sebetralstat (KVD900) / KalVista, Kaken Pharma - LARVOL DELTA

IL-1ß INDUCE CAR-T-ASSOCIATED COAGULOPATHY VIA THE HSP90/KALLIKREIN/UPA PATHWAY (EHA 2025) - "These manifestations could be mitigated by IL-1β receptor inhibitor (Anakinra), Hsp90 inhibitor (17-DMAG), and kallikrein inhibitor (Sebetralstat) (Fig1 G-J). IL-1β is responsible for CARAC, through promoting the release of Hsp90 by endothelial cells, which subsequently induces hyperfibrinolysis through the kallikrein-uPA pathway."

IO biomarker • Gastroenterology • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Oncology • CDC37 • HSP90AA1 • HSP90AB1 • IL1B • IL6 • VCAM1

IL-1ß Induce CAR-T-associated coagulopathy via the Hsp90/Kallikrein/uPA Pathway (ISTH 2025) - "Aims To explore the potential pathogenesis and treatment strategy of CARAC...These manifestations could be mitigated by IL-1β receptor inhibitor (Anakinra), Hsp90 inhibitor (17-DMAG), and kallikrein inhibitor (Sebetralstat) (Fig1 G-J). Additionally, anakinra suppressed the expression of Hsp90, 17-DMAG decreased kallikrein production, ultimately decreasing uPA levels and ameliorating coagulopathy (Figure1 K-M). Table or Figure Upload"

IO biomarker • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Oncology • CDC37 • HSP90AA1 • HSP90AB1 • IL1B • IL6 • VCAM1

KalVista Pharmaceuticals Announces FDA Will Not Meet PDUFA Goal Date for Sebetralstat NDA for Hereditary Angioedema Due to FDA Resource Constraints (Businesswire) - "KalVista Pharmaceuticals, Inc...announced that the U.S. Food and Drug Administration (FDA) has notified the Company that it will not meet the PDUFA goal date for the New Drug Application (NDA) for sebetralstat, the Company’s investigational oral on-demand treatment for hereditary angioedema (HAE). The FDA notified the Company on June 13, 2025, that the previously disclosed June 17, 2025 PDUFA goal date will not be met due to heavy workload and limited resources. The FDA indicated that it expects to deliver a decision within approximately four weeks."

PDUFA • Hereditary Angioedema

Systematic Literature Review of Recombinant C1 Esterase Inhibitor (rhC1-INH) and Other Products for the On-Demand Treatment of Hereditary Angioedema Attacks (ISPOR 2025) - "Eligible publications included phases 2, 3, and 4 randomized controlled trials (RCTs) and open-label extension (OLE) studies assessing HAE attacks in patients aged ≥12 years with the following interventions: Ruconest ® (conestat alfa), Firazyr ® (icatibant), Kalbitor ® (ecallantide), sebetralstat (KVD900), and Berinert (C1 esterase inhibitor, human). The study populations and end point definitions used in clinical trials assessing acute HAE treatments have changed over time. Key study differences included route of administration, trial setting, time of treatment, attack severity at enrollment, attack location, redosing and rescue therapy criteria, patient-reported outcome assessments, and outcome definitions. Further investigation is warranted to evaluate these differences and determine whether they affected study outcomes."

Review • Cardiovascular • Complement-mediated Rare Disorders • Genetic Disorders • Hereditary Angioedema

KONFIDENT-KID: Open-Label Safety, PK, and Efficacy Trial of Sebetralstat (KVD900) in Pediatric Patients (Ages 2-11) With HAE Type I or II (clinicaltrials.gov) - P3 | N=36 | Recruiting | Sponsor: KalVista Pharmaceuticals, Ltd. | N=24 ➔ 36

Enrollment change • Cardiovascular • Complement-mediated Rare Disorders • Hereditary Angioedema • Pediatrics

KalVista Pharmaceuticals Enters Into Licensing Agreement With Kaken Pharmaceutical to Commercialize Sebetralstat for HAE in Japan (Businesswire) - "KalVista Pharmaceuticals, Inc...announced that its wholly-owned subsidiary, KalVista Pharmaceuticals, Ltd., has licensed commercialization rights in Japan to Kaken Pharmaceutical, Co., Ltd. (JPX: 4521.T) for sebetralstat, an investigational, oral on-demand treatment for hereditary angioedema (HAE). KalVista will receive an upfront payment of $11 million, with an additional payment of up to $11 million upon achievement of a regulatory milestone anticipated in early 2026. Beyond these payments, the Company is also eligible for commercial milestone payments, plus royalties based on the Japan National Health Insurance (NHI) price, with the royalty rate as a percentage of sales approximately in the mid-twenties."

Licensing / partnership • Hereditary Angioedema

An evaluation of sebetralstat as the first oral on-demand therapy for hereditary angioedema. (PubMed, Expert Opin Pharmacother) - "Clinical trials demonstrated that sebetralstat exhibits rapid absorption, effective plasma kallikrein inhibition, and a favorable safety and efficacy profile. Its pharmacokinetic and pharmacodynamic properties suggest its potential for reliable control of HAE attacks."

Journal • Review • Cardiovascular • Complement-mediated Rare Disorders • Genetic Disorders • Hereditary Angioedema

Indirect treatment comparison of oral sebetralstat and intravenous recombinant human C1 esterase inhibitor for on-demand treatment of hereditary angioedema attacks. (PubMed, Allergy Asthma Clin Immunol) - P2/3, P3 | "This ITC found no significant differences in time to beginning of symptom relief and overall treatment-related treatment-emergent adverse events between sebetralstat and rhC1INH."

Journal • Cardiovascular • Complement-mediated Rare Disorders • Hereditary Angioedema • STAT3

KalVista Pharmaceuticals to Host Investor Webcast Highlighting Commercialization Strategy, Plans and Progress for Sebetralstat in Hereditary Angioedema (Businesswire) - "KalVista Pharmaceuticals, Inc...today announced that it will host a virtual event to provide an overview of the commercialization strategy, plans and progress for sebetralstat, the Company’s investigational treatment for hereditary angioedema (HAE). The event will take place on Tuesday, March 25, 2025, from 8:00 a.m. to 10:00 a.m. ET."

Commercial • Hereditary Angioedema

On-demand Treatment of Hereditary Angioedema Attacks with Sebetralstat In Adolescents: Pooled Analysis From KONFIDENT And KONFIDENT-S (Businesswire) - P3 | N=145 | KONFIDENT-S (NCT05505916) | P3 | N=136 | KONFIDENT (NCT05259917) | Sponsor: KalVista Pharmaceuticals, Ltd. | "The pooled data from the KONFIDENT and KONFIDENT-S studies show that adolescents administered sebetralstat in a median of 4 minutes after attack onset, which compares favorably to a median of 3 hours and mean of 5.2 hours based on international survey data...Importantly, the safety and effectiveness of sebetralstat were consistent with what was observed in adults."

P3 data • Hereditary Angioedema

Effectiveness of Sebetralstat for the On-demand Treatment of Laryngeal Hereditary Angioedema Attacks: Interim Analysis from KONFIDENT-S (Businesswire) - P3 | N=145 | KONFIDENT-S (NCT05505916) | Sponsor: KalVista Pharmaceuticals, Ltd. | "32 laryngeal attacks were treated with sebetralstat (September 14, 2024 cutoff); Median time to treatment with sebetralstat: 11.5 minutes after attack onset; Median time to beginning of symptom relief: 1.27 hours; 96% of those achieving beginning of symptom relief within 12 hours did so with a single dose; No reports of difficulty swallowing film-coated tablet."

P3 data • Hereditary Angioedema

KalVista Pharmaceuticals to Present New Sebetralstat Data at the American Academy of Allergy, Asthma & Immunology 2025 Annual Meeting (Businesswire) - "KalVista Pharmaceuticals, Inc...today announced that six abstracts have been accepted for presentation at the American Academy of Allergy, Asthma & Immunology (AAAAI) / World Allergy Organization (WAO) 2025 Joint Congress taking place in San Diego, CA from February 28–March 3, 2025."

P3 data • Hereditary Angioedema

Effectiveness of Sebetralstat for the On-demand Treatment of Laryngeal Hereditary Angioedema Attacks: Interim Analysis from KONFIDENT-S (AAAAI-WAO 2025) - P3 | "Of attacks reaching beginning of symptom relief within 12h (89.3%), 96.0% did so before or without an additional sebetralstat administration. Conclusions In this interim analysis, sebetralstat enabled rapid treatment of mild to very severe attacks involving the larynx, was well-tolerated, and provided rapid symptom relief."

Late-breaking abstract • Cardiovascular • Complement-mediated Rare Disorders • Hereditary Angioedema

On-demand Treatment Of Hereditary Angioedema Attacks With Sebetralstat In Adolescents: Pooled Analysis From KONFIDENT And KONFIDENT-S (AAAAI-WAO 2025) - P3 | "Conclusions Oral sebetralstat enabled rapid self-administration and rapid symptom relief in adolescents with HAE-C1INH. Sebetralstat was well tolerated, and no adolescents discontinued treatment secondary to adverse events."

Retrospective data • Cardiovascular • Complement-mediated Rare Disorders • Hereditary Angioedema • Movement Disorders

Sebetralstat for the Treatment of HAE Attacks in Patients Receiving Berotralstat: Interim Analysis from the KONFIDENT-S Open-Label Study. (Businesswire) - "Participants receiving berotralstat treated 178 attacks with sebetralstat (mean 1.8 attacks per month). Sebetralstat enabled early treatment (median 20 minutes), early symptom relief (median 1.3 hours), and was well-tolerated with no increase in gastrointestinal side effects."

P3 data • Hereditary Angioedema

Safety and Effectiveness of Sebetralstat in Patients with Hereditary Angioedema Receiving Long-Term Prophylaxis: Interim Analysis from the KONFIDENT-S Open-Label Study. (Businesswire) - "Participants receiving LTP treated 382 attacks with sebetralstat (mean 1.7 attacks per month), of which more than half involved the abdomen and/or larynx. Sebetralstat enabled early treatment (median 6 minutes) and early symptom relief (median 1.3 hours), and was well-tolerated, regardless of LTP mechanism of action or route of administration."

P3 data • Hereditary Angioedema

Impact of Long-Term Prophylaxis (LTP) Adherence in Hereditary Angioedema Patients: Results of a Claims Database Analysis. (Businesswire) - "According to a US commercial claims analysis, nearly 40% of HAE patients who initiated LTP had substantial refill gaps in claims over 12 months, with more than half of those discontinuing LTP. For patients with substantial refill gaps, which increase the likelihood of non-adherence, on-demand claims remained unchanged before and after one year of starting LTP...'We saw no decrease in on-demand claims for patients with LTP refill gaps. These findings are important as most HAE patients in the US now receive LTP, and a greater focus on monitoring appears warranted, as LTP effectiveness is not a given. These data may also help to explain why on-demand treatment volumes in HAE have remained steady despite the advent of several effective subcutaneous and oral LTP options since 2017.'"

Clinical data • Hereditary Angioedema

KalVista Announces Orphan Drug Designation and NDA Submission for Sebetralstat in Japan for Hereditary Angioedema (Businesswire) - "KalVista Pharmaceuticals, Inc...announced that Japan’s Ministry of Health, Labour and Welfare (MHLW) has granted sebetralstat Orphan Drug Designation. The Company has also submitted a New Drug Application (NDA) for sebetralstat to the Agency. If approved, sebetralstat, a novel, investigational oral plasma kallikrein inhibitor for the on-demand treatment of hereditary angioedema (HAE) attacks in adults and adolescents aged 12 years and older, would be the first oral on-demand treatment for HAE in Japan....The NDA submission is supported by previously disclosed results, including data from the KONFIDENT phase 3 clinical trial and ongoing KONFIDENT-S open-label extension trial."

Japan filing • Orphan drug • Hereditary Angioedema

Interplay between on-demand treatment trials for hereditary angioedema and treatment guidelines. (PubMed, J Allergy Clin Immunol) - "Pivotal trials for on-demand injectable treatments (plasma-derived C1 esterase inhibitor [C1INH], icatibant, ecallantide [US only], recombinant C1INH), which were approved in the US and EU between 2008-2014, were designed accordingly. This approach remains the cornerstone of current treatment guidelines and has shaped the design of recent clinical trials, such as those for the investigational agents, oral plasma kallikrein inhibitor sebetralstat and oral bradykinin B2 receptor antagonist deucrictibant. This narrative review discusses the evolution of on-demand treatment guidelines, the clinical trial and real-world data that prompted significant revisions, and the subsequent changes to trial designs introduced to facilitate guideline compliance."

Journal • Review • Cardiovascular • Complement-mediated Rare Disorders • Hereditary Angioedema

IL-1β Induce CAR-T-Associated Coagulopathy Via the Hsp90/Kallikrein/uPA Pathway (ASH 2024) - "These manifestations can be improved by IL-1β receptor inhibitor (Anakinra), Hsp90 inhibitor (17-DMAG hydrochloride), and kallikrein inhibitor (sebetralstat). Conclusion CARAC is characterized by bleeding and hypofibrinogenemia and is closely related to the inflammation-immune-endothelium-coagulation-fibrinolysis network. IL-1β of CRS promotes the release of Hsp90 by endothelial cells, which subsequently induces hyperfibrinolysis through the kallikrein-uPA pathway."

IO biomarker • Gastroenterology • Gastrointestinal Disorder • Hematological Disorders • Hematological Malignancies • Leukemia • Lymphoma • Oncology • CDC37 • HSP90AA1 • HSP90AB1 • IL1B • IL6 • VCAM1

Oral Sebetralstat for On-Demand Treatment of Hereditary Angioedema Attacks. (PubMed, Pediatrics) - No abstract available

Journal • Cardiovascular • Complement-mediated Rare Disorders • Hereditary Angioedema

CORRELATION OF TIME TO TREATMENT WITH ATTACK DURATION IN THE SEBETRALSTAT PHASE 3 KONFIDENT TRIAL (ACAAI 2024) - P3 | "Oral sebetralstat enables early treatment by reducing administration barriers associated with injectable on-demand therapies. In KONFIDENT, earlier administration was correlated with a faster time to complete attack resolution."

P3 data • Cardiovascular • Complement-mediated Rare Disorders • Hereditary Angioedema • STAT3

INDIRECT TREATMENT COMPARISON OF ORAL SEBETRALSTAT AND INTRAVENOUS RHC1-INH AS ON-DEMAND TREATMENTS FOR HEREDITARY ANGIOEDEMA (ACAAI 2024) - P2/3, P3 | "This ITC study found no significant differences in time to beginning of symptom relief and overall treatment-related adverse events between sebetralstat and IV-rhC1-INH."

Cardiovascular • Complement-mediated Rare Disorders • Hereditary Angioedema • STAT3

ON-DEMAND TREATMENT OF LARYNGEAL HEREDITARY ANGIOEDEMA ATTACKS WITH SEBETRALSTAT: POOLED ANALYSIS FROM KONFIDENT AND KONFIDENT-S (ACAAI 2024) - P3 | "Sebetralstat was self-administered rapidly and its efficacy in treating laryngeal attacks was consistent with that observed across all attacks in both KONFIDENT and KONFIDENT-S. Table IQR, interquartile range. IQR, interquartile range."

Retrospective data • Cardiovascular • Complement-mediated Rare Disorders • Hereditary Angioedema

SUBSTANTIAL REDUCTION OF HEREDITARY ANGIOEDEMA ATTACK SYMPTOM BURDEN IN THE SEBETRALSTAT PHASE 3 KONFIDENT TRIAL (ACAAI 2024) - P3 | "In KONFIDENT, participants who experienced attacks that had progressed to “Moderate” or worse severity prior to treatment achieved substantial reduction of symptom burden faster with sebetralstat than with placebo. Time to PGI-S Rating of “Mild” for Attacks “Moderate” or Worse at Time of Treatment. PGI-S, Patient Global Impression of Severity."

P3 data • Cardiovascular • Complement-mediated Rare Disorders • Hereditary Angioedema • STAT3