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BackgroundHereditary angioedema (HAE) due to C1 inhibitor deficiency manifests as recurrent swelling attacks that can be disabling and sometimes fatal. Long-term prophylaxis with twice-weekly intravenous injections of plasma-derived C1-inhibitor (pdC1-INH) has been established as an effective treatment. Subcutaneous (SC) administration of pdC1-INH has not been studied in patients with HAE.MethodsThis open-label, dose-ranging, crossover study (COMPACT Phase II) was conducted in 18 patients with type I or II HAE who received two of twice-weekly 1500, 3000, or 6000 IU SC doses of highly concentrated volume-reduced CSL830 for 4 weeks each. The mean trough plasma levels of C1-INH functional activity, C1-INH and C4 antigen levels during Week 4, and overall safety and tolerability were evaluated. The primary outcome was model-derived steady-state trough C1-INH functional activity.ResultsAfter SC CSL830 administration, a dose-dependent increase in trough functional C1-INH activity was observed. C1-INH and C4 levels both increased. The two highest dose groups (3000 and 6000 IU) achieved constant C1-INH activity levels above 40% values, a threshold that was assumed to provide clinical protection against angioedema attacks. Compared with intravenous injection, pdC1-INH SC injection with CSL830 showed a lower peak-to-trough ratio and more consistent exposures. All doses were well tolerated. Mild-to-moderate local site reactions were noted with pain and swelling being the most common adverse event.ConclusionsSubcutaneous volume-reduced CSL830 was well tolerated and led to a dose-dependent increase in physiologically relevant functional C1-INH plasma levels. A clinical outcome study of SC CSL830 in patients with HAE warrants further investigation.

Background: Garadacimab is a fully human immunoglobulin G4 monoclonal antibody targeting activated factor XII. This study evaluated long-term efficacy, health-related quality of life (HRQoL), and safety data for garadacimab in adults with hereditary angioedema., Methods: This global phase 2 study comprised a treatment period 1 (TP1: 12 weeks, double-blind, placebo-controlled) and a treatment period 2 (TP2: ≥44-week open-label extension). Patients aged 18-65 years with clinically confirmed hereditary angioedema were eligible. In TP1, 32 patients were randomly assigned (1:1:1:1) to receive subcutaneous garadacimab (75 mg, 200 mg, or 600 mg) or placebo every 4 weeks (once monthly). Randomisation was done using interactive response technology via block randomisation (block sizes 1-4). Subsequently, six additional patients in TP1 were assigned to open-label garadacimab 400 mg every 2 weeks. At the start of TP2, patients were re-randomised (if receiving placebo, garadacimab 75 mg, or garadacimab 400 mg) or continued to receive garadacimab 200 mg or garadacimab 600 mg once monthly. After a protocol amendment on March 20, 2020, patients originally assigned to the 600 mg dose were down-titrated to 200 mg at their next visit. The primary endpoint (published previously) was monthly attack rate for patients receiving 200 mg or 600 mg garadacimab in TP1 in the intention-to-treat population. Here, we assessed the impact of garadacimab on patient-reported and investigator-reported outcomes and HRQoL as well as long-term efficacy and safety. This trial is registered with ClinicalTrials.gov, NCT03712228, and is completed., Findings: Of 54 patients screened between Oct 29, 2018, and Aug 28, 2019, 32 randomised and six open-label patients completed TP1 and entered TP2 (20 in the garadacimab 200 mg group; 18 in the garadacimab 600 mg group; total 38 patients). Median age was 39·0 years (IQR 27·0-53·0), and 21 patients (55%) were female and 17 (45%) were male. In TP2, the median garadacimab exposure was 87·9 weeks (IQR 50·0-106·6) in the garadacimab 200 mg group and 44·1 weeks (24·1-56·1) in the garadacimab 600 mg group. Median monthly attack rates were 0·0 (IQR 0·0-0·1) in the garadacimab 200 mg group and 0·1 (0·0-0·4) in the garadacimb 600 mg group. Median reduction in monthly attack rate versus run-in was 100% (IQR 98-100) with garadacimab 200 mg. HRQoL improvements observed during TP1 with garadacimab were sustained throughout TP2. TP2 safety signals were consistent with TP1. Two patients experienced serious adverse events of diverticular perforation and asthma (not garadacimab-related). Treatment-emergent adverse events were mostly mild or moderate in severity. The most common adverse events were headache (nine of 38, 24%) and abdominal pain (seven of 38, 18%). There were no treatment-related deaths., Interpretation: Once-monthly garadacimab for more than 2 years in patients with hereditary angioedema was well tolerated and efficacious in reducing monthly attack rate and improving HRQoL. These results reveal the potential of long-term prophylactic treatment with 200 mg once-monthly garadacimab towards complete disease control of patients with hereditary angioedema., Funding: CSL Behring., Competing Interests: Declaration of interests TJC is a speaker for CSL Behring, Takeda, BioMarin, Astria, Regeneron, and Grifols, and has received research and consultancy grants from CSL Behring, Takeda, BioCryst, Ionis, BioMarin, Intellia, KalVista, Pharvaris, Ionis, Astria, and GlaxoSmithKline; he is on the Medical Advisory Board for the US Hereditary Angioedema Association and is Director of the Angioedema Centers of Reference and Excellence International Angioedema Center at Penn State University, Hershey, PA, USA. DSL received research grants from, and is a speaker and consultant for, CSL Behring, Takeda, BioCryst, Grifols, Pharming, and KalVista. AR received research grants as a principal investigator, speaker, and adviser for CSL Behring, Takeda/Shire, BioCryst, Pharming, Pharvaris, Ionis, and Shulov Innovative Science. WRL is a speaker for CSL Behring, Pharming, AstraZeneca, Sanofi and Regeneron, GlaxoSmithKline, and Takeda/Shire, and has served as a consultant for BioCryst, BioMarin, CSL Behring, Fresenius Kabi, Intellia, KalVista, Pharming, Pharvaris, and Takeda/Shire; WRL is also 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. IM-S 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. 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. WHY has been a speaker and advisory board member for, and has received honoraria from, CSL Behring, Takeda/Shire, Novartis, Sanofi Genzyme, and Merck; he has received research grants from CSL Behring, Takeda/Shire, BioCryst, Pharming, Aimmune, DBV Technologies, Eli Lilly, Pharvaris, AstraZeneca, Novartis, GlaxoSmithKline, Genentech/Roche, Amgen, Sanofi Genzyme, Regeneron, Galderma, AnaptysBio, Glenmark, ALK, Dermira, Ionis, and Celgene; and he also serves as a medical adviser (volunteer) for Hereditary Angioedema Canada, a patient organisation, and is a member of ACARE. BR has been a speaker and advisory board member for CSL Behring and Takeda but has not received personal reimbursement for these activities; he has participated in multiple clinical trials involving investigational drugs for CSL Behring, Takeda, BioCryst, Dyax, and Pharming; and he serves as a volunteer medical scientific adviser to Hereditary Angioedema Canada, a patient organisation. EA-P has received honoraria as a speaker, adviser, or as grant support or clinical trial investigator support from Astria Therapeutics, BioCryst, BioMarin Europe, Centogene, CSL Behring, Intellia, KalVista, Pharming Technologies, Pharvaris, and Takeda/Shire. PKK has been a speaker, advisory board member, or consultant for, and has received honoraria from, ALK, AstraZeneca, Bausch, BioCryst, Canadian Agency for Drugs and Technologies in Health, Canadian Pharmacists Association, CSL Behring, GlaxoSmithKline, Medexus, Merck, Novartis, Sanofi Genzyme, Takeda/Shire, and Valeo; has received research grants from CSL Behring and Takeda/Shire; serves as a medical adviser (volunteer) for Hereditary Angioedema Canada, a patient organisation; serves as a board member (volunteer) for the Canadian Hereditary Angioedema Network, a physician organisation; and is an employee of McMaster University. PB has been a speaker, advisory board member, or consultant for, and has received honoraria from, BioMarin, BioCryst, CSL Behring, CVS Specialty, Ionis, KalVista, Medscape, Novartis, Pharvaris, Prime, Regeneron, and Takeda; and has received research funding from CSL Behring, KalVista, and Takeda. MM has received financial support from CSL Behring for acting as a study-centre investigator during the conduct of the study, and consulting fees from CSL Behring, Takeda/Shire, Pharming Technologies, BioCryst, Novartis, Octapharma, and KalVista outside of the submitted work. At the time of the study, HF, MAB, IJ, and IP were employees of CSL Behring Innovation GmbH (HF, MAB, IP) or CSL Behring LLC (IJ) and shareholders of CSL Ltd., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

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: Hereditary angioedema (HAE) due to C1-inhibitor (C1-INH) deficiency is a rare genetic disorder characterized by disabling episodes of edema that commonly affect the skin as well as the gastrointestinal tract and upper airway. Prophylactic therapy can decrease the severity and number of attacks. Long-term symptom control and rescue medication use were evaluated in patients with HAE who received subcutaneous (SC) C1-INH enrolled in an open-label extension (OLE) of the phase III COMPACT (Clinical Studies for Optimal Management of Preventing Angioedema with Low-Volume Subcutaneous C1-Inhibitor Replacement Therapy) trial, including a subgroup analysis of patients treated for ≥12 months. Methods: The OLE study evaluated patients ≥ 6 years old who had had four or more attacks over 2 consecutive months before enrollment. Patients naive for C1-INH (SC) and patients in the COMPACT rollover trial were included. The patients were randomized to receive C1-INH (SC) 40 or 60 IU/kg twice weekly for 52 weeks. U.S. patients were eligible to continue for up to 140 weeks. Results: A total of 63 patients were randomized to the U.S. Food and Drug Administration approved dose of 60 IU/kg; 24 subjects were treated for at least 12 months. For the 63 subjects, the median (range) attacks per month were 0.09 (0.0-4.0) and per year were 1.0 (0.0-48.0). Two-thirds of the patients used rescue medication fewer than once per year. For the 24 patients with ≥ 12 months of exposure, the median (range) attacks per month and per year were 0.017 (0.000-2.4) and 0.199 (0.000-28.94), respectively. Of these patients, 12 (50%) were attack free throughout the duration of the study, and 3 (12.5%) had fewer than one attack per year. Conclusion: Prophylaxis with C1-INH (SC) provided sustained reductions in attack frequency and decreased rescue medication use, with a substantial proportion of patients being attack free.

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.)

Factor XII (FXII) is the principal initiator of the plasma contact system and has proinflammatory and prothrombotic activities. This single-center, first-in-human phase I study aimed to assess the safety and tolerability of single escalating doses of garadacimab, a monoclonal antibody that specifically inhibits activated FXII (FXIIa), in healthy male volunteers. Volunteers were randomized to eight cohorts, with intravenous (i.v.) doses of 0.1, 0.3, 1, 3, and 10 mg/kg and subcutaneous (s.c.) doses of 1, 3, and 10 mg/kg. Six volunteers in each cohort received garadacimab or placebo in a ratio of 2:1. Follow-up for safety lasted 85 days after dosing. Blood samples were collected throughout for pharmacokinetic/pharmacodynamic analysis. Forty-eight volunteers were enrolled: 32 received garadacimab and 16 received placebo. Most volunteers experienced at least one treatment-emergent adverse event (TEAE), predominantly grade 1. No serious TEAEs, deaths, or TEAEs leading to discontinuation were reported. No volunteers tested positive for garadacimab antidrug antibodies. Garadacimab plasma concentrations increased in a dose-dependent manner. Sustained inhibition of FXIIa-mediated kallikrein activity beyond day 28 resulted from 3 and 10 mg/kg garadacimab (i.v. and s.c.). A dose-dependent increase in activated partial thromboplastin time with no change in prothrombin time was demonstrated. Garadacimab (single-dose i.v. and s.c.) was well-tolerated in healthy volunteers. Dose-dependent increases in plasma concentration and pharmacodynamic effects in relevant kinin and coagulation pathways were observed. These results support the clinical development of garadacimab, including in phase II studies in hereditary angioedema and coronavirus disease 2019 (COVID-19)., (© 2021 CSL Behring LLC. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: Patients aged 65 years and older with hereditary angioedema (HAE) owing to C1-inhibitor (C1-INH) deficiency may have an altered response to treatment and are at higher risk for treatment-related adverse events (AEs) because of comorbidities and polypharmacy., Objective: To investigate the safety and efficacy of subcutaneous C1 esterase inhibitor (C1-INH) in patients aged 65 years and older treated in an open-label extension of a phase 3 trial., Methods: Eligible patients (≥4 attacks for more than 2 consecutive months) were randomized to receive twice-weekly subcutaneous C1-INH with a dosage of 40 IU/kg or 60 IU/kg for 52 to 140 weeks. Safety end points and efficacy outcomes were evaluated for patients aged 65 years and above and younger than 65 years., Results: Of the 126 patients treated, 10 were 65 years and older (mean age [range], 68 [65-72 years]). A total of 8 of 10 patients had multiple comorbidities, and 6 of these 10 patients were taking more than 5 non-HAE-related drugs concomitantly. AEs occurring in more than 1 patient included injection site bruising (n = 2, related), injection site pain (n = 2, related), urinary tract infection (n = 2, unrelated), and diarrhea (n = 2, unrelated). No thromboembolic events or cases of anaphylaxis were reported. Two patients aged 65 years and older experienced unrelated serious AEs (dehydration and hypokalemia in 1 and pneumonia and an HAE attack leading to hospitalization in another). A total of 6 of 9 evaluable patients were responders, with a greater than or equal to 50% reduction in HAE attacks vs prestudy; 6 of 10 patients had less than 1 attack over 4 weeks and 3 were attack-free (median attack rate, 0.52 attacks per month)., Conclusion: Subcutaneous C1-INH was well-tolerated and effective in the management of HAE in patients aged 65 years and older with multiple comorbid conditions and polypharmacy., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Hereditary angioedema (HAE) due to C1 inhibitor (C1INH) deficiency is characterized by recurrent attacks of edema of the skin and mucosal tissues. Symptoms usually present during childhood (mean age at first attack, 10 years). Earlier symptom onset may predict a more severe disease course. Subcutaneous (SC) C1INH is indicated for routine prophylaxis to prevent HAE attacks in adolescents and adults. We analyzed the long-term efficacy of C1INH (SC) in subjects ≤17 years old treated in an open-label extension (OLE) of the pivotal phase III Clinical Study for Optimal Management of Preventing Angioedema with Low-Volume Subcutaneous C1 Inhibitor Replacement Therapy (COMPACT) trial. Methods: Eligible subjects (age ≥6 years, with ≥4 attacks over 2 consecutive months before entry into the OLE or placebo-controlled COMPACT trial) were treated with C1INH (SC) 40 or 60 IU/kg twice weekly for 52-140 weeks. Subgroup analyses by age (≤17 vs. >17 years) were performed for key efficacy endpoints. Results: Ten subjects were ≤17 years old [mean (range) age, 13.3 (8-16) years, 3 subjects <12 years old; exposure range, 51-133 weeks]. All 10 pediatric subjects experienced ≥50% reduction (mean, 93%) in number of attacks versus the prestudy period, with a 97% reduction in the median number of attacks/month (0.11). All subjects had <1 attack/4-week period and 4 had <1 attack/year (1 subject was attack free). No subject discontinued treatment due to a treatment-related adverse event. Conclusions: Data from pediatric subjects treated with C1INH (SC) for up to 2.55 years and adult subjects revealed similar efficacy. C1INH (SC) is effective and well tolerated as long-term prophylaxis in children, adolescents, and adults with HAE., Competing Interests: Donald S. Levy, is a consultant with Takeda, Biocryst, CSL Behring, Pharming; is a speaker for Takeda and CSL Behring; has received clinical research grants from CSL Behring. Teresa Caballero has received grant research, grant support and/or speaker/consultancy fees from BioCryst, CSL Behring, Merck, Novartis, Octapharma, Pharming, and Shire (a Takeda company); has received funding to attend conferences/educational events from CSL Behring, Novartis and Shire; is/has been a clinical trial/registry investigator for Biocryst, CSL Behring, Novartis, Pharming and Shire; and is a researcher from the IdiPAZ program for promoting research activities. Iftikhar Hussain is a speaker for CSL Behring, Grifols, and Optionse; is/has been on the advisory board for Blueprint Medicine and Pfizer; is Principal Investigator for Adare, Sanofi, Cara Therapeutics, Dermira, Lilly, Pfizer, Abbvie, CSL Behring, Astra-Zeneca, and Genentech, ALK. Avner Reshef has received research funding, travel grants, and/or speaker honorarium-consultation fee from CSL-Behring, Pharming, BioCryst, Takeda-Shire, Teva, Stallergens. John Anderson has potential conflicts of interest with CSL Behring, Takeda, BioCryst. James Baker has no conflicts of interest. Lawrence B. Schwartz is/has been HAE clinical trial principal investigator for CSL Behring and Takeda; is/has been on the advisory board for CSL Behring LLC, Takeda Pharmaceuticals, Pharming Healthcare, and BioCryst Pharmaceuticals. Marco Cicardi has potential conflicts of interest with CSL Behring, Shire, and Pharming. Subhransu Prusty, Henrike Feuersenger, and Ingo Pragst are/have been CSL Behring employees. Michael Manning has received grant support from CSL Behring, Takeda/Shire, BioCryst, and KalVista; is a speaker for CSL Behring, Takeda/Shire, and Pharming; is a consultant with and on the advisory boards for CSL Behring, Takeda/Shire, BioCryst, and Pharming., (© Donald Levy et al., 2020; Published by Mary Ann Liebert, Inc.)

Background: Women with hereditary angioedema due to C1-inhibitor deficiency (HAE-C1INH) experience more frequent and severe angioedema attacks compared with men. Fluctuations in female sex hormones can influence HAE attack frequency and severity. Subcutaneous C1-INH (C1-INH [SC]) is indicated as routine prophylaxis to prevent HAE attacks. In this post hoc subgroup analysis, we evaluated the efficacy and safety of C1-INH (SC) in female subjects with HAE-C1INH enrolled in an open-label extension of the pivotal phase III COMPACT trial., Methods: In this multicenter, randomized, parallel-arm trial, eligible subjects (age ≥ 6 years with ≥ 4 attacks over 2 consecutive months) received C1-INH (SC) 40 IU/kg or 60 IU/kg twice weekly for 52 to 140 weeks. Analyses of efficacy endpoints were performed for all female subjects and those of childbearing age (age ≥ 15 to ≤ 45 years), including subjects who became pregnant during the evaluation period., Results: Overall, 91% (69/76) of female subjects were classified as responders (≥ 50% reduction in HAE attacks relative to the pre-study period); 82% experienced < 1 attack/4 weeks. The median number of attacks/month was 0.10, with 96% median reduction in attacks relative to the pre-study period. Results were similar in the subgroup of subjects of childbearing age. Four women who became pregnant during the trial and were exposed to C1-INH (SC) during the first trimester delivered healthy babies with no congenital abnormalities., Conclusions: C1-INH (SC) prophylaxis was safe and effective in women with HAE-C1INH, including those of childbearing age. Four women exposed to C1-INH (SC) during the first trimester had uneventful pregnancies and delivered healthy babies. Trial registration Clinicaltrials.gov identifier NCT02316353 (Registered December 10, 2014); https://clinicaltrials.gov/ct2/show/NCT02316353., Competing Interests: Competing interestsD. Levy has served on the speaker’s bureau, as a consultant, on a steering committee, and as a clinical investigator for CSL Behring; consultant for BioCryst; and speaker for Takeda. H. Farkas received institutional support for a clinical trial for this study from CSL Behring; advisory board/consultancy fees and/or speaker’s honoraria from BioCryst, CSL Behring, Shire, and Sobi (Swedish Orphan Biovitrum); and travel support from CSL Behring. M. Riedl reports grant support from CSL Behring during the conduct of the study and has received research grants from BioCryst, CSL Behring, Dyax, Ionis Pharmaceuticals, Pharming Technologies, and Shire; has served as a consultant and/or speaker for Adverum Biotechnologies, Alnylam Pharmaceuticals, Arrowhead Pharmaceuticals, BioCryst, CSL Behring, Dyax, Global Blood Therapeutics, Ionis Pharmaceuticals, KalVista Pharmaceuticals, Pharming Technologies, Salix Pharmaceuticals, and Shire; and is an uncompensated advisory board member for the US Hereditary Angioedema Association, outside the submitted work. F. Hsu reports serving as a consultant for BioCryst; serving as a speaker for CSL Behring, Pharming Technologies BV, and Takeda Pharmaceutical Company Ltd; and performing contracted research for Hoffman-La Roche. J.P. Brooks declares that he has no competing interests. M. Cicardi received grants from Shire and personal fees from Alnylam, BioCryst, CSL Behring, Dyax, KalVista, Pharming Technologies, Shire, Sobi (Swedish Orphan Biovitrum), and ViroPharma. H. Feuersenger and I. Pragst are employees of CSL Behring. A. Reshef reports grant support from CSL Behring during the conduct of the study and has received grant support from Pharming., (© The Author(s) 2020.)

Background: Hereditary angioedema (HAE) is a debilitating disorder resulting from C1-esterase inhibitor (C1-INH) deficiency. In the COMPACT phase 3 study the prophylactic use of a subcutaneous C1 inhibitor (C1-INH [SC], HAEGARDA ® , CSL Behring) twice weekly significantly reduced the frequency of acute edema attacks. Analysis of treatment effects by subgroups, onset of effect, and other exploratory analysis have not been reported., Methods: This is a post hoc exploratory analysis on data from the randomized, placebo-controlled COMPACT study. 90 patients with C1-INH-HAE were randomized to 1 of 4 treatment sequences: C1-INH (SC) 40 or 60 IU/kg of body weight twice weekly for 16 weeks, preceded or followed by a placebo period. The pre-specified primary efficacy endpoint was the time-normalized number of HAE attacks, and pre-specified secondary efficacy endpoints were the percentage of patients with a certain treatment response (≥ 50% reduction on C1-INH (SC) versus placebo in the time-normalized number of attacks) and the time-normalized number of use of rescue medication. Pre-specified exploratory endpoints included severity of attacks, alone and combined with rescue medication use. Post hoc analyses included exploration of onset of effect and clinical assessment of patients with < 50% of response., Results: Subgroup findings by various patient characteristics showed a consistent preventive effect of C1-INH (SC). In a post hoc analysis of attacks, the onset of the preventive effect within the first 2 weeks after treatment initiation in COMPACT showed that 10/43 patients (23%) experienced attacks of any severity with 60 IU/kg versus 34/42 patients (81%) with placebo. The need for rescue medication was tenfold lower with 60 IU/kg (35 treated attacks) versus placebo (358 treated attacks). A qualitative analysis of the 4 patients treated with 60 IU/kg and with < 50% reduction of attacks demonstrated a reduction in severity of attacks, rescue medication use, and symptom days which was considered a clinically meaningful treatment effect., Conclusions: C1-INH (SC) prophylaxis demonstrated a preventive treatment effect with evidence of benefit within 2 weeks. A consistent treatment effect at recommended C1-INH (SC) dosing was evident in all subgroups of patients with type I/II HAE and by various measures of disease and treatment burden. Trial registration EU Clinical Trials Register, 2013-000916-10, Registered 10 December 2013, https://www.clinicaltrialsregister.eu/ctr-search/trial/2013-000916-10; ClinicalTrials.gov Register, NCT01912456, Registered 31 July 2013, https://clinicaltrials.gov/ct2/show/NCT01912456., Competing Interests: Competing interestsHHL received institutional support from CSL Behring for the conduct of this study, and travel expenses and/or consultancy fees and speaker’s honoraria from CSL Behring, Shire/Dyax/ViroPharma, and Salix/Pharming. TC is a speaker for CSL Behring, Grifols and Dyax/Shire. He performs research for BioCryst, Boehringer Ingelheim, CSL Behring, Genentech, GlaxoSmithKline, Grifols, Merck, Novartis, Pharming, Sanofi, and Shire. He has received consultancy fees and/or speaker’s honoraria from BioCryst, Bellrose, CSL Behring, Dyax, Merck, Novartis, Pharming Technologies, and Shire, and has received non-financial support from CSL Behring, Shire, and Grifols. BZ reports grant support from the Department of Defense and consultancy fees from Alnylam, Arrowhead Pharmaceuticals, BioCryst Pharmaceuticals, Nektar, CSL Behring, and Shire, and led the Scientific Steering Committee for this study. HJL has received grant support from CSL Behring, consultancy fees, and speaker’s honoraria from CSL Behring, Pharming, and Shire, and travel support from CSL Behring. MC has received grants from Shire and personal fees from Alnylam, BioCryst Pharmaceuticals, CSL Behring, Dyax, KalVista Pharming Technologies, Shire, Sobi (Swedish Orphan Biovitrum), and ViroPharma. KB reports personal fees from CSL Behring and Shire, outside the submitted work. HB received consultancy fees and speaker’s honoraria from CSL Behring, Pharming, and Shire. WL reports grant support from BioCryst Pharmaceuticals, CSL Behring, and Shire/Viropharma/Dyax; consultancy fees paid to his institution from Adverum, BioCryst Pharmaceuticals, CSL Behring, Pharming Technologies, and Shire/Virophama/Dyax; speaker’s fees from Pharming Technologies, Shire/Viropharma and CSL Behring; and non-financial support from the US Hereditary Angioedema Association outside the submitted work. JB reports grant support and personal fees from BioCryst Pharmaceuticals, CSL Behring, and Shire, outside the submitted work. MM reports grant support and consultant/speaker’s fees from CSL Behring, Shire, Dyax, and Shire; and personal fees from Salix and Pharming Technologies, outside the submitted work. DL has served on the speaker’s bureau, as a consultant, on a steering committee, and as a clinical investigator for CSL Behring. MR has received research grants from BioCryst Pharmaceuticals, CSL Behring, Dyax, Pharming Technologies, and Shire; consultant fees from Adverum Biotechnologies, Alnylam Pharmaceuticals, BioCryst Pharmaceuticals, CSL Behring, Global Blood Therapeutics, Ionis Pharmaceuticals, KalVista Pharmaceuticals, Pharming Technologies, and Shire; speaker’s honoraria from CSL Behring, Shire, and Pharming; and is an uncompensated advisory board member for the US Hereditary Angioedema Association. TM, SP HF and IP are employees of CSL Behring.

Background: For the prevention of attacks of hereditary angioedema (HAE), the efficacy and safety of subcutaneous human C1-esterase inhibitor (C1-INH[SC]; HAEGARDA, CSL Behring) was established in the 16-week Clinical Study for Optimal Management of Preventing Angioedema with Low-Volume Subcutaneous C1-Inhibitor Replacement Therapy (COMPACT)., Objective: To assess the long-term safety, occurrence of angioedema attacks, and use of rescue medication with C1-INH(SC)., Methods: Open-label, randomized, parallel-arm extension of COMPACT across 11 countries. Patients with frequent angioedema attacks, either study treatment-naive or who had completed COMPACT, were randomly assigned (1:1) to 40 IU/kg or 60 IU/kg C1-INH(SC) twice per week, with conditional uptitration to optimize prophylaxis (ClinicalTrials.gov registration no. NCT02316353)., Results: A total of 126 patients with a monthly attack rate of 4.3 in 3 months before entry in COMPACT were enrolled and treated for a mean of 1.5 years; 44 patients (34.9%) had more than 2 years of exposure. Mean steady-state C1-INH functional activity increased to 66.6% with 60 IU/kg. Incidence of adverse events was low and similar in both dose groups (11.3 and 8.5 events per patient-year for 40 IU/kg and 60 IU/kg, respectively). For 40 IU/kg and 60 IU/kg, median annualized attack rates were 1.3 and 1.0, respectively, and median rescue medication use was 0.2 and 0.0 times per year, respectively. Of 23 patients receiving 60 IU/kg for more than 2 years, 19 (83%) were attack-free during months 25 to 30 of treatment., Conclusions: In patients with frequent HAE attacks, long-term replacement therapy with C1-INH(SC) is safe and exhibits a substantial and sustained prophylactic effect, with the vast majority of patients becoming free from debilitating disease symptoms., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The first subcutaneous (SC) C1-esterase inhibitor concentrate (C1-INH) was approved by the U.S. Food and Drug Administration in June 2017 as routine prophylaxis to prevent hereditary angioedema attacks in adolescents and adults at a dose of 60 IU/kg twice weekly based on the phase III Clinical Study for Optimal Management of Preventing Angioedema With Low-volume Subcutaneous C1-Inhibitor Replacement Therapy (COMPACT) trial., Objective: This article aimed to evaluate the relationship of the C1-INH (SC) dose regimens tested in the COMPACT trial (40 IU/kg and 60 IU/kg twice weekly) and the occurrence of adverse events (AEs)., Methods: Patients were instructed to record any AEs in their e-diary daily. Safety and tolerability were assessed based on reported AEs, including injection-site reactions (ISRs); unsolicited AEs (AEs other than ISRs); serious AEs; thrombotic, thromboembolic, anaphylactic, hypersensitivity, sepsis, and bacteremia events; inhibitory antibodies to C1-INH; and clinically significant abnormalities in laboratory assessments. Information on ISRs was specifically solicited., Results: No relationship between the dose of C1-INH (SC) and the incidence of ISRs or unsolicited AEs was observed. The proportion of injections followed by at least one ISR was 12% with C1-INH (SC) 40 IU/kg versus 5% with 60 IU/kg and 6% with placebo. No ISRs were serious or led to treatment discontinuation, and all resolved. There were no anaphylaxis, thromboembolic, sepsis, or bacteremia events reported during treatment with C1-INH (SC). All hypersensitivity AEs were nonserious, and the majority were assessed as being unrelated to treatment. No inhibitory antibodies to C1-INH were observed., Conclusion: C1-INH (SC) is safe and well tolerated with no dose-dependent safety concerns, as demonstrated in the COMPACT trial.Clinical trial NCT01912456, www.clinicaltrials.gov.

Background: Hereditary angioedema is a disabling, potentially fatal condition caused by deficiency (type I) or dysfunction (type II) of the C1 inhibitor protein. In a phase 2 trial, the use of CSL830, a nanofiltered C1 inhibitor preparation that is suitable for subcutaneous injection, resulted in functional levels of C1 inhibitor activity that would be expected to provide effective prophylaxis of attacks., Methods: We conducted an international, prospective, multicenter, randomized, double-blind, placebo-controlled, dose-ranging, phase 3 trial to evaluate the efficacy and safety of self-administered subcutaneous CSL830 in patients with type I or type II hereditary angioedema who had had four or more attacks in a consecutive 2-month period within 3 months before screening. We randomly assigned the patients to one of four treatment sequences in a crossover design, each involving two 16-week treatment periods: either 40 IU or 60 IU of CSL830 per kilogram of body weight twice weekly followed by placebo, or vice versa. The primary efficacy end point was the number of attacks of angioedema. Secondary efficacy end points were the proportion of patients who had a response (≥50% reduction in the number of attacks with CSL830 as compared with placebo) and the number of times that rescue medication was used., Results: Of the 90 patients who underwent randomization, 79 completed the trial. Both doses of CSL830, as compared with placebo, reduced the rate of attacks of hereditary angioedema (mean difference with 40 IU, -2.42 attacks per month; 95% confidence interval [CI], -3.38 to -1.46; and mean difference with 60 IU, -3.51 attacks per month; 95% CI, -4.21 to -2.81; P<0.001 for both comparisons). Response rates were 76% (95% CI, 62 to 87) in the 40-IU group and 90% (95% CI, 77 to 96) in the 60-IU group. The need for rescue medication was reduced from 5.55 uses per month in the placebo group to 1.13 uses per month in the 40-IU group and from 3.89 uses in the placebo group to 0.32 uses per month in the 60-IU group. Adverse events (most commonly mild and transient local site reactions) occurred in similar proportions of patients who received CSL830 and those who received placebo., Conclusions: In patients with hereditary angioedema, the prophylactic use of a subcutaneous C1 inhibitor twice weekly significantly reduced the frequency of acute attacks. (Funded by CSL Behring; COMPACT EudraCT number, 2013-000916-10 , and ClinicalTrials.gov number, NCT01912456 .).

Background: The plasma-derived, pasteurized, nanofiltered C1-inhibitor concentrate (pnfC1-INH) is approved in the United States as an intravenous (IV) on-demand treatment for hereditary angioedema (HAE) attacks, and, in Europe, as on demand and short-term prophylaxis., Objective: This analysis evaluated Berinert Patient Registry data regarding IV pnfC1-INH used as long-term prophylaxis (LTP)., Methods: The international registry (2010-2014) collected prospective and retrospective usage, dosing, and safety data on individuals who used pnfC1-INH for any reason., Results: The registry included data on 47 subjects (80.9% female subjects; mean age, 44.8 years), which reflected 4082 infusions categorized as LTP and a total of 430.2 months of LTP administration. The median absolute dose of pnfC1-INH given for LTP was 1000 IU (range, 500-3000 IU), with a median time interval between infusion and a subsequent pnfC1-INH-treated attack of 72.0 hours (range, 0.0-166.4 hours). Fifteen subjects (31.9%) had no pnfC1-INH-treated HAE attacks within 7 days after pnfC1-INH infusion for LTP; 32 subjects (68.1%) experienced 246 attacks, with rates of 0.06 attacks per infusion and 0.57 attacks per month. A total of 81 adverse events were reported in 16 subjects (34.0%) (0.02 events per infusion; 0.19 events per month); only 3 adverse events were considered related to pnfC1-INH (noncardiac chest pain, postinfusion headache, deep vein thrombosis in a subject with an IV port)., Conclusion: In this international registry, IV pnf-C1-INH given as LTP for HAE was safe and efficacious, with a low rate of attacks that required pnfC1-INH treatment, particularly within the first several days after LTP administration.

Background: Limited data are available regarding C1 inhibitor (C1-INH) administration and anti-C1-INH antibodies., Objective: To assess the incidence of antibody formation during treatment with pasteurized, nanofiltered plasma-derived C1-INH (pnfC1-INH) in patients with hereditary angioedema with C1-INH deficiency (C1-INH-HAE) and the comparative efficacy of pnfC1-INH in patients with and without antibodies., Methods: In this multicenter, open-label study, patients with C1-INH-HAE (≥12 years of age) were given 20 IU/kg of pnfC1-INH per HAE attack that required treatment and followed up for 9 months. Blood samples were taken at baseline (day of first attack) and months 3, 6, and 9 and analyzed for inhibitory anti-C1-INH antibody (iC1-INH-Ab) and noninhibitory anti-C1-INH antibodies (niC1-INH-Abs)., Results: The study included 46 patients (69.6% female; mean age, 38.9 years; all white) who received 221 on-site pnfC1-INH infusions; most patients received 6 or fewer infusions. No patient tested positive (titer ≥1:50) for iC1-INH-Ab at any time during the study. Thirteen patients (28.2%) had detectable niC1-INH-Abs in 1 or more samples. Nine patients (19.6%) had detectable niC1-INH-Abs at baseline; 3 of these had no detectable antibodies after baseline. Of 10 patients (21.7%) with 1 or more detectable result for niC1-INH-Abs after baseline, 6 had detectable niC1-INH-Abs at baseline. Mean times to symptom relief onset and complete symptom resolution per patient were similar for those with or without anti-niC1-INH-Abs., Conclusion: Administration of pnfC1-INH was not associated with iC1-INH-Ab formation in this population. Noninhibitory antibodies were detected in some patients but fluctuated during the study independently of pnfC1-INH administration and appeared to have no effect on pnfC1-INH efficacy., Trial Registration: clinicaltrials.gov Identifier: NCT01467947., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The plasma-derived, highly purified, nanofiltered C1-inhibitor concentrate (Berinert; "pnfC1-INH") is approved in the United States for treating hereditary angioedema (HAE) attacks and in many European countries for attack treatment and short-term prophylaxis., Objective: The objective of this study was to describe safety and usage patterns of pnfC1-INH., Methods: A multicenter, observational, registry was conducted between 2010 and 2014 at 30 United States and 7 European sites to obtain both prospective (occurring after enrollment) and retrospective (occurring before enrollment) safety and usage data on subjects receiving pnfC1-INH for any reason., Results: Of 343 enrolled patients, 318 received 1 or more doses of pnfC1-INH for HAE attacks (11,848 infusions) or for prophylaxis (3142 infusions), comprising the safety population. Median dosages per infusion were 10.8 IU/kg (attack treatment) and 16.6 IU/kg (prophylaxis). Approximately 95% of infusions were administered outside of a health care setting. No adverse events (AEs) were reported in retrospective data. Among prospective data (n = 296 subjects; 9148 infusions), 252 AEs were reported in 85 (28.7%) subjects (rate of 0.03 events/infusion); 9 events were considered related to pnfC1-INH. Two thromboembolic events were reported in subjects with thrombotic risk factors. No patient was noted to have undergone viral testing for suspected blood-borne infection during registry participation., Conclusions: The findings from this large, international patient registry documented widespread implementation of pnfC1-INH self-administration outside of a health care setting consistent with current HAE guidelines. These real-world data revealed pnfC1-INH usage for a variety of reasons in patients with HAE and showed a high level of safety regardless of administration setting or reason for use., (Copyright © 2016. Published by Elsevier Inc.)

Background: Although treatment with C1 esterase inhibitor (C1-INH) concentrate is well established for hereditary angioedema (HAE) attacks in general, data that assess its efficacy for cutaneous attack treatment are sparse., Objective: To assess efficacy of plasma-derived, nanofiltered C1-INH concentrate for cutaneous attack treatment by comparing treated attacks from the uncontrolled I.M.P.A.C.T.2 study with historical data for untreated attacks., Methods: Cutaneous attack data from patients with HAE who were treated for cutaneous edema with 20 IU/kg body weight C1-INH concentrate in the uncontrolled I.M.P.A.C.T.2 study (38 patients) were compared with data from untreated patients from an historical data base (46 patients) and included subset analyses for facial edema (treated group, 21 patients; untreated group, 33 patients) and peripheral edema (30 patients in each group). Average attack duration (AAD) per patient was the efficacy end point used to compare treated and untreated patients. Differences were assessed with a Wilcoxon test (primary analysis) and a log-rank test; AAD per patient was analyzed descriptively and graphically with Kaplan-Meier curves., Results: The AAD per patient of all cutaneous attacks or facial and peripheral cutaneous attack subsets was significantly faster with C1-INH treatment than without treatment (Wilcoxon and log-rank tests, both p < 0.0001 for all comparisons). Mean AADs per patient for all, facial, and peripheral attacks were 2.04, 1.45, and 2.16 days, respectively, in the C1-INH-treated group, and were 3.74, 4.45, and 2.98 days, respectively, in the untreated group. Kaplan-Meier curves corroborated the observed group differences., Conclusion: Treatment of cutaneous HAE attacks (all attacks or facial and peripheral attack subsets) with 20 IU/kg C1-INH concentrate provided faster attack resolution compared with no treatment.

Background: Atrial fibrillation (AF) is the most common cardiac arrhythmia reducing the health-related quality of life. Radiofrequency catheter ablation (CA) became the therapy of choice in patients with drug-resistant AF with success rates between 30% and 86%. However, CA remains a challenging intervention with major complications in about 5% of cases. Therefore, stratification into high and low success patient groups would be helpful. The aim of this study was to investigate the predictive value of B-type natriuretic peptide (BNP) on the outcome of pulmonary vein isolation (PVI) in patients with paroxysmal (PAF) and persistent (Pers-AF) atrial fibrillation., Materials and Methods: In 73 patients (median age 53 years, 77% men) undergoing PVI for drug-refractory PAF (n = 45) or Pers-AF (n = 28), the serum BNP concentration was measured before and 3 months after the ablation procedure to assess any association of pre- and post-interventional BNP concentrations with therapeutic outcome. The patients had suffered from AF for a median of 40 months. No patient had structural heart disease or an impaired left-ventricular ejection fraction., Results: A total of 54 patients (74%) had stable sinus rhythm 3 months after PVI. The median baseline BNP levels in both PAF and Pers-AF patients were significantly lower in patients with a 3-month successful PVI than those in which it was unsuccessful, 57.5 pg/ml (20.4-87.9) versus 159.0 pg/ml (124.1-177.5; p = 0.001) in PAF patients and 90.3 pg/ml (41.0-155.0) versus 176 pg/ml (89.6-297.4; p = 0.026) in patients with Pers-AF, respectively. A multiple logistic regression analysis identified pre-interventional BNP levels as the only independent predictor for 3-month PVI outcomes (p = 0.010). Nevertheless, in this study, the predictive value of BNP for PVI outcomes was not high enough to permit individual outcome prediction. After successful PVI, BNP levels were significantly lower in patients with PAF and Pers-AF (median changes -16.9 and -23.8 pg/ml; p = 0.010 and p = 0.022, respectively), but not in patients with AF in follow-up (median change 9.0 pg/ml and -29.6 pg/ml; p = 1.000 and p = 0.109, respectively)., Conclusion: Pre-ablation BNP level seems to be an independent marker for successful PVI procedures in patients with paroxysmal and persistent AF; however, the observed level of association is moderate.