Sebetralstat Resolves Breakthrough HAE Attacks Despite Prior Prophylaxis

Interim KONFIDENT-S data show oral sebetralstat produced rapid, consistent symptom relief for breakthrough hereditary angioedema (HAE) attacks in patients already on long-term prophylaxis (LTP) and left just 1.6% of attacks untreated.¹ Effectiveness was consistent regardless of which prophylactic agent patients were taking, with a median time to symptom relief of 1.3 hours.^1,2

The analysis evaluated 35 participants with HAE due to C1-inhibitor deficiency receiving LTP with berotralstat (n = 16), lanadelumab (n = 13), or C1 inhibitor replacement (n = 6).¹ Despite background prophylaxis, these participants experienced 504 breakthrough attacks and treated 382 of them (75.8%) with sebetralstat 600 mg, an oral plasma kallikrein inhibitor.¹

“Even people who are on those preventative therapies…can have breakthrough attacks of hereditary angioedema, and when that happens, the sebetralstat product worked well for them, even though it has an overlapping mechanism of action with some of those products," Investigator Daniel F. Soteres, MD, a physician from Asthma & Allergy Associates, PC, told HCPLive.

He added that global guidelines call for every patient with HAE to keep 2 doses of on-demand medication available at all times in case an attack does not respond to the first.³

KONFIDENT-S Data Show Consistent Relief Across LTP Regimens

Median time to beginning of symptom relief was 1.3 hours for participants on berotralstat, 1.3 hours for lanadelumab, and 1.8 hours for C1 inhibitor LTP.¹ Median time from attack recognition to sebetralstat administration was 6 minutes overall, ranging from 1 minute in participants on C1 inhibitor LTP to 20 minutes in those on berotralstat, and nearly 30% of attacks were treated while still mild.¹

Only 1.6% of the 504 breakthrough attacks went untreated, compared with roughly 50% of attacks in a prior real-world study of injectable on-demand therapy.¹ A second dose of sebetralstat was needed within 12 hours in 22.3% of attacks, and conventional injectable therapy was used in just 5.2% of sebetralstat-treated attacks.¹ Treatment-emergent adverse events occurred in 65.7% of participants, with 14.3% considered treatment-related, most commonly headache, nausea, and vomiting; no serious or severe treatment-related events were reported.¹

Counseling Patients Through Overlapping Mechanisms And Treatment Timing

Soteres said the overlapping mechanism of action between sebetralstat and kallikrein-inhibiting LTP agents was never a concern for him clinically.

"I'm an allergy and asthma doctor,” Soteres said. “We use overlapping mechanisms of action to treat disease in many regards.”

He also pointed to the oral, self-administered format as a likely driver of earlier treatment, since patients no longer need a private setting to self-inject and may feel more comfortable taking it. On setting expectations, Soteres cautioned that sebetralstat should not be framed to patients like an epinephrine autoinjector.

"It's not going to work in seconds," he said. “You do have to take the medicine and calm yourself. Let your loved one know what's going on and let the medicine do its job. You have to let the medicine do its work [for] over 20 minutes.”

Editor’s note: Reported disclosures for Soteres include KalVista Pharmaceuticals, BioCryst, CSL Behring, Intellia Therapeutics, Ionis Pharmaceuticals, Pharming, Pharvaris, and Takeda.

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 Glob. 2026;5(5):100750. Published 2026 Jun 12. doi:10.1016/j.jacig.2026.100750

2. Johnson V. Sebetralstat Shows Long Term Fast Relief of Breakthrough HAE Attacks. HCPLive. Published July 21, 2026. Accessed July 24, 2026. https://www.hcplive.com/view/sebetralstat-shows-long-term-fast-relief-breakthrough-hae-attacks

3. New international guideline for HAE management - HAE International (HAEi). HAE International (HAEi). Published May 3, 2022. Accessed July 24, 2026. https://haei.org/new-international-guideline-for-hae-management/