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Background: Hereditary angioedema is a rare and potentially life-threatening genetic disease that is associated with kallikrein-kinin system dysregulation. Garadacimab (CSL312), a novel, fully-human monoclonal antibody that inhibits activated factor XII (FXIIa), is being studied for the prevention of hereditary angioedema attacks. The aim of this study was to evaluate the efficacy and safety of once-monthly subcutaneous administrations of garadacimab as prophylaxis for hereditary angioedema., Methods: VANGUARD was a pivotal, multicentre, randomised, double-blind, placebo-controlled, phase 3 trial that recruited patients (aged ≥12 years) with type I or type II hereditary angioedema across seven countries (Canada, Germany, Hungary, Israel, Japan, the Netherlands, and the USA). Eligible patients were randomly assigned (3:2) to receive garadacimab or placebo for 6 months (182 days) by an interactive response technology (IRT) system. Randomisation was stratified by age (≤17 years vs >17 years) and baseline attack rate (1 to <3 attacks per month vs ≥3 attacks per month) for the adult group. The randomisation list and code were kept by the IRT provider during the study, with no access by site staff and funding representatives. All patients and investigational site staff, and representatives from the funder (or their delegates) with direct interaction with the study sites or patients, were masked to treatment assignment in a double-blind fashion. Randomly assigned patients received a 400-mg loading dose of subcutaneous garadacimab as two 200-mg injections or volume-matched placebo on day 1 of the treatment period, followed by five additional self-administered (or caregiver-administered) monthly doses of 200-mg subcutaneous garadacimab or volume-matched placebo. The primary endpoint was the investigator-assessed time-normalised number of hereditary angioedema attacks (number of hereditary angioedema attacks per month) during the 6-month treatment period (day 1 to day 182). Safety was evaluated in patients who received at least one dose of garadacimab or placebo. The study is registered with the EU Clinical Trials Register, 2020-000570-25 and ClinicalTrials.gov, NCT04656418., Findings: Between Jan 27, 2021, and June 7, 2022, we screened 80 patients, 76 of whom were eligible to enter the run-in period of the study. Of 65 eligible patients with type I or type II hereditary angioedema, 39 were randomly assigned to garadacimab and 26 to placebo. One patient was randomly assigned in error and did not enter the treatment period (no dose of study drug received), resulting in 39 patients assigned to garadacimab and 25 patients assigned to placebo being included. 38 (59%) of 64 participants were female and 26 (41%) were male. 55 (86%) of 64 participants were White, six (9%) were Asian (Japanese), one (2%) was Black or African American, one (2%) was Native Hawaiian or Other Pacific Islander, and one (2%) was listed as other. During the 6-month treatment period (day 1 to day 182), the mean number of investigator-confirmed hereditary angioedema attacks per month was significantly lower in the garadacimab group (0·27, 95% CI 0·05 to 0·49) than in the placebo group (2·01, 1·44 to 2·57; p<0·0001), corresponding to a percentage difference in means of -87% (95% CI -96 to -58; p<0·0001). The median number of hereditary angioedema attacks per month was 0 (IQR 0·00-0·31) for garadacimab and 1·35 (1·00-3·20) for placebo. The most common treatment-emergent adverse events were upper-respiratory tract infections, nasopharyngitis, and headaches. FXIIa inhibition was not associated with an increased risk of bleeding or thromboembolic events., Interpretation: Monthly garadacimab administration significantly reduced hereditary angioedema attacks in patients aged 12 years and older compared with placebo and had a favourable safety profile. Our results support the use of garadacimab as a potential prophylactic therapy for the treatment of hereditary angioedema in adolescents and adults., Funding: CSL Behring., Competing Interests: Declaration of interests TJC is a speaker for Pharming, CSL Behring, Takeda, Fresenius Kabi, and Grifols; has received research and consultancy grants from CSL Behring, Takeda, BioCryst, Ionis, Spark, BioMarin, Fresenius Kabi, and Grifols; and is on the medical advisory board for the US Hereditary Angioedema Association, Director of ACARE Angioedema Center at Penn State University, Hershey, and on the Board of Directors for the American Academy of Allergy, Asthma, and Immunology. AR received research grants as a principal investigator, speaker, and advisor for CSL Behring, Takeda-Shire, BioCryst, Pharming, Pharvaris, Ionis, and Shulov Innovative Science. HHL is a speaker for Pharming, CSL Behring, Takeda, and BioCryst and has received research and consultancy grants from CSL Behring, Takeda, BioCryst, Ionis, BioMarin, Pharming, and Phavaris. JSJ is a speaker for Takeda-Shire, CSL Behring, Teva, AstraZeneca, GSK, Sanofi Genzyme, and Regeneron and has received research funding or consultancy fees from CSL Behring, Takeda-Shire, BioCryst, Novartis, Genentech, AstraZeneca, Allakos, Fresenius Kabi, GSK, and Regeneron. JAB is a consultant, principal investigator, and speaker for CSL Behring, Takeda-Shire, Pharming, and BioCryst; is a consultant or principal investigator for KalVista, Biomarin, and Ionis; and is a consultant for Astria, ONO Pharmaceutical, Pharvaris, and Cycle Pharmaceuticals. HFa received research grants from CSL Behring, Takeda, and Pharming; has served as an advisor for CSL Behring, Takeda, Pharming, KalVista, ONO Pharmaceutical, and BioCryst; and has participated in clinical trials or registries for BioCryst, CSL Behring, Pharming, KalVista, Pharvaris, and Takeda. WHY has been a speaker and advisory board member and has received honoraria from CSL Behring, Takeda-Shire, Novartis, Sanofi Genzyme, and Merck; has received research grants from CSL Behring, Takeda-Shire, BioCryst, Pharming, Aimmune, DBV Technologies, Eli Lilly, Pharvaris, AstraZeneca, Novartis, GSK, Genentech-Roche, Amgen, Sanofi Genzyme, Regeneron, Galderma, AnaptysBio, Glenmark, ALK Pharma, Dermira, Ionis, and Celgene; serves as a medical advisor (volunteer) for HAE Canada, a patient organisation; and is a member of Angioedema Centers of Reference and Excellence. ESGS has received lecturing or advertising board fees from Amgen, Sanofi, Novartis, AstraZeneca, Esperion, Ionis-Akcea, and Merck, paid to their institution. IO has received honoraria or served as a consultant or participated in advisory boards for CSL Behring, Takeda-Shire, and Torii Pharmaceutical Company. RTa is a speaker for BioCryst, CSL Behring, Pharming, AstraZeneca, Sanofi-Regeneron, GSK, and Takeda; has served as a consultant for BioCryst, CSL Behring, KalVista, Pharming, and Takeda; and has received grants or research support from BioCryst, CSL Behring, Ionis, KalVista, Pharvaris, and Takeda. MEM is a speaker for CSL Behring, Takeda, Pharming, BioCryst, GSK, Amgen, Sanofi-Regeneron, AstraZeneca, Blueprint, and Genentech; has received research grants from CSL Behring, Takeda, Pharming, BioCryst, KalVista, Pharvaris, GSK, Novartis, Merck, and Allakos; and has been a consultant for CSL Behring, Takeda, Pharming, BioCryst, KalVista, and Cycle Pharmaceuticals. WRL is a speaker for CSL Behring, Pharming, AstraZeneca, Sanofi-Regeneron, GSK, and Takeda-Shire; has served as a consultant for BioCryst, BioMarin, CSL Behring, Fresenius Kabi, Intellia, KalVista, Pharming, Pharvaris, and Takeda-Shire; is a board member of the US Hereditary Angioedema Association Medical Advisory Board; and has received grants or research support from ALK Pharma, BioCryst, CSL Behring, Ionis, Gossamer, KalVista, Kedrion, Therapure, and Takeda-Shire. IMS has received honoraria, research funding, and travel grants from BioCryst, CSL Behring, Pharming, Octapharma, KalVista, and Takeda-Shire and has served as a consultant or participated in advisory boards for these companies. EA-P has received honoraria as a speaker or advisor or grant support or clinical trial investigator support from BioCryst, BioMarin Europe, Centogene, CSL Behring, KalVista, Pharming, Pharvaris, and Takeda-Shire. BR has been a speaker and advisory board member for CSL Behring and Takeda, but has not received personal reimbursement for these activities. BR has participated in multiple clinical trials involving investigational drugs for CSL Behring, Takeda, BioCryst, Dyax, and Pharming, but does not hold patents or investments with these companies or involving this product, and serves as a volunteer Medical Scientific Advisor to HAE Canada, a patient organisation. GLS has been an advisory board member for CSL Behring and has participated in clinical trials for investigational drugs for CSL Behring, Takeda, BioCryst, Dyax, Pharming, Pharvaris, and KalVista. JA is a speaker bureau member for CSL Behring, Pharming, BioCryst, and Takeda and has received consulting fees from; is a clinical trial investigator for BioCryst, CSL Behring, Pharming, Takeda, KalVista, Pharvaris, and BioMarin; and has received consulting fees from Cycle Pharmaceuticals. KK has been a clinical trial investigator for CSL Behring. YS has received speaker fees from Novartis, AstraZeneca, Takeda-Shire, and Torii Pharmaceutical Company and has been a clinical trial investigator for CSL Behring. PS has received honoraria, research funding, travel grants, or has served as a consultant or participated in advisory boards for CSL Behring, Octapharma, Pharming, Shire, and Takeda. RTr has received honoraria, travel grants, or has participated in clinical trials or advisory boards for CSL Behring, Shire, and Takeda. HFe, FG, and IJ are full-time employees and shareholders of CSL Behring. MM has received financial support from CSL Behring for acting as a study centre investigator during the conduct of the study and personal fees from CSL Behring, Takeda-Shire, Pharming, BioCryst, Novartis, Octapharma, and KalVista outside the submitted work., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Guidelines recommend effective on-demand therapy for all individuals with hereditary angioedema. We aimed to assess the novel oral plasma kallikrein inhibitor, sebetralstat, which is in development, for on-demand treatment of hereditary angioedema attacks., Methods: In this two-part phase 2 trial, individuals with type 1 or 2 hereditary angioedema aged 18 years or older were recruited from 25 sites, consisting of specialty outpatient centres, across nine countries in Europe and the USA. Individuals were eligible if they had experienced at least three hereditary angioedema attacks in the past 93 days, were not on prophylactic therapy, and had access to and the ability to self-administer conventional attack treatment. In part 1 of the trial, participants were given a single 600 mg open-label oral dose of sebetralstat to assess safety, pharmacokinetics, and pharmacodynamics of the dose. Part 2 was a randomised, double-blind, placebo-controlled, two-sequence, two-period (2 × 2) crossover trial; participants were randomly assigned (1:1) to either sequence 1, in which they were given a single dose of 600 mg of sebetralstat to treat the first eligible attack and a second dose of placebo to treat the second eligible attack, or sequence 2, in which they were given placebo to treat the first eligible attack and then 600 mg of sebetralstat to treat the second eligible attack. Participants and investigators were masked to treatment assignment. The primary endpoint was time to use of conventional attack treatment within 12 h of study drug administration, which was assessed in all participants who were randomly assigned to treatment and who received study drug for two attacks during part 2 of the study. Safety was assessed in all participants who received at least one dose of study drug, starting in part 1. This study is registered with ClinicalTrials.gov, NCT04208412, and is completed., Findings: Between July 2, 2019, and Dec 8, 2020, 84 individuals were screened and 68 were enrolled in part 1 and received sebetralstat (mean age 38·3 years [SD 13·2], 37 [54%] were female, 31 [46%] were male, 68 [100%] were White). 42 (62%) of 68 participants completed pharmacokinetic assessments. Sebetralstat was rapidly absorbed, with a geometric mean plasma concentration of 501 ng/mL at 15 min. In a subset of participants (n=6), plasma samples obtained from 15 min to 4 h after study drug administration had near-complete protection from ex vivo stimulated generation of plasma kallikrein and cleavage of high-molecular-weight kininogen. In part 2, all 68 participants were randomly assigned to sequence 1 (n=34) or sequence 2 (n=34). 53 (78%) of 68 participants treated two attacks (25 [74%] in the sequence 1 group and 28 [82%] in the sequence 2 group). Time to use of conventional treatment within 12 h of study drug administration was significantly longer with sebetralstat versus placebo (at quartile 1: >12 h [95% CI 9·6 to >12] vs 8·0 h [3·8 to >12]; p=0·0010). There were no serious adverse events or adverse event-related discontinuations., Interpretation: Oral administration of sebetralstat was well tolerated and led to rapid suppression of plasma kallikrein activity, resulting in increased time to use of conventional attack treatment and faster symptom relief versus placebo. Based on these results, a phase 3 trial to evaluate the efficacy and safety of two dose levels of sebetralstat in adolescent and adult participants with hereditary angioedema has been initiated (NCT05259917)., Funding: KalVista Pharmaceuticals., Competing Interests: Declaration of interests EA-P has received grants from or has served as consultant or speaker for BioCryst, Biomarin, Centogene, CSL Behring, KalVista, Pharming, Pharvaris, and Shire/Takeda. AZ has received speaker or consultancy fees from BioCryst, CSL Behring, Pharming, and Takeda. DMC has received speaker fees or consultancy fees from BioCryst, CSL Behring, Ionis Pharmaceuticals, KalVista, Pharming, Pharvaris, and Shire/Takeda. MC has received funding for research projects from or served on advisory boards for CSL Behring, BioCryst, and Shire/Takeda. RH has received consultancy or speaker honoraria from CSL Behring, Shire/Takeda, and has served as a principal investigator for clinical trials sponsored by BioCryst, Pharvaris Netherlands BV, Pharming, CSL Behring, and KalVista. TK has received research grants from Takeda and speaker or consultancy fees from BioCryst, CSL Behring, KalVista and Takeda. MMag has been a speaker or advisor for or has received research funding from BioCryst, CSL Behring, KalVista, Octapharma, Pharming, and Shire/Takeda. IM-S has received speaker or consultancy fees from BioCryst, CSL Behring, Pharming, and Takeda. MS has received speaker and consultant fees from CSL Behring, Takeda, Pharming, and BioCryst. HF has received research grants from CSL Behring, Shire/Takeda, and Pharming and served as an advisor for BioCryst, KalVista, and ONO Pharmaceuticals. SK-A has received speaker or consultancy fees from BioCryst, CSL Behring, Pharming, and Takeda. VG-P has served as principal investigator for CSL Behring, Pharming, BioCryst, and KalVista. JAB has received speaker or consultancy fees from or served as principal investigator for KalVista, Celldex, Pharvaris, Biomarin, Amgen, Allakos, CSL Behring, Shire, Pharming, BioCryst, AstraZeneca, Sanofi-Regeneron, Novartis, and Genentech. HHL has received speaker or consultant fees from BioCryst, CSL Behring, Pharming, and Takeda. HJL has served as consultant, speaker, or engaged in research with or educational projects with BioCryst, CSL Behring, Intellia, KalVista, Pharming, Pharvaris, and Takeda. PKA, MDS, CMY, DKL, and EPF are employees of KalVista Pharmaceuticals. AM was an employee of KalVista Pharmaceuticals at the time of the study. RG has received research grants from Takeda, BioCryst, KalVista, and Pharvaris and consulting and speaker fees from BioCryst, Fresenius Kabi, and Takeda. WRL is a member of advisory boards for BioCryst, CSL Behring, and Takeda; has received research grants from BioCryst, CSL Behring, Ionis, and Takeda; consulting fees from BioCryst, CSL Behring, Fresenius Kabi, Pharming, and Takeda; payments for lectures from CSL Behring, Pharming, and Takeda; and is an advisory board member of the US Hereditary Angioedema Association. AB has received research grants from Takeda and BioCryst and consulting fees from Takeda, BioCryst, Pharming, CSL, Pharvaris, KalVista, and Biomarin. MAR has received research grants from BioCryst, CSL Behring, Ionis, KalVista, Pharvaris; consulted for BioCryst, Biomarin, CSL Behring, Cycle Pharma, Fresenius-Kabi, Ionis, KalVista, Pfizer, Pharming, Pharvaris, RegenexBio, Regeneron, Shire/Takeda, and Spark; and provided speaker presentations for CSL Behring, Grifols, Pharming, and Shire. MMau has been a speaker or advisor for or has received research funding from Alnylam, BioCryst, Centogene, CSL Behring, Dyax, KalVista, Pharming, Pharvaris, and Shire/Takeda., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Hereditary angioedema is associated with dysregulation of the kallikrein-kinin system. Factor XII (FXII) is a key initiator of the kallikrein-kinin system, which produces bradykinin, a central mediator of angioedema. Garadacimab (CSL Behring) is a first-in-class, fully human, immunoglobulin G4 monoclonal antibody targeting activated FXII, intended to prevent attacks in patients with C1-esterase inhibitor-deficient hereditary angioedema (HAE-C1-INH). We aimed to investigate garadacimab as a treatment every 4 weeks for patients with HAE-C1-INH., Methods: In this double-blind, placebo-controlled, phase 2 study, patients with HAE-C1-INH were recruited from 12 research centres in Canada, Germany, Israel, and the USA. Eligible patients were aged 18-65 years and must have had at least four attacks of any severity over a consecutive 2-month period during the 3 months before screening or initiation of previous hereditary angioedema prophylaxis. After a run-in period of 4-8 weeks, patients were randomly assigned (1:1:1:1), using an interactive response technology via block randomisation (block sizes of 1-4), to either placebo or 75 mg, 200 mg, or 600 mg garadacimab. Patients were given an initial intravenous loading dose, and then, on day 6 and every 4 weeks for 12 weeks, they were given a subcutaneous dose of their allocated treatment. The primary endpoint was the number of monthly attacks in the intention-to-treat population (defined as all patients who underwent screening, provided consent, and were assigned to treatment) during the 12-week subcutaneous administration period assessed in the 200 mg and 600 mg garadacimab groups versus placebo. Safety was assessed in all patients who received at least one dose or partial dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03712228., Findings: Between Oct 29, 2018, and Aug 28, 2019, 54 patients were screened, of whom 32 were randomly assigned to either placebo (n=8) or 75 mg (n=9), 200 mg (n=8), or 600 mg (n=7) garadacimab. The median age was 39·5 years (28·0-52·5) and 18 (56%) of 32 patients were female and 14 (34%) were male. The median number of monthly attacks during the 12-week subcutaneous treatment period was 4·6 (IQR 3·1-5·0) with placebo, 0·0 (0·0-0·4) with 75 mg garadacimab, 0·0 (0·0-0·0) with 200 mg garadacimab, and 0·3 (0·0-0·7) with 600 mg garadacimab. Compared with placebo, the rate of attacks was significantly reduced with garadacimab at 200 mg (reduced by 100% [95% CI 98-101]; p=0·0002) and 600 mg (reduced by 93% [54-110]; p=0·0003). No serious adverse events, deaths, or adverse events of special interest (anaphylaxis, thromboembolic events, and bleeding events) were observed., Interpretation: Garadacimab 200 mg and 600 mg every 4 weeks significantly reduced the number of monthly attacks versus placebo and was well tolerated during the study. Garadacimab is an efficacious, subcutaneous prophylaxis in patients with HAE-C1-INH and warrants phase 3 evaluation., Funding: CSL Behring., Competing Interests: Declaration of interests TC is a speaker for Pharming, CSL Behring, Takeda, Fresenius Kabi, and Grifols; has received research and consultancy grants from CSL Behring, Takeda, BioCryst, Ionis, Spark, BioMarin, Fresenius Kabi, and Grifols; and is on the medical advisory board for the US Hereditary Angioedema Association, the Board of Directors for the Mid-Atlantic American Lung Association, and the Board of Directors for the American Academy of Allergy, Asthma and Immunology. EA-P has received honoraria as a speaker or advisor from Adverum Biotechnologies, BioCryst, BioMarin, Centogene, CSL Behring, KalVista, Pharming, Pharvaris, and Shire/Takeda; and has received grants or clinical trial investigator support from BioCryst, CSL Behring, KalVista, Pharvaris, and Shire/Takeda. PB has consulted for CSL Behring, Takeda, Pharming, Pearl Therapeutics, BioCryst, CVS Health, Novartis, AstraZeneca and GlaxoSmithKline; and has received clinical trial support from CSL Behring, Takeda, BioCryst, and Novartis. MKD and DP are former full-time employees of CSL Behring and own stocks in CSL Behring. HF, IJ, and IP are full-time employees of CSL Behring and own stocks in CSL Behring. JSJ is a speaker for Takeda/Shire, CSL Behring, Teva, AstraZeneca, GlaxoSmithKline, Sanofi Genzyme, and Regeneron; and has received research funding or consultancy fees from CSL Behring, Takeda/Shire, BioCryst, Novartis, Genentech, AstraZeneca, Allakos, Fresenius Kabi, GlaxoSmithKline, and Regeneron. PKK is or recently was a speaker or an advisor for ALK Pharma, AstraZeneca, CSL Behring, GlaxoSmithKline, Kaleo, Merck, Mylan, Novartis, Pediapharm/Medexus, Sanofi and Takeda/Shire; and has received research funding from CSL Behring, Green Cross, and Takeda/Shire. DSL is a speaker, researcher, and consultant for CSL Behring, Takeda, Pharming, BioCryst, and Grifols. WRL is a speaker for CSL Behring, Pharming, AstraZeneca, Sanofi/Regeneron, GlaxoSmithKline, and Shire/Takeda; has served as a consultant for BioCryst, BioMarin, CSL Behring, Fresenius Kabi, Intellia, KalVista, Pharming, Pharvarius, and Shire/Takeda; is a board member of the US Hereditary Angioedema Association Medical Advisory Board; and has received grants or research support from ALK, BioCryst, CSL Behring, Ionis, Gossamer, KalVista, Kedrion, Therapure, and Takeda/Shire. MM has received financial support from CSL Behring for acting as a study centre investigator during the conduct of the study, and personal fees from CSL Behring, Shire/Takeda, Pharming, BioCryst, Novartis, Octapharma, and KalVista. IM-S has received honoraria, research funding, and travel grants from BioCryst, CSL Behring, Pharming, Octapharma, KalVista, and Takeda/Shire. IM-S served as a consultant for BioCryst, CSL Behring, Pharming, Octapharma, KalVista, and Takeda/Shire; and participated in advisory boards for BioCryst, CSL Behring, Pharming, Octapharma, KalVista, and Takeda/Shire. AR is a speaker, researcher, and advisor for CSL Behring, Takeda/Shire, BioCryst, Pharming, and Shulov Innovative Science. BR has been a speaker and advisory board member for CSL Behring and Takeda and has not received personal reimbursement for these activities; has participated in multiple clinical trials involving investigational drugs for CSL Behring, Takeda, BioCryst, Dyax, and Pharming and he does not hold patents or investments with these companies or involving this product; and he serves as a volunteer medical scientific advisor to the patient organisation Hereditary Angioedema Canada. WHY has received fees for consulting services from CSL Behring, Takeda/Shire, Novartis, Sanofi Genzyme, and Merck, and research grants from CSL Behring, Takeda/Shire, BioCryst, Pharming, AstraZeneca, Novartis, Sanofi Genzyme, Regeneron, Galderma, AnaptysBio, Glenmark, ALK Pharma, and Dermira., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: In the emergency department, patients with laryngeal swelling and an inconclusive patient history may receive treatment for allergy-mediated angioedema. Intubation may be necessary if the patient does not respond to treatment. Because angioedema subtypes respond to different interventions, a correct diagnosis is vital., Objectives: Review the differential diagnosis of angioedema and characteristics differentiating subtypes. Discuss therapies for angioedema subtypes. Introduce therapies for prevention and acute treatment of hereditary angioedema (HAE)., Case Report: A 10-year-old girl presented with laryngeal swelling unresponsive to diphenhydramine, methylprednisolone, and epinephrine. It was later revealed that she had a family history of HAE, was C1 inhibitor deficient, and enrolled in a clinical study of acute HAE treatment. She was given 1000 units of nanofiltered C1 inhibitor and was able to swallow within 30 min. She was prescribed routine prophylaxis with C1 inhibitor concentrate and has had no subsequent severe HAE swelling attacks., Conclusion: This case illustrates the need for providers to consider HAE in light of available diagnostic testing and recent Food and Drug Administration approval of specific therapies for HAE., (Copyright © 2012 Elsevier Inc. All rights reserved.)