Back Back
2024 AAAAI HAE Conference Coverage

CE / CME

Key Updates on Hereditary Angioedema: CCO Independent Conference Coverage of the 2024 AAAAI Annual Meeting

Physician Assistants/Physician Associates: 0.50 AAPA Category 1 CME credit

Nurses: 0.50 Nursing contact hour

Physicians: maximum of 0.50 AMA PRA Category 1 Credit™

Released: March 22, 2024

Expiration: March 21, 2025

Marc Riedl
Marc Riedl, MD, MS
CME/CE Information

Activity

Progress
1 2
Course Completed

KONFIDENT: Oral Sebetralstat vs Placebo for On-Demand Treatment of HAE Attacks

Finally, I discuss oral sebetralstat for the on-demand treatment of HAE attacks, as was presented from the KONFIDENT trial at AAAAI 2024. Sebetralstat is an oral plasma kallikrein inhibitor that is used for on-demand treatment during symptoms to stop the attack. Phase II trial data demonstrated promising efficacy results.13

The international, double-blind, placebo-controlled phase III KONFIDENT trial evaluated the efficacy and safety of 300 mg and 600 mg of sebetralstat for the on-demand treatment of HAE attacks.

This study enrolled adults and adolescents with type I or II HAE and ≥2 documented HAE-C1-INH attacks within 3 months. In addition, patients had to have access to conventional on-demand treatments if needed. For those on long-term prophylaxis, patients must have been on a stable dose/regimen for ≥3 months.

In total, 136 enrolled patients were randomized in a crossover design to 1 of 6 different arms—with varying regimens of placebo, oral sebetralstat 300 mg, and oral sebetralstat 600 mg. During the trial, each patient treated 3 attacks in a blinded fashion, according to their assigned arm. Of note, patients were allowed to take a single dose of sebetralstat or placebo followed by an optional second dose a few hours later, based on their own judgement. The distinction between use of 1 and 2 doses is important when analyzing the efficacy results.

Time to start of symptom relief, using Patient Global Impression of Change (PGI-C) scale, was the primary endpoint. This scale ranged in responses from “much worse” to “no change” to “much better.” Patients were required to fill out this PGI-C following administration of the agent. To meet the endpoint, patients had to rank their symptom as “a little better” at the least for ≥2 sequential time points within 12 hours after taking the first dose. Other key secondary endpoints included the time to reduction in attack severity, time to complete attack resolution, and safety.14

Download

KONFIDENT: Baseline Characteristics

Among the 136 patients enrolled, 110 had ≥1 treated attack. Similar to other studies, most (≥60%) patients were female, White, and diagnosed with type I HAE. In addition, 78% of the patients were only using on-demand treatment, with 22% also using long-term prophylaxis.14

Download

KONFIDENT: Primary and Key Secondary Efficacy Endpoints by Dosing

For the primary endpoint (time to start of symptom relief), sebetralstat-treated attacks significantly improved at 1.61 hours with 300 mg (P <.0001) and 1.79 hours with 600 mg (P = .0013) compared with 6.72 hours with placebo. When looking at time to reduced attack severity, sebetralstat-treated attacks improved at 9.27 hours with 300 mg (P = .0036) and 7.75 hours with 600 mg (P = .0032) compared with >12 hours with placebo. Finally, time to full attack resolution was 24 hours with sebetralstat 300 mg (P = .0022) and 600 mg (P <.0001), which was statistically significant. Time to full attack resolution with placebo was >24 hours. Of note, this endpoint is difficult to meet because the symptoms have to be entirely resolved.

As previously mentioned, patients were allowed to take a second dose a few hours after the first dose of the assigned agent at their discretion. This raises the question: How often did patients need a second dose to achieve efficacy? The proportion of attacks that reached the start of symptom relief without a second dose or before the second dose was 93.9% with sebetralstat 300 mg and 95.8% with sebetralstat 600 mg. Therefore, >90% of patients in both treatment groups reached the endpoint before they took the second dose. The proportion of attacks that decreased in severity without a second dose was similar: 90.9% and 95.9% had a decrease in severity without the second dose, or before they took the second dose for sebetralstat 300 mg and 600 mg, respectively. This is reassuring that a single dose of sebetralstat met the study’s primary endpoints for the vast majority of patients, including attack resolution—91.9% and 84.8% for sebetralstat 300 mg and 600 mg, respectively.14

Download

KONFIDENT: Primary and Key Secondary Efficacy Outcomes

The graphical representations of the endpoints I have just discussed illustrate the significant separation between on-demand treatment with sebetralstat vs placebo.14

Download

KONFIDENT: Safety

The 300-mg and 600-mg doses of sebetralstat were well tolerated, as TEAEs were comparable to placebo. No TEAEs resulted in study discontinuation or death. One severe and 1 serious TEAE occurred in the sebetralstat 300-mg group, and 2 serious TEAEs occurred in the sebetralstat 600-mg group. None was deemed treatment related, which is reassuring since there were no concerning safety signals.14

Download

KONFIDENT: Conclusions

Sebetralstat was effective, both in terms of symptom relief, decreasing attack severity, and achieving complete attack resolution. It met all primary and secondary endpoints, including significantly earlier symptom relief when compared with placebo. Efficacy between the 2 sebetralstat doses (300 mg vs 600 mg) was quite similar. Finally, >90% of attacks reached the primary endpoint without a second dose or prior to the administration of a second medication dose.

The safety data are also reassuring because sebetralstat was well tolerated. There were no serious or severe TEAE deemed to be related to treatment, and all TEAEs were comparable to placebo.

The 2-year OLE trial (KONFIDENT-S) is recruiting and will hopefully provide additional safety and efficacy data, as well as longer term efficacy data, for this investigational oral treatment for on-demand therapy of patients with HAE.14

Download

When considering referring a patient to a clinical trial studying sebetralstat for on-demand HAE attacks, which of the following outcomes demonstrated in the phase III KONFIDENT clinical trial should you discuss?

BACK | NEXT