rapid, patient-controlled intervention at the earliest sign of symptoms. The committee issued a strong recommendation for sebetralstat in adolescents, based on clinical trial evidence and recent regulatory approvals.2
Sebetralstat (Ekterly) is a small-molecule, oral plasma kallikrein inhibitor designed for on-demand treatment of acute HAE attacks. Its US Food & Drug Administration (FDA) approval in July 2025 for patients aged ≥12 years was supported by the phase 3 KONFIDENT trial, which demonstrated significantly faster time to beginning of symptom relief compared with placebo.3 The drug has also received marketing authorization in the European Union and other regions.4
“The first-line recommendation for EKTERLY so soon after becoming commercially available underscores the strength of our clinical data and reinforces the importance of ensuring patients have immediate access to effective on-demand therapy,” said Paul Audhya, MD, MBA, chief medical officer of KalVista.1 “As the first and only oral on-demand treatment for HAE, EKTERLY uniquely enables guideline-aligned care by supporting early intervention and simplifying self-administration.”
Pooled data from KONFIDENT and KONFIDENT-S demonstrated that the mean time to achieve symptom relief was less than 2 hours (1.79; range, 0.76 – 7.12).3 On average, reduction in severity took 3.58 hours, and complete attack resolution took 15.09 hours.
The new pediatric guideline incorporates these data into broader management recommendations. The panel advises that all pediatric patients with HAE should have immediate access to on-demand therapy, treat attacks as early as possible, and consider treating all attacks regardless of location or severity.2 Patients should maintain an adequate supply to treat ≥ 2 attacks, even if receiving long-term prophylaxis. The guideline also recommends ensuring on-demand treatment is available during medical, dental, or surgical procedures and emphasizes maintaining normal activities when rapid treatment access is secured.2
These recommendations build on prior international consensus guidance, including the 2022 WAO/EAACI HAE guideline, which also stressed early treatment and universal access to on-demand therapy.5 What distinguishes the pediatric update is its explicit framing around developmental and psychosocial considerations, including the burden of injections in adolescents and the importance of self-efficacy in disease management.
Before the availability of oral on-demand therapy, acute HAE treatment options included intravenous or subcutaneous plasma-derived C1-INH, recombinant C1-INH, the bradykinin B2 receptor antagonist icatibant, and the kallikrein inhibitor ecallantide.6 Although effective, these agents require injection or infusion, which may contribute to delays in treatment, particularly in younger patients dependent on caregivers.
Although the guideline strongly recommends sebetralstat in adolescents aged ≥ 12 years, several caveats remain. Head-to-head comparative data between sebetralstat and injectable therapies are lacking. Real-world effectiveness and adherence data in pediatric populations are still emerging.
Younger children remain an unmet need. The ongoing KONFIDENT-KID study is evaluating sebetralstat in children aged 2 to 11 years, with safety and pharmacokinetic data anticipated to inform future regulatory submissions.1 At present, sebetralstat is not approved for patients younger than 12 years.
The guideline signals a maturation of pediatric HAE care, integrating pathophysiologic rationale, trial evidence, and patient-centered considerations.2 For clinicians, the key message is less about replacing existing therapies and more about ensuring rapid, reliable access to early treatment in a population for whom timing and feasibility are critical determinants of outcome.
“Ped-HAE-C1INHs deserve special attention in the diagnosis and management of their disease,” wrote first author Henriette Farkas, from Semmelweis University, in Hungary, and colleagues.2 “Early diagnosis, family screening, education and counseling of patients and their caregivers, selection of appropriate individualized therapy, development of a therapeutic strategic plan with shared decision making, centralized care, and regular follow-up of patients are essential to reach the goal of ensuring that these young patients can lead normal lives similar to their peers.”
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