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Early Treatment With Sebetralstat Correlates With Shorter Duration of Hereditary Angioedema Attacks

Key Takeaways

  • Sebetralstat, an oral plasma kallikrein inhibitor, showed significant efficacy in early treatment of HAE attacks, leading to milder attacks and faster resolution.
  • Early administration of sebetralstat resulted in a higher probability of shorter attack duration, with a strong correlation between treatment timing and attack resolution.
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Patients with hereditary angioedema who received sebetralstat earlier had faster complete resolution of their attacks.

Hereditary angioedema (HAE) attacks treated earlier with sebetralstat were more likely to be mild than attacks treated later, according to results from the KONFIDENT trial (NCT05259917) presented at the American College of Allergy, Asthma, and Immunology Annual Scientific Meeting 2024 in Boston, Massachusetts.1-3

Male hand, swollen after a wasp bite.

Hereditary angioedema attacks can cause swelling in the limbs. | Image Credit: © Andrei | stock.adobe.com

HAE, a rare genetic disorder caused by C1 esterase inhibitor deficiency, is characterized by episodes of swelling that can affect the face, limbs, intestinal tract, and airway. These attacks can be painful and debilitating, and even life-threatening depending on the affected location—swelling of the larynx, leading to asphyxiation, is a particular concern for patients with the disorder.4

Treatment guidelines recommend that those living with HAE treat attacks early after their onset, as previous trials have demonstrated early treatment is associated with reduced attack duration. However, delays in treatment are common with parenterally administered on-demand treatments.2

The KONFIDENT trial evaluated sebelralstat, an oral plasma kallikrein (PKa) inhibitor, in patients with HAE, finding that the drug led to significantly faster times to beginning of symptom relief, reduction in attack severity and, ultimately, complete attack resolution compared with placebo. Thus, in this current analysis, the investigators sought to assess the relationship between the time from attack onset to sebetralstat administration and the time to complete attack resolution in the KONFIDENT trial.2

In KONFIDENT, 39 patients treating their attacks with sebetralstat received treatment “earlier”—within 6 minutes—and 29 received treatment “later”—after 140 minutes or longer. When patients were treated earlier, the probability for shorter attack duration was higher, with the relationship between time to treatment and time to complete attack resolution being 0.88 (95% CI, 0.79-0.97).2

About the Trial

Trial Name: A Phase III, Crossover Trial Evaluating the Efficacy and Safety of KVD900 for On-Demand Treatment of Angioedema Attacks in Adolescent and Adult Patients With Hereditary Angioedema (HAE)

ClinicalTrials.gov ID: NCT05259917

Sponsor: KalVista Pharmaceuticals, Ltd

Completion Date: December 31, 2023

Furthermore, complete attack resolution was reached faster (HR: 2.72 [1.33, 5.59]) in attacks treated with sebetralstat earlier compared with those treated later. Individuals treated with sebetralstat had a faster reduction in substantial symptom burden compared with placebo, with median times of 5.0 hours for 300 mg sebetralstat and 5.2 hours for 600 mg, and greater than 12 hours for placebo.1,2

William Lumry, MD, medical director at Arizona Arthritis & Rheumatology Associates Research Center in Dallas and KONFIDENT investigator, provided some context on the trial design. “All other clinical trial designs for on-demand therapy have required attacks to be at least moderate in severity to be eligible to treat,” he said. “This changed with the sebetralstat phase 2 and 3 trials which, consistent with modern HAE guidelines, instructed patients to treat attacks early.”1

“While injectable on-demand therapies are effective, there are numerous barriers patients face that lead to delay or denial of HAE on-demand treatment,” Tim Craig, DO, professor at the departments of medicine and pediatrics in the division of pulmonary, allergy, and critical care medicine at Penn State Health and KONFIDENT investigator, said in the news release. “This is the first time in a phase 3 on-demand trial where we can see that treating attacks within minutes versus hours has a meaningful impact on clinical outcomes.”1

REFERENCES
1. KalVista Pharmaceuticals. KalVista Pharmaceuticals presents new sebetralstat data at the 2024 American College of Allergy Asthma and Immunology. BusinessWire. News Release. Released October 28, 2024. Accessed October 29, 2024. https://www.businesswire.com/news/home/20241028943529/en
2. Craig TJ, Bernstein JA, Longhurst H, et al. Correlation of time to treatment with attack duration in the sebetralstat KONFIDENT phase 3 trial. Presented at the American College of Allergy Asthma and Immunology Annual Scientific Meeting 2024. October 24-28, 2024; Boston, Massachusetts. https://www.kalvista.com/wp-content/uploads/2024/10/ACAAI-2024_KONFIDENT_Time-to-Treatment_Poster_FINAL_09Oct2024.pdf
3. ClinicalTrials.gov. A phase III, crossover trial evaluating the efficacy and safety of KVD900 for on-demand treatment of angioedema attacks in adolescent and adult patients with hereditary angioedema (HAE). National Library of Medicine. Last updated July 19, 2024. Accessed October 29, 2024. https://clinicaltrials.gov/study/NCT05259917
4. Longhurst HJ, Bork K. Hereditary angioedema: an update on causes, manifestations, and treatment. Br J Hosp Med (Lond). 2019;80(7):391-398. doi:10.12968/hmed.2019.80.7.391
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