Ekterly provides early relief in laryngeal and abdominal HAE attacks
Extension study shows fast symptom improvement with oral therapy
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People with hereditary angioedema (HAE) began experiencing symptom relief from swelling attacks of the larynx (voice box) or abdomen in less than two hours after taking oral Ekterly (sebetralstat).
The finding comes from an interim analysis of data from the open-label extension (OLE) study, KONFIDENT-S (NCT05505916), which is evaluating the long-term safety and effectiveness of the therapy in people with HAE ages 12 and older.
Overall, more than 95% of study participants achieved symptom relief from laryngeal and abdominal attacks within 12 hours after a single dose of Ekterly, according to the trial data.
Extension study highlights rapid onset of relief with oral sebetralstat
“Oral sebetralstat enabled rapid treatment of laryngeal and abdominal attacks of all severities, was well tolerated, and provided early symptom relief,” the researchers wrote.
The interim KONFIDENT-S analysis was reported in the study, “Sebetralstat for On-Demand Treatment of Mucosal Hereditary Angioedema Attacks in KONFIDENT-S,” published in Clinical and Translational Allergy.
HAE is a genetic disorder marked by episodes of swelling, often driven by overproduction of the signaling molecule bradykinin. These attacks most often affect deeper layers of the skin or mucous membranes, the soft tissue lining areas such as the gut and airways.
KalVista Pharmaceuticals’ Ekterly is designed to block an enzyme involved in bradykinin production, helping reduce bradykinin levels and prevent swelling. Ekterly has been approved in multiple regions, including the U.S., the U.K., the European Union, and Switzerland, as an on-demand treatment for HAE attacks in people ages 12 and older.
The approvals were largely supported by results from the Phase 3 KONFIDENT trial (NCT05259917), in which on-demand treatment led to faster symptom relief than placebo.
Earlier KONFIDENT-S results suggested that on-demand treatment with Ekterly provided rapid symptom improvement, including during severe attacks and those affecting the larynx. In addition, a recent analysis of more than 1,000 attacks across KONFIDENT and KONFIDENT-S found that attacks stopped worsening within about 20 minutes after on-demand treatment.
Interim analysis focuses on laryngeal and abdominal HAE attacks
This prespecified interim analysis, sponsored by KalVista, evaluated the safety and efficacy of Ekterly for treating mucosal HAE attacks affecting the larynx and abdomen in the KONFIDENT-S trial.
“This allows for a more comprehensive assessment of the safety and effectiveness of [Ekterly], specifically as an oral on-demand treatment for mucosal HAE attacks, which are associated with substantial [illness],” the team wrote.
In this interim analysis, 32 attacks (1.9%) involved the larynx, and 533 (31.2%) were abdominal attacks.
The median time from noticing an attack to taking Ekterly was shorter for laryngeal attacks than abdominal attacks (11.5 vs. 20 minutes). After treatment, the median time to the beginning of symptom relief was less than two hours for both laryngeal and abdominal attacks (1.29 and 1.27 hours).
“These times indicate a relatively rapid onset of action for [Ekterly] across mucosal attack locations,” the researchers wrote.
The ability to administer oral therapy, even during mucosal swelling, addresses a critical unmet need in HAE management and has the potential to significantly improve patient outcomes by enabling earlier intervention.
The median time to a reduction in attack severity was slightly longer for laryngeal attacks than for abdominal attacks (4.25 vs. 3.52 hours). By contrast, the median time to complete attack resolution was shorter for laryngeal attacks than for abdominal attacks (12.69 vs. 15.17 hours).
The median time to the end of attack progression, the point at which swelling was no longer worsening, was similar for laryngeal and abdominal attacks (20.0 vs. 21.0 minutes). Still, the median time to substantial symptom relief after Ekterly was slightly longer for laryngeal attacks (2.67 vs. 1.76 hours).
Among laryngeal attacks, 12.5% received a second dose of Ekterly within 12 hours, and 9.4% were treated with conventional medication. For abdominal attacks, 17.8% received a second dose, while 8.1% were treated with conventional medication.
Overall, symptom relief within 12 hours after a single dose of Ekterly was achieved for nearly all laryngeal attacks (96.0%) and abdominal attacks (95.8%).
Outcomes compared by use of preventive HAE therapy
Researchers then compared outcomes between participants who used Ekterly as an on-demand treatment only and those who used on-demand treatment plus long-term preventive therapy.
The median time to the beginning of symptom relief was similar between the two groups for laryngeal attacks (1.27 vs. 1.36 hours) and abdominal attacks (1.31 vs. 0.96 hours). However, the median time to a reduction in attack severity differed: it was shorter in the on-demand only group for laryngeal attacks (2.43 vs. 6.04 hours) but longer for abdominal attacks (4.46 vs. 1.78 hours).
The median time to complete attack resolution was similar between the two groups for laryngeal attacks (12.71 vs. 12.67 hours). For abdominal attacks, however, complete resolution took longer in the on-demand-only group (20.27 vs. 8.41 hours).
Regarding safety, no participants reported difficulty swallowing oral Ekterly during laryngeal or abdominal attacks. Moderate nausea and vomiting were reported in one participant who experienced both a laryngeal and an abdominal attack, leading to discontinuation from the study. Six treatment-related adverse events (5.9%) were reported among those with abdominal attacks, including flu-like symptoms, skin burning, diarrhea, headache, myalgia (muscle pain), and vomiting.
“The KONFIDENT-S OLE demonstrates that sebetralstat is a safe and effective oral on-demand treatment for both laryngeal and abdominal [HAE] attacks, resulting in rapid onset of symptom relief,” the researchers concluded. “The ability to administer oral therapy, even during mucosal swelling, addresses a critical unmet need in HAE management and has the potential to significantly improve patient outcomes by enabling earlier intervention.”
