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    Sebetralstat

    High Evidence

    Sebetralstat (brand name Ekterly) is a first-in-class, orally administered small-molecule inhibitor of plasma kallikrein and the first and only oral on-demand treatment approved for acute attacks of hereditary angioedema (HAE). HAE is a rare, sometimes life-threatening genetic disease in which unchecked activation of the plasma contact system floods the body with bradykinin, causing sudden, recurrent swelling of the skin, gut and airway. Plasma kallikrein is the enzyme that liberates bradykinin, so sebetralstat stops an attack by blocking kallikrein the moment symptoms begin - delivered as a tablet that can be taken at home rather than as an injection or infusion. The approved dose is 600 mg (two 300 mg tablets) at the earliest recognition of an attack, with a second 600 mg dose allowed at least 3 hours later if the response is inadequate or symptoms recur, up to a maximum of 1200 mg in 24 hours. Approval rests on the pivotal Phase 3 KONFIDENT trial (NCT05259917) - the largest HAE trial ever conducted, with 136 patients at 66 sites across 20 countries - a randomized, double-blind, placebo-controlled, event-driven crossover study in which sebetralstat cut the median time to the beginning of symptom relief to 1.61 hours (300 mg) and 1.79 hours (600 mg) versus 6.72 hours for placebo (p<0.0001 and p=0.0013), and also shortened the time to reduced attack severity and to complete resolution; results were published in the New England Journal of Medicine in 2024. The FDA approved Ekterly on July 7, 2025 for patients aged 12 and older, followed by European Commission and Swissmedic approvals on September 19, 2025 and UK MHRA approval. In 2026 the program widened further: an international pediatric HAE guideline named sebetralstat a first-line on-demand option for adolescents aged 12 and older, and in March 2026 KalVista reported positive interim Phase 3 results from the KONFIDENT-KID study in children aged 2 to 11 using an orally disintegrating tablet, with a US filing planned for late 2026. Developed by KalVista Pharmaceuticals, sebetralstat is a rescue (on-demand) therapy that complements the prophylactic HAE drugs garadacimab, donidalorsen, lanadelumab and berotralstat rather than replacing them.

    AliasesSebetralstat+5 more
    EvidenceHigh Evidence
    Last Updated 2026-10-01
    Reading Time 11 min

    What It Is

    Sebetralstat (Ekterly; development code KVD900) is an orally available, small-molecule inhibitor of plasma kallikrein, and the first on-demand treatment for hereditary angioedema (HAE) attacks that can be taken as a tablet rather than given by injection or infusion. It is designed to be swallowed at the first sign of an attack, anywhere, turning acute HAE treatment into something closer to reaching for a pill than preparing a syringe. To see why plasma kallikrein is the target, it helps to follow the biology of an HAE attack. Most HAE is caused by a deficiency or dysfunction of C1-esterase inhibitor (C1-INH), the body's natural brake on the plasma contact system. Without enough working brake, Factor XII is activated to FXIIa, FXIIa converts plasma prekallikrein into active plasma kallikrein, and kallikrein cleaves high-molecular-weight kininogen to release bradykinin. Bradykinin is the key mediator of HAE swelling: it makes blood vessels leaky, producing the sudden, painful, sometimes dangerous edema of the hands, feet, face, abdomen and larynx that defines the disease. Sebetralstat acts at the kallikrein step, directly inhibiting the enzyme that generates bradykinin so that an attack already under way is halted and reversed. What makes sebetralstat notable is less its target - plasma kallikrein is a well-validated node, shared with the injectable antibody lanadelumab and the oral prophylactic berotralstat - than its role and route. Before sebetralstat, every on-demand (rescue) option for an HAE attack was a drug given by subcutaneous injection (icatibant, ecallantide) or intravenous infusion (C1-esterase-inhibitor concentrates). That burden leads many patients to delay or skip treating milder attacks, even though earlier treatment produces better outcomes. An oral on-demand medicine removes the needle from the moment of greatest urgency and is intended to let patients treat attacks sooner and more consistently. The pivotal evidence is KONFIDENT (NCT05259917), described by its sponsor as the largest clinical trial ever conducted in HAE: 136 adult and adolescent patients at 66 sites in 20 countries, in a randomized, double-blind, placebo-controlled, event-driven, crossover design in which each patient treated up to three eligible attacks with up to two doses of study drug per attack. The primary endpoint was the time to the beginning of symptom relief. Sebetralstat shortened that median time to 1.61 hours at the 300 mg dose (p<0.0001) and 1.79 hours at 600 mg (p=0.0013), compared with 6.72 hours on placebo. Key secondary endpoints also favored sebetralstat: faster time to a reduction in attack severity and faster time to complete attack resolution. The drug was well tolerated, with treatment-related adverse-event rates of about 2% on either dose versus roughly 5% on placebo and no serious adverse events. The results were published in the New England Journal of Medicine in 2024, and a KONFIDENT-S open-label extension has reported durable, real-world effectiveness, including for mucosal attacks and for breakthrough attacks in patients already on prophylaxis. Regulators approved it in quick succession. The U.S. FDA approved Ekterly on July 7, 2025 for the treatment of acute HAE attacks in adults and pediatric patients aged 12 and older, making it the first and only oral on-demand therapy for the disease. The European Commission and Swissmedic followed on September 19, 2025 (for adults and adolescents aged 12 and older), and the UK MHRA also approved it. The approved regimen is 600 mg (two 300 mg tablets) taken at the earliest recognition of an attack, with a repeat 600 mg dose permitted at least 3 hours later if the response is inadequate or symptoms recur or worsen, and a maximum of 1200 mg in any 24-hour period. The program is now reaching younger children. On March 30, 2026 KalVista reported positive interim Phase 3 data from KONFIDENT-KID, a study in children aged 2 to 11 that uses a purpose-built orally disintegrating tablet with weight-based dosing. Enrollment was expanded from a planned 24 to roughly 36 children across seven countries because of strong demand and was completed about a year ahead of schedule; an interim analysis covering 172 attacks in 33 participants showed a median of 25 minutes from attack onset to treatment, with 67% of attacks treated within an hour, and in the 150 mg group a median 1.5 hours to the beginning of symptom relief - with no serious or treatment-related adverse events and no reports of difficulty swallowing. KalVista said it planned to submit a U.S. new drug application in the second half of 2026, with a potential launch in 2027; the pediatric (under-12) indication is not yet approved. Separately, a 2026 international pediatric HAE guideline recommended sebetralstat as a first-line on-demand option for adolescents aged 12 and older, reinforcing early, self-administered treatment of attacks. Sebetralstat fits into HAE care as a rescue therapy, not a preventive one. It is meant to stop attacks once they begin, and it sits alongside - not in place of - the on-demand injectables icatibant and ecallantide and C1-esterase-inhibitor concentrates, and complements the long-term prophylactic drugs that aim to prevent attacks in the first place: the FXIIa antibody garadacimab, the prekallikrein-lowering antisense drug donidalorsen, the anti-kallikrein antibody lanadelumab, the oral kallikrein inhibitor berotralstat and C1-INH replacement. Its distinct contribution is practical: a kallikrein blocker that a patient can carry and swallow at the first symptom of an attack.

    Also known as: Sebetralstat, Ekterly, KVD900, oral plasma kallikrein inhibitor, KalVista sebetralstat, oral on-demand HAE treatment

    Why Researchers Study It

    Sebetralstat is studied because it tests a deceptively simple proposition in a disease defined by a runaway biochemical cascade: that a small molecule, taken by mouth, can block plasma kallikrein fast enough to stop a hereditary angioedema (HAE) attack as it happens. Plasma kallikrein is the enzyme that liberates bradykinin, the peptide that drives HAE swelling, so inhibiting it directly interrupts the step that causes symptoms. The scientific interest is less in the target - which is shared with the injectable antibody lanadelumab and the oral prophylactic berotralstat - than in whether oral pharmacology can deliver rescue-level speed: the KONFIDENT trial showed that it can, cutting the median time to the beginning of symptom relief from nearly seven hours on placebo to under two hours. That matters clinically because the biggest practical problem in on-demand HAE care has been treatment delay; every prior rescue option required an injection or infusion, and patients often wait or skip treating milder attacks. Sebetralstat is therefore a real-world test of whether removing the needle changes behavior and outcomes - whether patients treat earlier, treat more attacks, and do better as a result. For immunologists and biochemists it is a probe of the kallikrein-kinin system and of how quickly contact-system activation can be switched off pharmacologically; for clinicians it is a test of whether a carry-anywhere tablet can match injectable rescue agents; and for drug developers it is a proof of concept that oral small molecules can serve acute, time-critical indications historically dominated by biologics, with the ongoing pediatric program extending that question to young children.

    Proposed Mechanisms

    • Direct plasma kallikrein inhibition: sebetralstat is a small-molecule inhibitor that binds and blocks active plasma kallikrein, the enzyme at the center of the contact-system cascade that drives HAE attacks.
    • Cutting off bradykinin generation: by inhibiting kallikrein, sebetralstat prevents the cleavage of high-molecular-weight kininogen and therefore the release of bradykinin - the vasoactive peptide that makes vessels leaky and causes the swelling of an HAE attack.
    • On-demand (acute) action: taken at the earliest recognition of an attack, it is designed to halt and reverse an attack already under way, rather than to prevent future attacks like a prophylactic.
    • Rapid oral pharmacology: sebetralstat is formulated for fast oral absorption so that a swallowed tablet can achieve kallikrein inhibition quickly enough to shorten the time to symptom relief, as demonstrated in the KONFIDENT trial.
    • Needle-free rescue: because it is a pill rather than an injection or infusion, it lowers the practical barrier to treating an attack early, which is associated with better outcomes in HAE.
    • Pediatric orally disintegrating formulation: a weight-based orally disintegrating tablet (studied in KONFIDENT-KID) is intended to extend the same kallikrein-blocking mechanism to young children who cannot easily swallow a standard tablet.

    Evidence Snapshot

    High Evidence
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    Study Type Model Outcome Link
    Phase 3 randomized, double-blind, placebo-controlled, event-driven crossover trial KONFIDENT (NCT05259917) in patients aged 12+ with hereditary angioedema; published in the New England Journal of Medicine (2024). 136 adult and adolescent patients at 66 sites in 20 countries (the largest HAE trial conducted), each treating up to three attacks with up to two doses of sebetralstat 300 mg, sebetralstat 600 mg, or placebo per attack. Met the primary endpoint: median time to the beginning of symptom relief of 1.61 hours (300 mg; p<0.0001) and 1.79 hours (600 mg; p=0.0013) versus 6.72 hours for placebo; faster time to reduced attack severity and to complete resolution; treatment-related adverse events about 2% on either dose versus about 5% on placebo, with no serious adverse events. Basis for FDA approval (Ekterly) on July 7, 2025. Source
    KONFIDENT-S open-label extension study of on-demand sebetralstat for HAE attacks (long-term, real-world use). Patients with HAE treating recurrent attacks with sebetralstat on demand over extended follow-up, including mucosal attacks and breakthrough attacks occurring despite long-term prophylaxis. Interim analyses reported durable, fast relief of attacks consistent with the pivotal trial and a favorable safety profile, supporting real-world effectiveness of oral on-demand treatment, including in patients already receiving prophylaxis. Source
    Phase 3b/pediatric KONFIDENT-KID study of sebetralstat in children aged 2-11 (positive interim results reported March 30, 2026). Approximately 36 children aged 2-11 across seven countries using a weight-based orally disintegrating tablet; interim analysis of 172 attacks in 33 participants. Median 25 minutes from onset to treatment with 67% of attacks treated within one hour; in the 150 mg group a median 1.5 hours to the beginning of symptom relief; well tolerated with no serious or treatment-related adverse events and no difficulty swallowing. Supports a planned U.S. filing in the second half of 2026 (under-12 indication not yet approved). Source
    Mechanism-of-action and clinical pharmacology of sebetralstat as an oral plasma kallikrein inhibitor (supporting the on-demand dosing regimen). Biochemical inhibition of active plasma kallikrein and pharmacokinetic studies supporting rapid oral absorption and the 600 mg on-demand regimen (repeatable once after at least 3 hours; maximum 1200 mg per 24 hours). Demonstrated potent, selective inhibition of plasma kallikrein and a pharmacokinetic profile enabling fast onset of action after oral dosing - the rationale for a carry-anywhere oral rescue therapy that blocks bradykinin generation at the kallikrein step. Source

    Commonly Discussed Benefits

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    Safety & Cautions

    • Sebetralstat (Ekterly) is an FDA-approved oral prescription medicine for the on-demand treatment of hereditary angioedema attacks in people aged 12 and older - it is NOT a supplement, nootropic or research chemical, and any 'sebetralstat', 'Ekterly' or 'KVD900' offered by a vendor outside a pharmacy or clinical trial is unverified and should not be used.
    • It is an acute (rescue) treatment taken when an attack begins, NOT a preventive (prophylactic) therapy - it does not reduce how often attacks occur, so patients with frequent or severe attacks may still need a long-term prophylactic such as garadacimab, donidalorsen, lanadelumab, berotralstat or a C1-esterase inhibitor, decided with a specialist.
    • Laryngeal (throat/airway) swelling is a medical emergency: sebetralstat should be taken at the earliest recognition of an attack, and patients should still seek immediate emergency care for airway involvement and follow their physician's plan rather than relying on an oral tablet alone for a life-threatening attack.
    • As an oral drug, sebetralstat can be affected by drug-drug interactions and should be taken exactly as prescribed; patients should review all concomitant medications with their prescriber. Use in pregnancy and breastfeeding has not been established, and use in children under 12 is not yet FDA-approved (a Phase 3 pediatric study in ages 2-11 reported positive interim results in 2026, with a filing planned).
    • Sebetralstat should be prescribed and monitored by a physician experienced in managing HAE as one part of an overall attack-management plan. It is a targeted therapy for a specific rare disease, not a component of a peptide 'stack'.

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    Citations

    1. [1] Oral Sebetralstat for On-Demand Treatment of Hereditary Angioedema Attacks (KONFIDENT) - New England Journal of Medicine (2024) PubMed
    2. [2] KalVista Reports Phase 3 KONFIDENT Trial Meets All Endpoints for Sebetralstat as First Oral On-demand Therapy for HAE - KalVista (2024) PubMed
    3. [3] Sebetralstat FDA-Approved as First Oral, On-Demand Treatment for Hereditary Angioedema - HCPLive (July 2025) PubMed
    4. [4] A Study of Sebetralstat (KVD900) for On-Demand Treatment of Angioedema Attacks (KONFIDENT) - ClinicalTrials.gov NCT05259917 PubMed
    5. [5] KalVista Announces European Commission and Swissmedic Approval of EKTERLY (sebetralstat) - KalVista (September 19, 2025) PubMed
    6. [6] KalVista Announces Positive Interim Phase 3 Data From KONFIDENT-KID Trial of EKTERLY (sebetralstat) for Children Aged 2-11 - KalVista (March 30, 2026) PubMed
    7. [7] Pediatric HAE Guideline Recommends Sebetralstat as First-Line Therapy for Adolescents 12 and Older - HCPLive (2026) PubMed
    8. [8] Sebetralstat (Ekterly) Dosage Guide - Drugs.com PubMed

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