Patients experience rapid relief from hereditary angioedema attacks with sebetralstat

Key takeaways:

• Guidelines recommend rapid use of on-demand treatment for attacks.
• Median times to reductions in attack severity included 9.27 hours with 300 mg and more than 12 hours with placebo.

WASHINGTON — Patients with hereditary angioedema experienced rapid symptom relief with sebetralstat compared with placebo, according to a poster presented at the American Academy of Allergy, Asthma & Immunology Annual Meeting.

These patients also saw reductions in attack severity and significantly faster complete attack resolution with the drug, Paul K. Audhya, MD, MBA, chief medical officer, KalVista Pharmaceuticals, said during his presentation.

“This is an on-demand treatment,” Audhya told Healio.

Paul K. Audhya

Global treatment guidelines recommend that patients with hereditary angioedema caused by deficiencies or dysfunction in the C1 inhibitor protein (HAE-C1INH) should address attacks as early as possible with on-demand treatment.

Currently approved therapies for on-demand treatment require parenteral administration, sometimes with subcutaneous injection, the researchers said, but their complexity has been associated with delays in treatment and withheld care.

Sebetralstat (KalVista Pharmaceuticals), which also is a plasma kallikrein inhibitor, is the first therapy available through oral administration, the researchers continued.

The phase 3 KONFIDENT trial comprised 136 adults and adolescents (median age, 39.5 years; 60% female; 83.6% white) with a confirmed HAE-C1NH diagnosis and two or more documented attacks within 3 months.

Baseline Patient Global Impression of Severity scores included mild for 113 (42.8%) of the patients, moderate for 102 (38.6%) of the patients and severe or very severe for 45 (17%) of the patients.

The researchers randomly assigned patients to one of six treatment sequences where patients would treat three eligible attacks with a 300 mg or 600 mg dose of sebetralstat or with placebo.

“Patients recognize they have an attack, and they treat that attack,” Audhya said. “Our guidance in the study was to treat as early as possible, consistent with the guidelines.”

Median times from attack onset to first administration included 35 minutes for 300 mg doses, 41 minutes for the 600 mg doses and 51 minutes for placebo, with 55.7% of attacks treated within 60 minutes overall. After 3 or more hours, participants were allowed to take a second dose if they felt it was necessary.

Overall, 110 patients treated at least one attack, with 264 attacks total. There were 87 attacks treated with one or two 300 mg doses of sebetralstat, 93 attacks treated with one or two 600 mg doses, and 84 attacks treated with placebo.

The most common attacks included the abdomen (n = 114; 43.2%); the arms and hands (n = 76; 28.8%); the legs and feet (n = 62; 23.5%); the head, face and neck (n = 29; 11%); and the torso (n = 15; 5.7%).

“The first step that has to happen physiologically is that the binding to plasma kallikrein has to occur, and then that level goes way down. That will halt the swelling. Then you start to feel better,” Audhya said.

Median times to symptom relief included 1.61 hours (95% CI, 0.78-7.04; P < .0001) with the 300 mg doses and 1.79 hours (95% CI, 1.02-3.79; P = .0013) with the 600 mg doses vs. 6.72 hours (95% CI, 1.34 to > 12) with placebo.

Also, median times to symptom relief included 1.6 hours with 300 mg doses and 2.1 hours with 600 mg doses for moderate attacks, in addition to 1.4 hours with 300 mg doses and 1.5 hours with 600 mg doses for severe attacks.

“You can see a very rapid increase in the proportion of patients who feel better,” Audhya said.

Median times to reductions in attack severity included 9.27 hours (95% CI, 1.53 to > 12; P = .0036) with the 300 mg doses and 7.75 hours (95% CI, 2.19 to > 12; P = .0032) with the 600 mg doses vs. more than 12 hours (95% CI, 6.23 to > 12) with placebo.

Moderate attacks had median times of 5 hours with 300 mg doses and 3.3 hours with 600 mg doses for reductions in severity, and severe attacks had median times of 1.3 hours with 300 mg doses and 1.4 hours with 600 mg doses for these reductions.

Median times to attack resolution included more than 24 hours (95% CI, 8.58 to > 24; P = .0022) with the 300 mg dose and 24 hours (95% CI, 7.54 to > 24; P < .0001) with the 600 mg dose vs. more than 24 hours (95% CI, 22.78 to > 24) with placebo.

“This is the hardest endpoint to meet,” Audhya said. “You have to be able to say none. Not kind of. It has to be none.”

Noting that there was a large proportion of patients who had attack resolution within 24 hours, Audhya said that later studies will indicate proportions of patients who had resolution within 48 hours.

Patients treated their attacks with a second dose 38.4% of the time in the 300 mg group, 41.1% of the time in the 600 mg group and 55.4% of the time in the placebo group.

Specifically, 93.9% of patients using the 300 mg dose and 95.8% of those using the 600 mg dose reached the beginning of symptom relief without a second dose or before using a second dose.

Similarly, 90.9% of those using the 300 mg dose and 95.9% of those using the 600 mg dose began experiencing reductions in attack severity without a second dose or before using a second dose.

Complete attack resolution occurred for 91.9% of those on the 300 mg dose and 84.8% of those on the 600 mg dose without a second dose or before using a second dose as well.

Two patients (2.3%) experienced treatment-related adverse events with 300 mg, three patients (3.2%) experienced them with 600 mg and four patients (4.8%) had them with placebo.

“Placebo looks the worst. I guess that’s good,” Audhya said. “And most of these were very mild.”

None of these treatment-related adverse events were serious, and there was one severe event in the 300 mg group (1.2%).

Based on these findings, the researchers said that a single 300 mg dose of sebetralstat would be appropriate for most attacks, but the secondary doses and 600 mg doses indicate the safety and flexibility of other treatment when needed.

Also, the study is ongoing.

“We’re collecting huge amounts of data from our open-label extension, with hundreds and hundreds of attacks accumulating,” Audhya said. “That’s going to give us really a little bit more of a real-world understanding.

Audhya was encouraged by these early results as well.

“We hope that this will be available for patients sometime, hopefully in the first half of next year,” he said.

References:

• Riedl MA, et al. J Allergy Clin Immunol. 2024;doi:10.1016/j.jaci.2023.11.900.
• KalVista Pharmaceuticals presents additional phase 3 KONFIDENT data at the 2024 American Academy of Allergy, Asthma & Immunology Annual Meeting. https://ir.kalvista.com/news-releases/news-release-details/kalvista-pharmaceuticals-presents-additional-phase-3-konfident. Published Feb. 26, 2024. Accessed March 5, 2024.