FDA Approves Sebetralstat for Hereditary Angioedema

Sebetralstat (Ekterly; KalVista Pharmaceuticals) is now approved by the FDA for on-demand treatment of hereditary angioedema, with supportive data from the phase 3, double-blind, 3-way crossover KONFIDENT trial (NCT05259917) and its open-label extension KONFIDENT-S (NCT05505916) forming the base of the application for this indication.¹ Patients need to be 12 years or older to receive the treatment.

The approval is especially significant because it means that sebetralstat, a plasma kallikrein inhibitor, not only is the first and only orally administered on-demand therapy specifically for hereditary angioedema attacks, but is the first new on-demand regimen approved for hereditary angioedema in more than 10 years. It also is the second approval for a hereditary angioedema therapeutic in just under 3 weeks, following the June 16 approval of garadacimab-gxii (Andembry; CSL), a once-monthly self-administered subcutaneous injection.^2,3

For the second time in under 3 weeks, the FDA has approved treatment for hereditary angioedema, an inherited genetic disorder characterized by recurrent episodes of severe swelling. | Image Credit: Maggie-sora.chatgpt.com

“Until now, on-demand treatment relied on injectable subcutaneous or intravenous administration, often resulting in delayed intervention,” said Marc A. Riedl, MD, professor of medicine and clinical director, US Hereditary Angioedema Association Center at the University of California, San Diego, and an investigator for the KONFIDENT phase 3 trial, in a statement.¹ “Having an oral option empowers patients to treat attacks early, which aligns with treatment guidelines and advances our goal as physicians to reduce the overall burden of disease.”

In the KONFIDENT trial, 136 patients with hereditary angioedema were enrolled from 66 sites in 20 countries, including the US, Bulgaria, France, Greece, Japan, Poland, and Puerto Rico.⁴ They were randomized to sebetralstat (known as KVD900 at the time) administered as two 300-mg tablets (600 mg total) or one 300-mg tablet (300 mg), with the primary outcome of interest being time to beginning of symptom relief as measured on the Patient Global Impression of Change scale within 12 hours of initial administration. Secondary outcomes were time to first incidence of decrease from baseline and time to complete hereditary angioedema attack resolution, both via the Patient Global Impression of Severity scale.

Previously published data demonstrated that compared with placebo, symptom relief, attack severity reduction, and complete attack resolution happened faster with sebetralstat.⁵ KONFIDENT results published last year in The New England Journal of Medicine show that at 300 mg (P < .001) and 600 mg (P = .001), sebetralstat took a median (IQR) 1.61 hours (0.78-7.04) and 1.79 (1.02-3.79), respectively, to first produce symptom relief, compared with 6.72 hours (1.34 to >12) with placebo. Corresponding rates of attacks with complete resolution within 24 hours were 42.5%, 49.5%, and 27.4%. Overall, the medication was well tolerated with a safety profile that echoed placebo.¹

More recent data from KONFIDENT-S show a shorter time to initial symptom relief of 1.3 hours for hereditary angioedema attacks specifically involving the larynx or the abdomen, and for breakthrough attacks if on long-term prophylaxis, as well that patients could self-treat in as fast as 10 minutes. Further, patients on the 600-mg dose demonstrated a similar safety profile over more than 1700 attacks, with the investigators explain this was “consistent with that observed in KONFIDENT.”

The approval follows reports that FDA Commissioner Marty Makary, MD, MPH, wanted to issue a complete response letter to KalVista to decline this approval, and the decision was delayed from the original June 17 Prescription Drug User Fee Act target date.⁶

Availability and US launch are immediate.

In an interview with The American Journal of Managed Care^®, Timothy Craig, DO, principal investigator on the phase 3 VANGUARD trial (NCT04656418), which served as the basis of the garadacimab approval for hereditary angioedema, explained that the 2 newly approved medications complement each other and can be used in combination, with sebetralstat “very good” as a rescue medication for attacks and garadacimab working as long-term prophylaxis.⁷

References

1. KalVista pharmaceuticals announces FDA approval of Ekterly (sebetralstat), first and only oral on-demand treatment for hereditary angioedema. News release. BusinessWire. July 7, 2025. Accessed July 7, 2025. https://www.businesswire.com/news/home/20250702871458/en/KalVista-Pharmaceuticals-Announces-FDA-Approval-of-EKTERLY-sebetralstat-First-and-Only-Oral-On-demand-Treatment-for-Hereditary-Angioedema
2. Steinzor P. FDA approves garadacimab-gxii in hereditary angioedema. AJMC^®. June 17, 2025. Accessed July 7, 2025. https://www.ajmc.com/view/fda-approves-garadacimab-in-hereditary-angioedema
3. US Food and Drug Administration approves CSL's Andembry (garadacimab-gxii), the only prophylactic hereditary angioedema (HAE) treatment targeting factor XIIa with once-monthly dosing for all patients from the start. News release. CSL. June 16, 2025. Accessed July 7, 2025. https://www.prnewswire.com/news-releases/us-food-and-drug-administration-approves-csls-andembry-garadacimab-gxii-the-only-prophylactic-hereditary-angioedema-hae-treatment-targeting-factor-xiia-with-once-monthly-dosing-for-all-patients-from-the-start-302483058.html
4. A phase III, crossover trial evaluating the efficacy and safety of KVD900 (sebetralstat) for on-demand treatment of angioedema attacks in adolescent and adult patients with hereditary angioedema (HAE). ClinicalTrials.gov. Updated May 2, 2025. Accessed July 7, 2025. https://clinicaltrials.gov/study/NCT05259917
5. Riedl MA, Farkas H, Aygören-Pürsün E, et al; KONFIDENT investigators. Oral sebetralstat for on-demand treatment of hereditary angioedema attacks. N Engl J Med. 2024;391(1):32-43. doi:10.1056/NEJMoa2314192
6. Al-Faruque F. This week at FDA: Makary and a CRL for KalVista, more FDA staff leaving, advisory panels slowed by staff cuts. Regulatory Focus. June 27, 2025. Accessed July 7, 2025. https://www.raps.org/news-and-articles/news-articles/2025/6/this-week-at-fda-makary-and-a-crl-for-kalvista-mor
7. Bonavitacola J. Combination of garadacimab, sebetralstat can help patients with HAE: Timothy Craig, DO. AJMC. June 18, 2025. Accessed July 7, 2025. https://www.ajmc.com/view/combination-of-garadacimab-sebetralstat-can-help-patients-with-hae-timothy-craig-do