Sebetralstat Shows Long Term Fast Relief of Breakthrough HAE Attacks

Participants with hereditary angioedema (HAE) receiving long-term prophylaxis (LTP) who treated breakthrough attacks with oral sebetralstat achieved beginning of symptom relief in a median 1.3 hours, according to an interim analysis of the KONFIDENT-S open-label extension study, with effectiveness consistent regardless of which prophylactic agent patients were taking.¹

The prespecified analysis, published in the Journal of Allergy and Clinical Immunology: Global, evaluated 35 participants with HAE due to C1-inhibitor deficiency (HAE-C1INH) who were receiving LTP with berotralstat (n = 16), lanadelumab (n = 13), or C1 inhibitor (C1INH) replacement (n = 6) while enrolled in the 2-year KONFIDENT-S extension of the phase 3 KONFIDENT trial.¹ Despite background prophylaxis, these participants experienced a mean ± standard deviation of 1.7 ± 1.5 breakthrough attacks per month and treated 382 of 504 total breakthrough attacks with on-demand sebetralstat 600 mg, the oral plasma kallikrein inhibitor approved by the US Food and Drug Administration (FDA) in July 2025 as the first oral on-demand HAE therapy, the second of 3 HAE treatments approved in successive months from June to August.¹⁻²

“In the span of just 3 months, there were 3 new treatment modalities approved in HAE, which is mind-blowing, really, but it's really a testament to all the work that's gone into [the field] in the last two decades. If we think back 16 years ago, that’s when the launch of modern-era medicine came out for hereditary angioedema and and to think of how far we’ve come in the treatment landscape just makes my other colleagues and other specialties envious of the advances that we have made,” Raffi Tachdjian, MD, MPH, from UCLA Health, previously told HCPLive.

Investigators, led by Tamar Kinaciyan, MD, of the Medical University of Vienna, found that median time from attack recognition to sebetralstat administration was just 6 minutes (interquartile range [IQR], 1-40), a finding the authors attributed to the study's protocol-driven instruction to treat as early as possible.¹ Nearly 30% of attacks were treated while still mild. Median time to reduction in attack severity was 4.2 hours (IQR, 1.3 to >12), and median time to complete attack resolution was 14.8 hours (IQR, 4.6 to >24).¹ A post hoc analysis of time to end of attack progression, added after the primary effectiveness end points were defined, showed a median of 20.4 minutes, with 91% of sebetralstat-treated attacks reaching end of progression within 4 hours.¹

Effectiveness was broadly similar across attack severities, anatomic locations, and participant age groups, and did not differ meaningfully between participants on plasma kallikrein-inhibiting LTP (berotralstat or lanadelumab) and those on C1INH replacement.¹ Hazard ratios comparing participants receiving LTP with those receiving on-demand treatment alone were 1.38 (95% CI, 0.93-2.04) for time to symptom relief, 1.53 (95% CI, 0.98-2.40) for time to reduction in severity, and 1.75 (95% CI, 1.03-2.99) for time to complete resolution; investigators characterized effectiveness as "generally consistent" between the 2 groups, though these were unadjusted comparisons within a descriptive, open-label dataset rather than a powered statistical test.¹

A second sebetralstat dose was administered within 12 hours in 22.3% of attacks, and conventional injectable on-demand therapy was used as rescue in only 5.2% of sebetralstat-treated attacks, suggesting a single oral dose was sufficient for most breakthrough episodes.¹ Angioedema Quality of Life (AE-QoL) scores trended toward improvement through month 15, with a least squares mean change from baseline of -10.3 (95% CI, -21.1 to 0.6) — a confidence interval that crosses the null, meaning the improvement did not reach statistical significance at that time point.¹ Treatment satisfaction was high: participants reported being satisfied or better with sebetralstat for 88.8% of 276 rated attacks.¹

Safety was consistent with the drug's established profile. Of the 35 participants receiving LTP, 65.7% experienced a treatment-emergent adverse event (TEAE), and 14.3% experienced a TEAE considered treatment-related, most commonly headache, myalgia, arthralgia, nausea, or vomiting.¹ No serious or severe treatment-related TEAEs occurred. Two participants discontinued sebetralstat because of adverse events — 1 for a TEAE later attributed to viral meningitis and hepatotoxic comedications rather than sebetralstat, and 1 for nausea and vomiting during a mixed abdominal/laryngeal attack, in which gastrointestinal drug effects can be difficult to distinguish from attack symptoms.¹

The authors acknowledged several limitations relevant to interpreting the findings. The open-label design, while reflective of real-world use and permitting a larger attack sample than the randomized KONFIDENT trial, introduces potential reporting bias.¹ The analysis was descriptive and explicitly not powered to detect differences by LTP agent or across subgroups, and the C1INH replacement cohort was particularly small (n = 6), limiting how generalizable those findings are to that population.¹ The study was funded by KalVista Pharmaceuticals, sponsor and manufacturer of sebetralstat; several authors reported consulting fees, honoraria, or research support from the company, and 3 authors are former employees and shareholders while 3 others are current employees and shareholders.¹ Medical writing assistance was also funded by KalVista.¹

Sebetralstat's role alongside targeted LTP has drawn increasing clinical attention as HAE guidelines shift toward earlier, patient-controlled on-demand treatment regardless of background prophylaxis.³ The KONFIDENT-S data build on the smaller LTP subgroup from the original KONFIDENT trial, which included 24 participants receiving targeted LTP who treated 58 attacks, and now offer a considerably larger real-world-like dataset to inform how clinicians counsel patients who continue to break through on prophylaxis.¹⁻²

References

1. Kinaciyan T, Aygören-Pürsün E, Martinez-Saguer I, et al. Sebetralstat for breakthrough attacks in patients with hereditary angioedema receiving long-term prophylaxis in KONFIDENT-S. J Allergy Clin Immunol Global. 2026;5:100750. https://doi.org/10.1016/j.jacig.2026.100750

2. Riedl MA, Farkas H, Aygören-Pürsün E, et al. Oral sebetralstat for on-demand treatment of hereditary angioedema attacks. N Engl J Med. 2024;391:32-43. https://www.nejm.org/doi/10.1056/NEJMoa2314192

3. FDA Approves Sebetralstat for Hereditary Angioedema. AJMC. https://www.ajmc.com/view/fda-approves-sebetralstat-for-hereditary-angioedema