Patient-reported outcomes in those with hereditary angioedema (HAE) with C1-inhibitor deficiency (HAE-C1-INH) have shown that on-demand treatment with sebetralstat exhibits potential efficacy, according to findings from the phase 3 KONFIDENT trial published in the journal Clinical and Translational Allergy.

The randomized, placebo-controlled, double-blind, 3-way crossover KONFIDENT study was designed to evaluate the efficacy and safety of sebetralstat in individuals 12 years of age or older with HAE-C1-INH. Patients with HAE experience unpredictable, recurrent episodes of mucosal swelling. The condition is most often associated with C1-inhibitor deficiency, which is related to reduced expression (HAE type I) or reduced functional activity (HAE type II).

C1-inhibitor deficiency, in turn, leads to “excessive formation of plasma kallikrein, cleavage of high-molecular-weight kininogen, and generation of the vasodilator bradykinin.” Overactivity of the kallikrein-kinin system is linked to angioedema and enhanced vascular permeability. Known to impact any part of the body, HAE attacks are frequently debilitating and can be life-threatening when the upper airways are involved.

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In the current analysis, the investigators sought to identify an optimal efficacy measure to assess a patient’s response to on-demand treatment of HAE-C1-INH attacks. They took a multipronged approach that provided the rationale for a selection of time to the beginning of symptom relief defined as a Patient Global Impression of Change (PGI-C) scale rating of at least “a little better” for 2 time points in a row within 12 hours of the first study drug administration as the primary efficacy endpoint in KONFIDENT.

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Feedback on patient-reported outcome measures was obtained from 7 individuals—4 females and 3 males—from the United States. The participants, who ranged in age from 18 to 74 years, had been experiencing symptoms of HAE-C1-INH for 8 to 64 years. The most common symptoms reported by the participants included swelling, pain, headache, gastrointestinal issues, and loss of mobility.

All of the participants noted that they considered the beginning of symptom relief following the treatment of an HAE attack as being “meaningful” to them. Patients reported that outcomes measured on the PGI-C, Patient Global Impression of Severity (PGI-S) scale, and Visual Analog Scale (VAS) were all meaningful. Overall, 71% (5 of 7) of the participants preferred the PGI-C scale to the PGI-S scale, believing that the PGI-C scale increments most appropriately reflected the gradual change most patients experienced when they were undergoing treatment for an HAE attack. None of the participants preferred the VAS scale.

The PGI-C scale rating of at least “a little better” at 2 consecutive time points exhibited 97% sensitivity for prediction of improvement on both the PGI-S scale and the composite VAS for abdominal pain, skin pain, and swelling, whereas the PGI-C scale rating of “better” exhibited slightly lower sensitivity (92% and 90% for prediction of improvements on these measures, respectively).

Further, the PGI-C rating of “a little better” or higher for 2 consecutive time points demonstrated higher sensitivity but somewhat lower specificity compared with the rating of “better.” The PGI-C rating was an early indicator of continued improvement of symptoms and resolution of attacks as well.

The researchers concluded, “Sebetralstat has the potential to become the first oral therapy for on-demand treatment of HAE-C1-INH, thereby addressing an unmet need and shifting the HAE-C1-INH treatment landscape.”


Cohn DM, Aygören-Pürsün E, Bernstein JA, et al. Evaluation of patient‐reported outcome measures for on‐demand treatment of hereditary angioedema attacks and design of KONFIDENT, a phase 3 trial of sebetralstat. Clin Transl Allergy. Published online September 4, 2023;13(9):e12288. doi:10.1002/clt2.12288