Sebetralstat quickly stops HAE attack progression in study
Treatment effective against bouts involving the larynx and abdomen
Kalvista Pharmaceuticals’ sebetralstat, an oral on-demand treatment for hereditary angioedema (HAE), rapidly stopped the progression of swelling attacks, according to interim data from a two-year open-label extension study.
It was also effective against attacks involving the larynx (voice box) and abdomen, as well as those rated as severe or very severe due to treatment delays.
KONFIDENT-S (NCT05505916) is assessing the efficacy and safety of sebetralstat in 145 HAE patients, ages 12 and older, who participated in the Phase 3 KONFIDENT trial (NCT05259917) or experienced recurrent swelling attacks.
These data were presented concurrently at the recent 14th C1-inhibitor Deficiency & Angioedema Workshop in Hungary and at the Eastern Allergy Conference in Florida.
“These new data underscore the potential of sebetralstat to fundamentally change HAE attack management,” Paul Audhya, MD, chief medical officer at Kalvista, said in a company press release. “The uniformity of these results, paired with an oral tablet formulation, solidifies our belief that sebetralstat can empower patients to act swiftly and recover quickly. We remain committed to bringing this innovative therapy to the HAE community as quickly as possible.”
Halting progression of HAE attack early is crucial
In HAE, genetic defects lead to the excessive production and release of a signaling molecule called bradykinin, which makes blood vessels more permeable. As a result, fluid leaks into the deeper layers of the skin or mucous membranes, resulting in repeated swelling attacks that can arise in different parts of the body.
Swelling attacks in the larynx, the part of the throat containing the vocal cords, are particularly dangerous because they can block the airways, making breathing difficult. In some cases, laryngeal attacks can cause life-threatening asphyxiation that requires emergency treatment.
Sebetralstat is a small molecule that blocks kallikrein, an enzyme that regulates bradykinin production and is overactive in HAE. As an on-demand treatment, sebetralstat is expected to rapidly reduce the severity and duration of swelling attacks as they occur. Sebetralstat is available in tablet form and can be taken orally, whereas other on-demand treatments are administered by intravenous (into-the-vein) or subcutaneous (under-the-skin) injection.
KONFIDENT-S participants are receiving two sebetralstat tablets of 300 mg each to treat a swelling attack. Study outcomes include the time to the end of attack progression, the therapy’s effectiveness against mucosal attacks, and sebetralstat’s ability to treat severe or very severe attacks.
The consistency of findings across the KONFIDENT and KONFIDENT-S trials underscores the potential of sebetralstat as an effective and rapid-acting on-demand treatment for HAE attacks.
In a poster titled, “Time to End of Progression of Hereditary Angioedema Attacks Treated with Sebetralstat,” William Lumry, MD, a professor at the University of Texas Southwestern Medical School, presented data on the time to the end of attack progression, or how long it takes for an attack to reach maximum severity before it begins to ease.
Of the 1,591 attacks during KONFIDENT-S, the median time to the end of attack progression after on-demand treatment with sebetralstat was 19.8 minutes. These results were consistent with those observed in the main KONFIDENT trial.
“Stopping the progression of an HAE attack as early as possible is paramount to mitigating its impact on patients,” Lumry said in the press release. “The consistency of findings across the KONFIDENT and KONFIDENT-S trials underscores the potential of sebetralstat as an effective and rapid-acting on-demand treatment for HAE attacks.”
Patients administered sebetralstat very early in attack
In a presentation titled, “Effectiveness of Sebetralstat for the On-demand Treatment of Mucosal HAE Attacks: Interim Analysis from KONFIDENT-S,” Henriette Farkas, MD, PhD, a professor at Semmelweis University in Hungary, showcased data on the therapy’s effectiveness against mucosal attacks.
In this analysis, the median time for patients to self-administer sebetralstat was 20 minutes for abdominal attacks and 11.5 minutes for laryngeal attacks. Most laryngeal attacks (81.3%) and abdominal attacks (70.5%) were treated within one hour of attack onset.
The median time to the beginning of symptom relief after treatment was similar for both attack sites at 1.3 hours, while the median time to complete attack resolution was shorter for attacks involving the larynx than for those affecting the abdomen (12.7 vs. 15.2 hours). The proportion of attacks in which symptom relief began within 12 hours before or without an additional dose of sebetralstat was 96% for both sites. Even with laryngeal attacks, no swallowing difficulties were reported with the oral tablet.
“Mucosal HAE attacks, particularly those affecting the larynx, are a significant concern for patients and clinicians due to the risk of rapid progression and severe consequences, including the possibility of asphyxiation if left untreated,” Farkas said in the press release. “Patients were able to self-administer sebetralstat very early in the course of an attack, when most attacks were still mild or moderate in severity.”
Symptom relief felt less than 90 minutes after treatment
In another poster titled, “Effectiveness of Sebetralstat for Severe or Very Severe Hereditary Angioedema Attacks in KONFIDENT-S,” H. Henry Li, MD, of the Institute for Asthma and Allergy in Maryland, presented data on 30 patients who were treated for attacks rated severe to very severe due to treatment delays beyond the recommended one-hour maximum.
“When attacks are not treated early in accordance with guidelines, they can escalate and become severe,” Li said in the press release.
For 76 attacks, the median time from onset to sebetralstat treatment was 2.2 hours and the median time to symptom relief after treatment was 1.4 hours. The median time for a reduction in attack severity was 1.8 hours, and the median time for a substantial decrease in symptom burden was 9.2 hours.
Within one day, more than half (63.4%) of the attacks rated severe to very severe achieved a substantial reduction of symptom burden. For about one-third (30.3%) of these attacks, a second dose of sebetralstat was taken within 12 hours, and in about 1 in 10 (11.8%) cases, conventional on-demand treatment was administered within 12 hours.
“We conducted this analysis of KONFIDENT-S to assess the utility of sebetralstat in more advanced stages of attacks that were associated with delayed treatment,” Li said. “Sebetralstat delivered symptom relief in a median time of 1.36 hours, reinforcing its potential as an on-demand treatment for challenging attack scenarios.”
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