SUBSTANTIAL REDUCTION OF HEREDITARY ANGIOEDEMA ATTACK SYMPTOM BURDEN IN THE SEBETRALSTAT PHASE 3 KONFIDENT TRIAL

Introduction

Although guidelines recommend treating attacks early to avoid symptomatic progression, many people with hereditary angioedema (HAE-C1INH) delay treatment with injectable on-demand therapies until attacks progress to higher severity, and therefore, experience greater symptom burden than those who treat attacks at onset.

Methods

In the double-blind, randomized, placebo-controlled, cross-over, phase 3 KONFIDENT trial (NCT05259917), participants ≥12 years with HAE-C1INH treated up to 3 attacks with sebetralstat 300mg, sebetralstat 600mg, or placebo. Patient Global Impression of Severity (PGI-S) ratings (range, “None” to “Very Severe”) were recorded at time of treatment and over 24 hours after treatment. A substantial reduction of symptom burden was defined as a decrease in PGI-S rating to “Mild” for 2 consecutive time points within 12 hours for attacks that were “Moderate” to “Very Severe” at baseline. Analyses were censored for conventional treatment administration.

Results

In 147 attacks rated “Moderate” or worse at time of treatment, substantial reduction in symptom burden was achieved faster with sebetralstat 300mg (n=49, P=0.002) and sebetralstat 600mg (n=52, P=0.034) than with placebo (n=46), with median times of 5.0 hours (IQR, 1.7–>12), 5.2 hours (2.2–>12), and >12 hours (4.6–>12) to substantial symptom reduction, respectively. The proportion of participants with attacks achieving substantial symptom relief within 12 hours was 69.4% with sebetralstat 300mg, 57.7% with sebetralstat 600mg, and 32.6% with placebo (Figure).

Conclusion

In KONFIDENT, participants who experienced attacks that had progressed to “Moderate” or worse severity prior to treatment achieved substantial reduction of symptom burden faster with sebetralstat than with placebo.