Single dose of sebetralstat found effective against HAE attacks
Oral therapy worked to ease or resolve most attacks in Phase 3 trial
Note: This story was updated March 12, 2024, to clarify the data pertaining to the proportion of sebetralstat-treated swelling attacks seen in HAE patients taking part in the KONFIDENT trial.
A single dose of oral sebetralstat — not the two allowed in trial — was sufficient to ease or completely resolve most swelling attacks for people with hereditary angioedema (HAE) participating in the Phase 3 KONFIDENT trial.
In fact, more than 90% of treated swelling attacks on both dosage amounts tested eased with just one dose of the experimental therapy, new analyses of trial data show.
Sebetralstat’s developer, KalVista Pharmaceuticals, presented these findings at the 2024 annual meeting of the American Academy of Allergy, Asthma and Immunology (AAAAI), in a late-breaking presentation titled “Sebetralstat for On-demand Treatment of Hereditary Angioedema Attacks: Results of the Double-blind, Placebo-controlled Phase 3 KONFIDENT Trial.”
“We believe that these additional efficacy and safety data only strengthen the case for sebetralstat to become the first, oral on-demand treatment available to the HAE community,” Andrew Crockett, CEO of KalVista, said in a company press release.
Trial participants allowed up to 2 doses for treating HAE attacks
Sebetralstat is an oral therapy designed to block the activity of an enzyme called kallikrein. This enzyme helps produce bradykinin, a signaling molecule whose overactivity drives swelling attacks in HAE. By blocking kallikrein, the therapy is designed to lower bradykinin levels and ultimately ease swelling.
The KONFIDENT trial (NCT05259917) enrolled 136 people with HAE types 1 and 2, ages 12 and older. Over the course of the three-way study, all participants thrice received on-demand treatment for swelling attacks: once with 300 mg sebetralstat, once with 600 mg sebetralstat, and once with a placebo, in a random order. For each attack, participants could take the therapy twice if needed.
Top-line results announced a few weeks ago showed that most participants given either dose of sebetralstat began experiencing symptom relief within two hours, whereas with the placebo, it took longer than six hours for most patients to start experiencing relief.
The new analyses now show that only one dose of the medication was enough to kickstart symptom relief for patients in the vast majority of the treated swelling attacks. In fact, 94% of swelling attacks treated with the low dose and 96% of those treated with the high dose eased with a single dose of the medication.
Given the unrestricted use of a second dose of oral sebetralstat in KONFIDENT, it was important to understand the proportion of attacks that achieved the primary and key secondary endpoints without a second dose. … What we observed was that the vast majority of attacks that successfully met the three endpoints did so with a single dose of sebetralstat.
The proportion of attacks whose severity diminished with just one dose of sebetralstat was similarly high: 91% for the low-dose group and 96% for the high dose. Similar results were seen with the proportion of attacks that resolved completely with a single dose of the therapy (92% and 85% for the low and high doses, respectively).
“Given the unrestricted use of a second dose of oral sebetralstat in KONFIDENT, it was important to understand the proportion of attacks that achieved the primary and key secondary endpoints without a second dose,” said Marc A. Riedl, MD, a professor at the University of California, San Diego, and an investigator on the study.
“What we observed was that the vast majority of attacks that successfully met the three endpoints did so with a single dose of sebetralstat,” Riedl said.
Developer now planning to seek US, EU approval of sebetralstat
Additional data also showed that for both sebetralstat doses, the median time to symptom relief was shorter for attacks deemed to be severe than for those that were considered to be moderate in severity. The same trend was observed in the median time to reduction in attack severity.
Safety data from the study showed the rates of side effects deemed to be treatment-related were similar among patients given sebetralstat or the placebo. There was one severe side effect judged to be related to sebetralstat, which was a lower back hernia that required hospitalization. No patients dropped out of the trial due to side effects.
Based on findings from KONFIDENT, Kalvista is planning to seek approval of sebetralstat in the U.S. and Japan, as well as in Europe. Ultimately, the company hopes that sebetralstat will become the first oral therapy available for the on-demand treatment of HAE.
“If approved, we believe that a single dose of sebetralstat 300 mg would appear to be appropriate for most HAE attacks,” Crockett said.
Crockett added, however, that the ability to dose flexibly depending on the characteristics of a specific attack is supported by the safety and tolerability observed with repeated dosing at both the 300 mg and 600 mg levels.
Kalvista now is running a two-year open-label extension study, dubbed KONFIDENT-S (NCT05505916), to collect further data on the use of sebetralstat for the on-demand treatment of HAE swelling attacks.
The extension study is open not only to patients completing KONFIDENT but also to new participants. It’s enrolling people with HAE types 1 or 2, ages 12 and older, who’ve experienced at least two swelling attacks in the prior three months, among other criteria. Recruitment is ongoing at dozens of sites worldwide.
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