Oral Sebetralstat Shows Rapid Relief for Breakthrough Attacks in HAE Patients on Long-Term Prophylaxis: Interim Analysis of KONFIDENT-S

• Oral sebetralstat 600 mg provided rapid symptom relief for breakthrough attacks in HAE patients receiving long-term prophylaxis (LTP).

• Median time to beginning of symptom relief was 1.3 hours; time to complete attack resolution was 14.8 hours.

• Effectiveness was similar regardless of LTP agent (berotralstat, lanadelumab, or C1 inhibitor).

• No serious or severe treatment-related adverse events were reported.

Study snapshot: KONFIDENT-S interim analysis

• Design: Open-label extension study (NCT05505916)

• Population: 35 patients with HAE (C1-inhibitor deficiency) on LTP experiencing breakthrough attacks

• Intervention: Oral sebetralstat 600 mg as needed for attacks

• Primary focus: Safety and effectiveness of sebetralstat for breakthrough attacks

• Key endpoints: Times to symptom relief, severity reduction, and attack resolution

• Data cutoff: September 14, 2024

What the study asked

The KONFIDENT-S open-label extension study (NCT05505916) is evaluating the long-term safety and effectiveness of oral sebetralstat 600 mg for on-demand treatment of hereditary angioedema (HAE) attacks in patients who also receive long-term prophylaxis (LTP). This interim analysis specifically examined outcomes in patients receiving LTP with lanadelumab, berotralstat, or C1 inhibitor who experienced breakthrough attacks and treated them with sebetralstat.

Why the question matters

HAE with C1-inhibitor deficiency is a rare, potentially life-threatening disorder characterized by recurrent, unpredictable swelling episodes. Although LTP reduces attack frequency, breakthrough attacks still occur and require effective on-demand treatment. Current on-demand options include parenteral therapies (intravenous or subcutaneous), which can be inconvenient and delay treatment. Oral sebetralstat, a plasma kallikrein inhibitor, offers a convenient oral option that could enable earlier treatment and improve outcomes. Understanding its performance in the context of LTP is clinically important.

How the study was conducted

This interim analysis included 35 participants with HAE (C1-INH deficiency) who were receiving LTP (lanadelumab, berotralstat, or C1 inhibitor) and experienced breakthrough attacks. Participants were enrolled in the KONFIDENT-S open-label extension, which followed the phase 3 KONFIDENT trial. They were instructed to take a single oral dose of sebetralstat 600 mg at the onset of an attack and could use additional on-demand medication as needed. Efficacy endpoints included times to beginning of symptom relief, reduction in attack severity, and complete attack resolution, assessed by patient-reported outcomes. Safety was evaluated through adverse event monitoring. The data cutoff for this analysis was September 14, 2024.

What the study found

Participants experienced a mean of 1.7 attacks per month while on LTP. Among 504 total breakthrough attacks, 382 (75.8%) were initially treated with sebetralstat. The median time from attack recognition to sebetralstat administration was 6 minutes (interquartile range, 1 to 40 minutes), indicating early treatment. The median time to beginning of symptom relief was 1.3 hours (IQR 0.8–3.8 hours), while the median time to reduction in attack severity was 4.2 hours (IQR 1.3 to >12 hours). The median time to complete attack resolution was 14.8 hours (IQR 4.6 to >24 hours).

Time to symptom relief within 12 hours, time to reduction in attack severity within 12 hours, and time to complete attack resolution within 24 hours in sebetralstat-treated breakthrough attacks

Fig. Subgroup analysis of time to beginning of symptom relief by participant age group, attack severity at time of sebetralstat administration, and attack location in participants receiving (A) any LTP agent and (B) LTP with plasma kallikrein–inhibiting agent (berotralstat or lanadelumab). Diamonds are medians; error bars, Q1 and Q3.

Effectiveness was similar regardless of the LTP agent used. For participants receiving berotralstat, lanadelumab, or C1 inhibitor, the median times to symptom relief were comparable. Notably, 29.6% of breakthrough attacks were mild at the time of sebetralstat treatment, and the majority of attacks were treated early. Among the 382 sebetralstat-treated attacks, 17 involved the larynx, a potentially dangerous site. The proportion of attacks initially treated with conventional injectable therapy (114 attacks) had a similar severity profile to those treated with sebetralstat.

Safety and tolerability

No serious or severe treatment-related treatment-emergent adverse events were reported in participants receiving LTP during this interim analysis. Sebetralstat was generally well tolerated, consistent with the safety profile observed in the parent KONFIDENT trial.

Important limitations

This is an interim analysis of an open-label extension study with no comparator group, which limits the ability to draw causal inferences. The sample size is small (35 participants), and the results may not be generalizable to all HAE patients on LTP. The study is ongoing, and long-term safety data are still being collected. Additionally, the analysis is based on patient-reported outcomes, which can be subject to recall bias, and the lack of blinding may influence reporting.

Implications for patients and clinicians

The findings suggest that oral sebetralstat can be an effective and well-tolerated on-demand option for breakthrough attacks in HAE patients who are already on LTP. The ability to treat attacks quickly with an oral medication—median 6 minutes from recognition to dosing—could improve quality of life and reduce reliance on injectable therapies. However, the absence of a control group and the small sample mean that larger, longer-term studies are needed to confirm these findings. Clinicians should consider individual patient preferences and attack patterns when selecting on-demand therapy. The ongoing KONFIDENT-S study will provide additional data on long-term safety and efficacy.

Funding and trial registration

The study was funded by the sponsor (likely the developer of sebetralstat). The trial is registered at ClinicalTrials.gov with identifier NCT05505916. The interim analysis was published in the Journal of Allergy and Clinical Immunology: Global.

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. doi:10.1016/j.jacig.2026.100750. PMID: 42436759.