Medical Literature - 2022

Malchair P, Otero A, Giol J, Solanich X, Carnaval T, Fernandez-Nistal A, Sanchez-Gabriel A, Montoto C, Lleonart R, Videla S. 04/2022 Trials [Electronic Resource].

BACKGROUND: COVID-19 has quickly become a global pandemic with a substantial number of deaths and is a considerable burden for healthcare systems worldwide. Although most cases are paucisymptomatic and limited to the viral infection-related symptoms, some patients evolve to a second phase, with an impaired inflammatory response (cytokine storm) that may lead to acute respiratory distress syndrome and death. This is thought to be caused by increased bradykinin synthesis.

METHODS: ICAT-COVID is a multicenter, randomized, open-label, proof-of-concept phase II clinical trial assessing the clinical efficacy and safety of adding icatibant to the standard of care in patients hospitalized with COVID-19 without invasive mechanical ventilation. Patients hospitalized with a confirmed COVID-19 pneumonia diagnosis (RT-PCR or antigen test <= 10 days prior to randomization, and radiographic evidence of pulmonary infiltrates), rated "4" or "5" on the WHO's clinical status scale, are eligible. Patients will be randomized on a 1:1 ratio to either standard of care-plus-icatibant (experimental group) or to standard of care alone (control group). The experimental group will receive 30 mg of icatibant subcutaneously 3 times a day for 3 days (for a total of 9 doses). The expected sample size is 120 patients (60 per group) from 2 sites in Spain. Primary outcomes are the efficacy and safety of Icatibant. The main efficacy outcome is the number of patients reaching grades "2" or "1" on the WHO scale within 10 days of starting treatment. Secondary outcomes include "long-term efficacy": number of patients discharged who do not present COVID-19-related relapse or comorbidity up until 28 days after discharge, and mortality.

DISCUSSION: Icatibant, a bradykinin type 2 receptor antagonist with proven effectiveness and safety against hereditary angioedema attacks, may be beneficial for COVID-19 patients by inhibiting bradykinin's action on endothelial cells and by inhibiting the SARS-CoV-2 M protease. Our working hypothesis is that treatment with standard of care-plus-icatibant is effective and safe to treat patients infected with SARS-CoV-2 admitted to hospital for pneumonia without invasive mechanical ventilation.

TRIAL REGISTRATION: EudraCT 2020-002166-13.

CLINICALTRIALS.gov NCT04978051. Copyright © 2022. The Author(s).

23(1):303

Available online at: dx.doi.org/10.1186/s13063-022-06219-7

Baeza ML, Gonzalez-Quevedo T, Caballero T, Guilarte M, Lleonart R, Varela S, Castro M, Diaz C, Escudero E, Garcia MG, Laffond E, Munoz-Bellido FJ, Nunez R, Prior N, Sala-Cunill A, Saenz de San Pedro B, Prieto-Garcia A. 04/2022 The Journal of Allergy & Clinical Immunology in Practice.

BACKGROUND: Data on acquired angioedema due to C1-inhibitor deficiency (C1-INH-AAE) from 4 European countries (France, Italy, Germany, and Hungary) were recently published.

OBJECTIVE: To report data from a group of 50 patients with acquired C1-INH deficiency from Spain, of whom 46 had angioedema, and compare them with other European series.

METHODS: We performed a retrospective observational study of 46 patients with C1-INH-AAE and 4 asymptomatic patients. Clinical and biological characteristics and associated diseases were assessed and compared with other European series.

RESULTS: Women accounted for 73.9% of cases. The prevalence of C1-INH-AAE related to hereditary forms was 1/10.1. Overall, 8.7% patients were aged <40 years. Diagnostic delay was 1.1 years. Angioedema mainly affected the face (91.3%), followed by the oropharynx (63%), extremities (50%), and abdomen (37%). Only 1 patient underwent orotracheal intubation. Erythema marginatum was present in 1 patient. A hematologic disorder was recorded in 50% of patients. Angioedema preceded all benign conditions, mostly monoclonal gammopathy of undetermined significance, but appeared very close to or after malignant hematologic diseases (median, 2.2 and 0.29 years). Autoimmune diseases were associated in 50% (autoimmune thyroiditis, 21.5%; systemic lupus erythematosus, 10.9%). Half of them coexisted with hematologic disorders. Anti-C1-INH antibodies were found in 67% of tested patients and were not related to the associated disease. Long-term prophylaxis was necessary in 52.2%, most of whom responded to tranexamic acid.

CONCLUSIONS: This study emphasizes the possibility of C1-INH-AAE in patients younger than 40 and in autoimmune diseases other than systemic lupus erythematosus such as autoimmune thyroiditis. Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

10(4):1020-1028

Available online at: dx.doi.org/10.1016/j.jaip.2021.11.018 (small fee)

McKenzie A, Roberts A, Malandkar S, Feuersenger H, Panousis C, Pawaskar D. 03/2022 Clinical and translational science.

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). Copyright © 2021 CSL Behring LLC. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.

15(3):626-637

Available online at: dx.doi.org/10.1111/cts.13180

Gao Y, Hwang J, Hwang G, Craig T. 02/2022 Drugs of Today.

Orladeyo, a once-daily oral formulation of berotralstat (formerly BCX-7353), is a novel oral small-molecule drug developed by BioCryst Pharmaceuticals for the prevention of hereditary angioedema (HAE) attacks. It was first approved by the U.S. Food and Drug Administration (FDA) in 2020, and in 2021 also gained approval for marketing in Japan and the European Union. Preclinical and phase I studies showed promising efficacy and safety, and several multicenter international Angioedema Prophylaxis (APeX) phase II and III trials have since been initiated to further evaluate berotralstat. The ongoing phase III APeX-2 trial showed a 67% reduction in HAE attacks at the standard 150-mg dosing. Mild to moderate gastrointestinal side effects are most commonly seen and minimal serious adverse effects have been reported. Other first-line therapies for HAE prophylaxis rely on burdensome subcutaneous or intravenous routes. Thus far berotralstat has shown to be effective and well tolerated for HAE prophylaxis with the convenience of once-daily oral dosing. Copyright 2022 Clarivate Analytics.

58(2):59-67

Available online at: scopus.com/record/display.uri?eid=2-s2.0-85125020229&origin=inward&txGid=4f06ca6f25a516134c0ec7cd0e18bd7f (small fee)

Chuamanochan M, Phuprasertsak S, Weesasubpong P, Ruengorn C, Phosuya C, Awiphan R, Hutton B, Thavorn K, Bernstein JA, Nochaiwong S. 05/2022 Genes (Basel).

BACKGROUND: Hereditary angioedema (HAE) is a rare genetic disease that can lead to potentially life-threatening airway attacks. Although novel therapies for HAE treatment have become available over the past decades, a comparison of all available treatments has not yet been conducted. As such, we will perform a systematic review and network meta-analysis to identify the best evidence-based treatments for the management of acute attacks and prophylaxis of HAE.

METHODS: This study will include both parallel and crossover randomized controlled trials that have investigated prevention or treatment strategies for HAE attacks. We will search electronic databases, including Medline, Embase, PubMed, Cochrane Library, Scopus, and CINAHL, from inception with no language restrictions. Potential trials will be supplemented through a gray literature search. The process of study screening, selection, data extraction, risk-of-bias assessment, certainty assessment and classification of treatments will be performed independently by a pair of reviewers. Any discrepancy will be addressed through team discussion. A two-step approach of pairwise and network meta-analysis will be performed. The summarized effect estimates of direct and indirect treatment comparisons will be pooled using DerSimonion-Laird random-effects models. The incoherence assumption, in terms of the consistency of direct and indirect effects, will be assessed. An evidence-based synthesis will be performed, based on the magnitudes of effect size, evidence certainty, and ranking of treatment effects, with respect to treatment benefits and harms.

DISCUSSION: This systematic review and network meta-analysis will summarize evidence-based conclusions with respect to the ratio of benefits and harms arising from interventions for the treatment of acute attacks and prophylaxis of HAE. Evidence from this network estimate could promote the rational use of interventions among people living with HAE in clinical practice settings. PROSPERO registration number: CRD42021251367.

13(5)

Available online at: dx.doi.org/10.3390/genes13050924

Zhang W, Vadlakonda S, Wu M, Chintareddy V, Vogeti LN, Juarez L, Muppa S, Parker C, Kellogg-Yelder D, Williams J, Polach K, Chen X, Raman K, Babu YS, Kotian P. 11/2022 Bioorganic & Medicinal Chemistry.

Hereditary angioedema (HAE) is a rare and potentially life-threatening disease that affects an estimated 1 in 50,000 individuals worldwide. Berotralstat (BCX7353) is the only small molecule approved by the US Food and Drug Administration (FDA) for the prophylactic treatment of HAE attacks in patients 12 years and older. During the discovery of BCX7353, we also identified a novel series of small molecules containing a quaternary carbon as potent and orally bioavailable Plasma Kallikrein (PKal) inhibitors. Lead compound was identified as a potent inhibitor following a detailed lead optimization process that balanced the lipophilic efficiency (LipE) and pharmacokinetic (PK) profile. Copyright © 2022 Elsevier Ltd. All rights reserved.

73:117035

Available online at: dx.doi.org/10.1016/j.bmc.2022.117035 (small fee)

Zanichelli A, Montinaro V, Triggiani M, Arcoleo F, Visigalli D, Cancian M. 06/2022 Expert Opinion on Emerging Drugs.

INTRODUCTION: Hereditary angioedema due to C1-inhibitor (C1-INH-HAE) is a rare disease characterized by unpredictable swelling attacks that may be life-threatening when affecting the upper airways. Understanding the pathophysiology of HAE and the mechanism of bradykinin-mediated angioedema allowed the development of new therapies for the treatment of HAE: clinical trials are ongoing to expand the number of drugs available for on-demand treatment and prophylaxis.

AREAS COVERED: Authors discuss the products that have been used to treat this disease for many years and present the most recently marketed products and those which are under development.

EXPERT OPINION: Significant therapeutic progress has been made in HAE. In particular, drugs targeting specific molecules involved in the angioedema formation were developed and studies with new drugs are ongoing. In the coming years, more effective therapies with easier administration route options for on-demand treatment and long-term prophylaxis will be available to treat this disease and the variety of patients. Gene therapy strategies may offer a definitive treatment. High costs of current and new drugs may be a limiting factor for their availability, especially in developing countries.

27(2):103-110

Available online at: dx.doi.org/10.1080/14728214.2022.2105834 (small fee)

Cao Y, Kan H, Wang X, Zhi Y. 04/2022 Annals of Allergy, Asthma, & Immunology.

BACKGROUND: Hereditary angioedema (HAE) is a rare disease with wide intra- and interindividual clinical variation. There are no reliable indicators available in clinical practice to predict the onset and severity of HAE. Uncovering the changes in the gut microbiota in HAE patients may offer insight into a missing piece of the pathogenesis and help explain the clinical heterogeneity.

OBJECTIVE: Explore whether dysbiosis exists in patients with HAE and whether there are biomarkers to indicate the episodes.

METHODS: Fecal samples and clinical data were collected from patients with C1-inhibitor-related HAE and their healthy family members. Patients were grouped on the basis of the most recent conditions of HAE episodes and major clinical manifestations. The gut microbiota was evaluated by sequencing the 16S ribosomal RNA gene and analyzed for diversity.

RESULTS: Microbial richness and diversity were significantly reduced among patients who had recent HAE attacks, especially for those presenting with abdominal symptoms (P = .003 and P = .048 compared with healthy controls and patients with no recent episodes, respectively). Decreased Firmicutes and increased Proteobacteria were found among the individuals with a recent episode, along with a marked increase of pathogenic bacteria on the basis of the predictive functional profiling. Dysbiosis was restored after regular use of danazol or tranexamic acid. A combined biomarker composed of Bifidobacterium, Lachnospira, Paraprevotella, Desulfovibrio, and Staphylococcus was proposed to detect the recent edema episodes.

CONCLUSION: We reported alterations of the gut microbiome in patients with HAE and explored the possible role of bacteria in the etiology of edema episodes, which may provide new clues for the prediction of disease course, clinical treatment, and therapeutic evaluation. Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

128(4):451-458.e6

Available online at: dx.doi.org/10.1016/j.anai.2022.01.021

Zafra H. 04/2022 WMJ.

Hereditary angioedema (HAE) is a rare and disabling disorder wherein there is excessive bradykinin production, with subsequent increased vascular permeability in the superficial tissues and gastrointestinal and respiratory mucosa. This article serves as a review of the pathogenesis of the disease, as well as an update of the evidence-based new treatment recommendations to help clinicians with the diagnosis and management of HAE. Copyright© Board of Regents of the University of Wisconsin System and The Medical College of Wisconsin, Inc.

121(1):48-53

Available online at: wmjonline.org/121no1/zafra/

Mansour E, Veronez CL, Craig T, Grumach AS. 01/2022 Allergologia et Immunopathologia.

Hereditary angioedema is a genetic disease with autosomal dominant inheritance and, in most cases, caused by C1 inhibitor deficiency. Patients present with recurrent edema affecting sub-cutaneous and mucus membranes with variable onset and severity. More than 50% of patients may become symptomatic before 10 years of age. Family history can help with the diagnosis; however, approximately 25% of the cases are de novo mutations. Biochemical diagnosis should be delayed until after 1 year of age. Children were often excluded from advances in therapy for hereditary angioedema since most of the new medicines were tested in adults and thus excluded by the Food and Drug Administration (FDA) and other agencies for approval to be used in children. Treatment of attacks is available for the pediatric patient; however, barriers still exist for the use of long-term prophylaxis in young children. © 2022 Codon Publications. Published by Codon Publications.

50(S Pt 1):1-6

Available online at: all-imm.com/index.php/aei/article/view/535/812

Beyaz S, Demir S, Oztop N, Colakoglu B, Buyukozturk S, Gelincik A. 03/2022 Allergy & Asthma Proceedings.

BACKGROUND: Patients' satisfaction is important for the success of the management of chronic diseases.

OBJECTIVE: Our aim was to evaluate the satisfaction level of the patients with hereditary angioedema (HAE) for icatibant treatment.

METHODS: Patients with HAE C1 esterase inhibitor (C1-INH) were evaluated by using a questionnaire that included details of their icatibant-treated attacks. Patients' demographic and clinical features were collected from their medical records and personal attack diaries. The visual analog scale was used for determining the attack severity.

RESULTS: Of the total 161 patients with HAE C1-INH, 91% had HAE type I and were included in the study. Patients reported a median (interquartile range [IQR]) attacks of 2 (0.5-3) per month and 16 (4.5-36) attacks per year. The median (IQR) frequency of attacks treated with icatibant was 6 (0-20) per year. The mean +/- standard deviation (SD) duration of treatment with icatibant was 3 +/- 2.3 years. The self-administration rate was 91.3%. The mean +/- SD time to administration and time to onset of symptom resolution were 1.6 +/- 1.1 hours and 1.7 +/- 1.3 hours, respectively. There was a correlation between the time to administration and time to onset of symptom resolution (r = 0.566; p < 0.0001). A total of 125 patients (77%) reported that they were very satisfied or satisfied with icatibant. No correlation was observed between the satisfaction level and the attack sites; however, the patients with more severe attacks were more satisfied with icatibant (p < 0.0001). A total of 52 patients reported 74 mild local reactions. Systemic reactions were not observed.

CONCLUSION: The current real-life study showed that icatibant was safe and effective. Moreover, the patients' satisfaction level with icatibant was high. We believe that the availability of icatibant should be encouraged during HAE attacks because it enables patients to be more involved in their disease management.

43(2):148-154

Available online at: dx.doi.org/10.2500/aap.2022.43.210104 (small fee)

Grumach AS, Henriques MT, Bardou MLD, Pontarolli DA, Botha J, Correa M. 07/2022 Anais Brasileiros de Dermatologia.

BACKGROUND: Hereditary angioedema can be caused by C1-Inhibitor (C1-INH) deficiency and/or dysfunction (HAE-1/2) or can occur in patients with normal C1-INH (HAE nC1-INH).

METHODS: The Icatibant Outcome Survey (IOS; NCT01034969) registry monitors the safety and effectiveness of icatibant for treating acute angioedema.

OBJECTIVE: Present findings from Brazilian patients with HAE-1/2 and HAE nC1-INH participating in IOS.

RESULTS: 42 patients were enrolled (HAE-1/2, n=26; HAE nC1-INH, n=16). Median age at symptom onset was significantly lower with HAE-1/2 vs. HAE nC1-INH (10.0 vs. 16.5y, respectively; p=0.0105), whereas median age at diagnosis (31.1 vs. 40.9y; p=0.1276) and the median time between symptom onset and diagnosis (15.0 vs. 23.8y; p=0.6680) were numerically lower vs. HAE nC1-INH, respectively. One icatibant dose was used for > 95% of HAE attacks. Median (range) time-to-event outcomes were shorter for patients with HAE nC1-INH vs. HAE-1/2, including time to first administration (0.5 [0-96.0] vs. 1.0 [0-94.0]h, respectively), time from first administration to complete resolution (1.0 [0-88.0] vs. 5.5 [0-96.0]h, respectively), and total attack duration (7.0 [0.3-99.0] vs. 18.5 [0.1-100.0]h, respectively). Mean (SD) time from attack onset to resolution was significantly shorter for patients with HAE nC1-INH vs. HAE-1/2 (9.8 [18.7] vs. 19.6 [24.0]h, respectively; p=0.0174). 83 adverse events (AEs) in 42 patients were reported; most were mild (66.3%) or moderate (13.3%) and non-serious (75.9%). The most common icatibant-related AE was injection site erythema (HAE-1/2, 34.6%; HAE nC1-INH, 18.8%).

STUDY LIMITATIONS: This was an observational study without a treatment comparator and that relied on patient recall.

CONCLUSIONS: Findings demonstrate effectiveness and tolerability of icatibant in Brazilian HAE patients. Copyright © 2022. Published by Elsevier Espana, S.L.U.

97(4):448-457

Available online at: dx.doi.org/10.1016/j.abd.2021.09.009

Fijen LM, Riedl MA, Bordone L, Bernstein JA, Raasch J, Tachdjian R, Craig T, Lumry WR, Manning ME, Alexander VJ, Newman KB, Revenko A, Baker BF, Nanavati C, MacLeod AR, Schneider E, Cohn DM. 03/2022 New England Journal of Medicine.

BACKGROUND: Hereditary angioedema is characterized by recurrent and unpredictable swellings that are disabling and potentially fatal. Selective inhibition of plasma prekallikrein production by antisense oligonucleotide treatment (donidalorsen) may reduce the frequency of attacks and the burden of disease.

METHODS: In this phase 2 trial, we randomly assigned, in a 2:1 ratio, patients with hereditary angioedema with C1 inhibitor deficiency to receive four subcutaneous doses of either donidalorsen (80 mg) or placebo, with one dose administered every 4 weeks. The primary end point was the time-normalized number of investigator-confirmed angioedema attacks per month (attack rate) between week 1 (baseline) and week 17. Secondary end points included quality of life, as measured with the Angioedema Quality of Life Questionnaire (scores range from 0 to 100, with higher scores indicating worse quality of life), and safety.

RESULTS: A total of 20 patients were enrolled, of whom 14 were randomly assigned to receive donidalorsen and 6 to receive placebo. The mean monthly rate of investigator-confirmed angioedema attacks was 0.23 (95% confidence interval [CI], 0.08 to 0.39) among patients receiving donidalorsen and 2.21 (95% CI, 0.58 to 3.85) among patients receiving placebo (mean difference, -90%; 95% CI, -96 to -76; P<0.001). The mean change from baseline to week 17 in the Angioedema Quality of Life Questionnaire score was -26.8 points in the donidalorsen group and -6.2 points in the placebo group (mean difference, -20.7 points; 95% CI, -32.7 to -8.7). The incidence of mild-to-moderate adverse events was 71% among patients receiving donidalorsen and 83% among those receiving placebo.

CONCLUSIONS: Among patients with hereditary angioedema, donidalorsen treatment resulted in a significantly lower rate of angioedema attacks than placebo in this small, phase 2 trial. (Funded by Ionis Pharmaceuticals; ISIS 721744-CS2 ClinicalTrials.gov number, NCT04030598.). Copyright © 2022 Massachusetts Medical Society.

386(11):1026-1033

Available online at: dx.doi.org/10.1056/NEJMoa2109329

Beard N, Frese M, Smertina E, Mere P, Katelaris C, Mills K. 11/2022 Cochrane Database of Systematic Reviews.

BACKGROUND: Hereditary angioedema (HAE) is a serious and potentially life-threatening condition that causes acute attacks of swelling, pain and reduced quality of life. People with Type I HAE (approximately 80% of all HAE cases) have insufficient amounts of C1 esterase inhibitor (C1-INH) protein; people with Type II HAE (approximately 20% of all cases) may have normal C1-INH concentrations, but, due to genetic mutations, these do not function properly. A few people, predominantly females, experience HAE despite having normal C1-INH levels and C1-INH function (rare Type III HAE). Several new drugs have been developed to treat acute attacks and prevent recurrence of attacks. There is currently no systematic review and meta-analysis that included all preventive medications for HAE.

OBJECTIVES: To assess the benefits and harms of interventions for the long-term prevention of HAE attacks in people with Type I, Type II or Type III HAE.

SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was 3 August 2021.

SELECTION CRITERIA: We included randomised controlled trials in children or adults with HAE that used medications to prevent HAE attacks. The comparators could be placebo or active comparator, or both; approved and experimental drug trials were eligible for inclusion. There were no restrictions on dose, frequency or intensity of treatment. The minimum length of four weeks of treatment was required for inclusion; this criterion excluded the acute treatment of HAE attacks.

DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were 1. HAE attacks (number of attacks per person, per population) and change in number of HAE attacks; 2. mortality and 3. serious adverse events (e.g. hepatic dysfunction, hepatic toxicity and deleterious changes in blood tests). Our secondary outcomes were 4. quality of life; 5. severity of breakthrough attacks; 6. disability and 7. adverse events (e.g. weight gain, mild psychological changes and body hair). We used GRADE to assess certainty of evidence for each outcome.

MAIN RESULTS: We identified 15 studies (912 participants) that met the inclusion criteria. The studies included people with Type I and II HAE. The studies investigated avoralstat, berotralstat, subcutaneous C1-INH, plasma-derived C1-INH, nanofiltered C1-INH, recombinant human C1-INH, danazol, and lanadelumab for the prevention of HAE attacks. We did not find any studies on the use of tranexamic acid for prevention of HAE attacks. All drugs except avoralstat reduced the number of HAE attacks compared with placebo. For breakthrough attacks that occurred despite prophylactic treatment, intravenous and subcutaneous forms of C1-INH and lanadelumab reduced attack severity. It is not known whether other drugs have a similar effect, as the severity of breakthrough attacks in people taking drugs other than C1-INH and lanadelumab was not reported. For quality of life, avoralstat, berotralstat, C1-INH (all forms) and lanadelumab increased quality of life compared with placebo; there were no data for danazol. Four studies reported on changes in disability during treatment with C1-INH, berotralstat and lanadelumab; all three drugs decreased disability compared with placebo. Adverse events, including serious adverse events, did not occur at a rate higher than placebo. However, serious adverse event data and other adverse event data were not available for danazol, which prevented us from drawing conclusions about the absolute or relative safety of this drug. No deaths were reported in the included studies. The analysis was limited by the small number of studies, the small number of participants in each study and the lack of data on older drugs, therefore the certainty of the evidence is low. Given the rarity of HAE, it is not surprising that drugs were rarely directly compared, which does not allow conclusions on the comparative efficacy of the various drugs for people with HAE. Finally, we did not identify any studies that included people with Type III HAE. Therefore, we cannot draw any conclusions about the efficacy or safety of any drug in people with this form of HAE.

AUTHORS' CONCLUSIONS: The available data suggest that berotralstat, C1-INH (subcutaneous, plasma-derived, nanofiltered and recombinant), danazol and lanadelumab are effective in lowering the risk or incidence (or both) of HAE attacks. In addition, C1-INH and lanadelumab decrease the severity of breakthrough attacks (data for other drugs were not available). Avoralstat, berotralstat, C1-INH (all forms) and lanadelumab increase quality of life and do not increase the risk of adverse events, including serious adverse events. It is possible that danazol, subcutaneous C1-INH and recombinant human C1-INH are more effective than berotralstat and lanadelumab in reducing the risk of breakthrough attacks, but the small number of studies and the small size of the studies means that the certainty of the evidence is low. This and the lack of head-to-head trials prevented us from drawing firm conclusions on the relative efficacy of the drugs. Copyright © 2022 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

11:CD013403

Available online at: dx.doi.org/10.1002/14651858.CD013403.pub2 (small fee)

Simac DV, Stimac T, Novak S. 10/2022 Current Allergy & Asthma Reports.

PURPOSE OF REVIEW: Hereditary angioedema (HAE) is a disorder affecting bradykinin regulation presenting as recurrent cutaneous or mucosal swelling. Treatment options include plasma-derived or human-recombinant C1-inhibitor, icatibant, or ecallantide. Due to the lack of knowledge and experience on the topic, the treatment of choice in pregnancy is plasma-derived C1-inhibitor, and reporting any new experience is recommended. This review presents current guidelines for HAE treatment with a focus on pregnancy and reviews all experience with icatibant use during pregnancy.

RECENT FINDINGS: Our experience of treating a pregnant nC1-INH HAE patient with icatibant is presented, with no adverse effects or abnormalities, to add to the growing knowledge of icatibant use during pregnancy. Considering the limited number of attacks that our patient usually experiences, which continued at more or less the same frequency during pregnancy, we feel icatibant to be a safe choice for on-demand HAE treatment during pregnancy for such cases. Copyright © 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

22(10):135-140

Kesh S, Bernstein JA 12/2022 Annals of Allergy, Asthma, & Immunology.

OBJECTIVE: To review the various types of angioedema including diagnosis and treatment.

DATA SOURCES: PubMed search of articles in the English language of various types of angioedema.

STUDY SELECTIONS: Articles on the subject matter were selected and reviewed.

RESULTS: Herein, a case-based approach is presented for discussing the major types of angioedema, including the following: hereditary angioedema types I and II and normal complement, acquired angioedema, angiotensin-converting enzyme-induced angioedema, and histaminergic and nonhistaminergic angioedema. Emerging treatments of hereditary angioedema including targets of prekallikrein, DNA vector technology replacing C1-INH protein, and CRIPSR technology targeting prekallikrein among many others are explored. In addition, other causes and mimickers of angioedema are briefly reviewed. Finally, a novel algorithm is proposed to help guide the treating physician through the workup and management of patients with suspected idiopathic angioedema unresponsive to conventional therapy with antihistamines.

CONCLUSION: Over the years, many strides have been made in both understanding the pathophysiology of various types of angioedema and expansion of treatment options. It is important for clinicians to be aware of current and emerging treatment options. We provide a novel practical algorithm to guide clinicians in challenging cases of idiopathic angioedema refractory to antihistamines. Copyright © 2022 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

129(6):692-702

Available online at: dx.doi.org/10.1016/j.anai.2022.08.003

Maetzel A, Smith MD, Duckworth EJ, Hampton SL, De Donatis GM, Murugesan N, Rushbrooke LJ, Li L, Francombe D, Feener EP, Yea CM. 06/2022 Journal of Allergy & Clinical Immunology.

BACKGROUND: Attacks of hereditary angioedema are attributed to excessive plasma kallikrein (PKa) activity, which cleaves high-molecular-weight kininogen to generate the proinflammatory hormone bradykinin.

OBJECTIVE: We evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of KVD900, an orally administered inhibitor of PKa in healthy adults.

METHODS: KVD900 was administered in 2 clinical studies. In the first study, healthy adult men received single ascending doses (5-600 mg) of KVD900 capsule or placebo, single 100 mg doses of KVD900 tablet and KVD900 capsule (crossover), and single 600 mg doses of KVD900 (6 x 100 mg tablets) under fed and fasting conditions (crossover). In a second study, 3 cohorts of healthy adults were provided 600 mg of KVD900 tablets at 8-, 4-, and 2-hour intervals.

RESULTS: Overall, 98 healthy participants received KVD900. All adverse events (AEs) were mild, except for a single moderate AE (headache). Exposure to KVD900 was proportional to dose. The PK parameters for KVD900 600 mg in tablet form under fasted conditions were mean (coefficient of variation) maximum plasma concentration of 6460 (22.0) ng/mL, mean (coefficient of variation) area under the curve (AUC0-24) of 18,600 (22.5) hng/mL, and median (range) time to maximum plasma concentration of 0.5 (0.33-1.5) hours. Mean PKa inhibition was essentially complete (>98%) between 20 minutes and 3 hours, and >90% inhibition was maintained for at least 8 hours after dosing. High-molecular-weight kininogen cleavage protection at the 600 mg dose was attained within 20 minutes and maintained for 8 to 10 hours.

CONCLUSION: These phase 1 studies evaluated the PK/PD profile of KVD900, showing that KVD900 rapidly achieves near-complete PKa inhibition and is generally safe and well tolerated.

CLINICALTRIALS.GOV IDENTIFIER: NCT04349800. Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

149(6):2034-2042

Available online at: dx.doi.org/10.1016/j.jaci.2021.10.038

Kesh S, Singh U, Bernstein JA. 09/2022 Allergy & Asthma Proceedings.

BACKGROUND: Acquired angioedema (AAE) is a rare form of angioedema (AE) and is often associated with lymphoproliferative conditions and/or anti-C1 esterase inhibitor (C1-INH) antibodies without clear treatment consensus. Current treatments have been reported to have variable effectiveness with different safety concerns. A large Italian cohort of patients with AAE was previously found to respond well to tranexamic acid (TXA). Herein, we report our experience treating AAE with TXA used as prophylaxis.

OBJECTIVE: The objective was to describe clinical characteristics of patients with AAE and to report our experience with treating AAE with TXA.

METHODS: A retrospective chart review of patients with AAE (N = 13) from a large practice was conducted to assess characteristics and treatment responses. Patient demographics in addition to C1-INH quantitative, C1-INH functional, C4, and C1q levels; the presence of C1-INH antibodies; and a history of lymphoproliferative disease were extracted. The patients were also characterized by their treatment response to TXA.

RESULTS: All the patients were white, with a mean age at diagnosis of 67 years, an average body mass index of 31.3 kg/m2, and a male-to-female ratio of 7:6. Nine patients had positive C1-INH antibodies. The patients were on various prophylaxis treatments before TXA, including chemotherapy that targeted malignancy, cyclophosphamide, rituximab, and plasmapheresis. Ultimately, 11 of the 13 patients were on TXA for prophylaxis. At 1, 12, and 24 months after TXA treatment, attacks decreased by 97, 86, and 99%, respectively. One patient developed a deep vein thrombosis and TXA was stopped.

CONCLUSION: These findings demonstrated that treatment of AAE with TXA was effective as prophylaxis for AE attacks. However, potential adverse effects remain a concern, which emphasizes the need for additional options.

43(5):413-418

Available online at: dx.doi.org/10.2500/aap.2022.43.220043 (small fee)

Banerji A, Bernstein JA, Johnston DT, Lumry WR, Magerl M, Maurer M, Martinez-Saguer I, Zanichelli A, Hao J, Inhaber N, Yu M, Riedl MA. 03/2022 Allergy.

BACKGROUND: The aim was to evaluate long-term effectiveness and safety of lanadelumab in patients >=12 y old with hereditary angioedema (HAE) 1/2 (NCT02741596).

METHODS: Rollover patients completing the HELP Study and continuing into HELP OLE received one lanadelumab 300 mg dose until first attack (dose-and-wait period), then 300 mg q2wks (regular dosing stage). Nonrollovers (newly enrolled) received lanadelumab 300 mg q2wks from day 0. Baseline attack rate for rollovers: >=1 attack/4 weeks (based on run-in period attack rate during HELP Study); for nonrollovers: historical attack rate >=1 attack/12 weeks. The planned treatment period was 33 months.

RESULTS: 212 patients participated (109 rollovers, 103 nonrollovers); 81.6% completed >=30 months on study (mean [SD], 29.6 [8.2] months). Lanadelumab markedly reduced mean HAE attack rate (reduction vs baseline: 87.4% overall). Patients were attack free for a mean of 97.7% of days during treatment; 81.8% and 68.9% of patients were attack free for >=6 and >=12 months, respectively. Angioedema Quality-of-Life total and domain scores improved from day 0 to end of study. Treatment-emergent adverse events (TEAEs) (excluding HAE attacks) were reported by 97.2% of patients; most commonly injection site pain (47.2%) and viral upper respiratory tract infection (42.0%). Treatment-related TEAEs were reported by 54.7% of patients. Most injection site reactions resolved within 1 hour (70.2%) or 1 day (92.6%). Six (2.8%) patients discontinued due to TEAEs. No treatment-related serious TEAEs or deaths were reported. Eleven treatment-related TEAEs of special interest were reported by seven (3.3%) patients.

CONCLUSION: Lanadelumab demonstrated sustained efficacy and acceptable tolerability with long-term use in HAE patients. Copyright © 2021 Takeda Development Center Americas, Inc. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.

77(3):979-990

Available online at: dx.doi.org/10.1111/all.15011

Bouillet L, Fain O, Armengol G, Aubineau M, Blanchard-Delaunay C, Dalmas MC, De Moreuil C, Du Thanh A, Gobert D, Guez S, Hoarau C, Jaussaud R, Jeandel PY, Maillard H, Marmion N, Masseau A, Menetrey C, Ollivier Y, Pelletier F, Plu-Bureau G, Sailler L, Vincent D, Bouquillon B, Verdier E, Clerson P, Boccon-Gibod I, Launay D. 09/2022 Allergy & Asthma Proceedings.

BACKGROUND: Hereditary angioedema (HAE) is characterized by unpredictable and potentially life-threatening attacks of cutaneous and submucosal swelling. Over the past decade, new agents, based on a better understanding of the underlying biologic mechanisms of HAE, have changed the face of long-term prophylaxis (LTP).

OBJECTIVE: The objective was to describe current practices and unmet needs with regard to LTP for HAE in expert centers in France.

METHODS: The study was conducted in France in 2020. Based on their experience with patients with HAE who had visited their center at least once in the past 3 years, physicians from 25 centers who are expert in the management of HAE were requested to fill in a questionnaire that encapsulated their active patient list, criteria for prescribing LTP, and medications used. They were asked about potential unmet needs with currently available therapies. They were asked to express their expectations with regard to the future of HAE management.

RESULTS: Analysis was restricted to 20 centers that had an active patient file and agreed to participate. There were 714 patients with C1 inhibitor (C1-INH) deficiency, of whom 423 (59.2%) were treated with LTP. Altered quality of life triggered the decision to start LTP, as did the frequency and severity of attacks. Ongoing LTP included androgens (28.4%), progestins (25.8%), lanadelumab (25.3%), tranexamic acid (14.2%), intravenous C1-INHs (5.6%), and recombinant C1-INH (0.7%). Twenty-nine percent of the patents with LTP were considered to still have unmet needs. Physicians' concerns varied among therapies: poor tolerability for androgens and progestins, a lack of efficacy for tranexamic acid and progestins, dosage form, and high costs for C1-INHs and lanadelumab. Physicians' expectations encompassed more-efficacious and better-tolerated medications, easier treatment administration for the sake of improved quality of life of patients, and less-expensive therapies.

CONCLUSION: Despite the recent enrichment of the therapeutic armamentarium for LTP, physicians still expressed unmet needs with currently available therapies.

43(5):406-412

Available online at: dx.doi.org/10.2500/aap.2022.43.220046 (small fee)

Guo Y, Zhang H, Lai H, Wang H, Chong-Neto HJ, Valle SOR, Zhu R. 11/2022 Orphanet Journal Of Rare Diseases.

Hereditary angioedema (HAE) is a rare autosomal dominant genetic disease characterized by repetitive subcutaneous or submucosal angioedema, activation of the kinin system, and increased vascular permeability. C1-inhibitor (C1-INH) deficiency, the main mechanism of HAE pathogenesis, occurs when abnormal activation of plasma kallikrein, bradykinin, and factor XII, or mutation of genes such as SERPING1 cause quantitative or functional C1-INH defects. Although androgens are not approved for HAE treatment in many countries, they are widely used in China and Brazil to reduce the frequency and severity of HAE attacks. The long-term adverse effects of androgen treatment are concerning for both physicians and patients. Virilization, weight gain, acne, hirsutism, liver damage, headache, myalgia, hematuria, menstrual disorders, diminished libido, arterial hypertension, dyslipidemia, and anxiety/depression are commonly observed during long-term treatment with androgens. These adverse effects can affect the quality of life of HAE patients and often lead to treatment interruption, especially in women and children. In-depth studies of the pathogenesis of HAE have led to the approval of alternative treatment strategies, including plasma-derived C1 inhibitor, recombinant human C1 inhibitor, plasma Kallikrein inhibitor (ecallantide; lanadelumab), and bradykinin B2 receptor antagonist (icatibant), some of which have achieved satisfactory results with mostly non-serious side effects. Therefore, a new standard of medical care may expand possibilities for the management of HAE in emerging countries. Copyright © 2022. The Author(s).

17(1):399

Available online at: dx.doi.org/10.1186/s13023-022-02536-x

Norris M, Ashoor Z, Craig T. 09/2022 Allergy & Asthma Proceedings.

BACKGROUND: The management of hereditary angioedema has rapidly changed over the past decade. With these changes there has been increased recognition of the unique challenges of diagnosing and managing hereditary angioedema in pediatric populations.

OBJECTIVES: The objective of this review was to identify and compare recently published consensus guidelines for the management of hereditary angioedema types 1 and 2 to identify areas of agreement and conflict.

METHODS: A MEDLINE database search was performed to identify guidelines that offered guidance on diagnosing or managing hereditary angioedema in pediatric populations. A limitation was placed on guidelines published in the past 5 years to reflect the most recent literature.

RESULTS: Six clinical practice guidelines were included in the analysis. Early detection of disease status, coordination with specialists, and empowering patients with self-administered medications are emphasized, with use of plasma derived C1 esterase inhibitor as first line therapy for aborting attacks. The guidelines are shifting away from attenuated androgens and tranexamic acid for long-term prophylaxis toward medications such as subcutaneous C1 esterase inhibitor, lanadelumab, and berotralstat.

CONCLUSION: Although some differences exist based on geographic region and health system where an included guideline was published, they have very minimal differences on close review.

43(5):388-396

Available online at: dx.doi.org/10.2500/aap.2022.43.220052 (small fee)

Jindal AK, Barman P, Chawla S, Kaur A, Tyagi R, Sikka P, Chopra S, Mahajan S, Longhurst H, Singh S. 03/2022 Immunobiology.

Hereditary angioedema (HAE) is a rare genetic disorder distinguished clinically by recurrent episodes of non-pruritic swelling. Although pregnancy has been considered a trigger, it may have variable effect on frequency of attacks of HAE. C1-inhibitor (C1-INH) is the treatment of choice for management of HAE during pregnancy. However, because of non-availability of C1-INH therapy in developing countries, fresh-frozen plasma (FFP) and tranexamic acid remain the drugs of choice in pregnancy for treatment of acute attacks and for prophylaxis respectively. There is paucity of data on outcome of pregnancy with patients with HAE from developing countries such as India where all the first line medications are not available. A retrospective review was done including four HAE patients who conceived (with a total of 9 pregnancies). Our results suggest that frequency of attacks may increase during pregnancy especially during second trimester and post-delivery (during breastfeeding). However, HAE attacks are rare at the time of delivery. In resource limited settings, treatment with FFP/tranexamic acid needs to be individualised. Copyright © 2022 Elsevier GmbH. All rights reserved.

227(2):152175

Available online at: haesi.in/pdf/publications/management-of-pregnancy.pdf

Lindsay K, Chua I, Jordan A, Stephens S. 12/2022 Internal Medicine Journal.

BACKGROUND: Hereditary angioedema (HAE) leads to significant morbidity and mortality from unpredictable intermittent peripheral, abdominal and laryngeal swelling. Access to appropriate healthcare and effective therapies, which can prevent and treat attacks, reduce the suffering and greatly improve quality of life. Although treatments such as C1 inhibitor (Berinert), and Icatibant are available in New Zealand (Aotearoa), there are no published data available on their use.

AIM: To present a national audit of HAE and acquired angioedema (AAE) in 2019.

METHODS: Patients were identfied and demographical and clinical data on HAE were collected retrospectively by interview and notes review.

RESULTS: The total number of known adult (48) and children (3) HAE and AAE (3) patients is 54. Of these, 41/54 (75%) of HAE and AAE patients were recruited to the audit. Icatibant has been available for the treatment of acute HAE attacks since 2016, and is now used in 73% of HAE patients. Icatibant is also used by patients for laryngeal attacks in the community, who may not then present to hospital. Androgens are used in half of the patients as prophylaxis, but 33% of the latter were identified as not having regular liver ultrasound screening. Tranexamic acid is used as prophylaxis in one-fifth of patients. Participants have had 40 children, half of whom may be affected. Three have been diagnosed with HAE, suggesting that the majority have not yet been tested.

CONCLUSIONS: Corrective actions arising from this audit will improve our capacity to provide long-term care for HAE patients and their families. Copyright © 2021 Royal Australasian College of Physicians.

52(12):2124-2129

Available online at: dx.doi.org/10.1111/imj.15466 (small fee)

Powell J, Piszczatoski C, Rubido E. Orladeyo 04/2022 Annals of Pharmacotherapy.

OBJECTIVE: The purpose of this article is to review the available trials that led to the Food and Drug Administration (FDA) approval of berotralstat, an oral kallikrein inhibitor, for the prevention of hereditary angioedema (HAE) attacks.

DATA SOURCES: PubMed and ClincalTrials.gov were searched using key term berotralstat to identify phase III clinical trials related to the FDA approval of berotralstat from April 2018 to May 2021.

STUDY SELECTION AND DATA EXTRACTION: Trials selected were those that influenced the FDA approval of berotralstat or provided novel information regarding the safety and efficacy of this therapy in the treatment of HAE.

DATA SYNTHESIS: Both APeX-2 and ApeX-J found clinically significant benefit with berotralstat 150 mg daily for reduction in HAE attacks when compared with placebo (1.31 vs 2.35, P < 0.001, and 1.11 vs 2.18, P < 0.001, attacks in the APeX-2 and APeX-J trials, respectively). APeX-2 also showed a statistically significant benefit for berotralstat 110 mg daily (1.65 vs 2.35 attacks [1.65 attacks, P = 0.024]).

RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: An advantage berotralstat has over the other approved therapies is that it is administered orally, which may garner patient preference because of ease of administration. Berotralstat has also shown a potential benefit in reducing the need for standard-of-care treatment for HAE attacks, which has not been studied with alternative agents.

CONCLUSIONS: Berotralstat 150 mg daily has been proven safe and effective in clinical studies and appears to be a viable oral alternative to parenteral medications currently used in HAE prophylaxis.

56(4):488-493

Available online at: dx.doi.org/10.1177/10600280211032982 (small fee)

Fijen LM, Petersen RS, Levi M, Lakeman P, Henneman L, Cohn DM. 09/2022 The Journal of Allergy & Clinical Immunology in Practice.

Hereditary angioedema (HAE) is an autosomal-dominant monogenic disorder, causing painful or hindering swellings that can even be life-threatening. The severity and frequency of attacks differ between patients, regardless of genotype. Genetic counseling is recommended for all patients with HAE. Besides natural pregnancy and accepting the risk or considering prenatal diagnosis (PND), couples could consider refraining from having children, gamete donation, adoption, or preimplantation genetic testing (PGT). In PGT, oocytes are fertilized by in vitro fertilization and intracytoplasmatic sperm injection, and after genetic testing unaffected embryos are eligible for transfer into the uterus. Only 40% to 50% of couples will have an ongoing pregnancy after several PGT cycles, with a misdiagnosis risk of 1% to 2%. Live birth rate per oocyte retrieval cycle is 22% to 32%. Patients without an identified pathogenic DNA variant (∼5%) are ineligible for PGT and PND. The field of reproductive decision making by patients with HAE is virtually unexplored, even though the risk of passing HAE to their children is a major source of anxiety among patients. We explored views of patients with HAE on reproductive options, because this will help inform physicians in their counseling, improve patients’ empowerment, and attribute to better informed decision making.

10(9):2483-2486.e1

Available online at: dx.doi.org/10.1016/j.jaip.2022.05.030

Martinez-Saguer I, Dominas N, Straben U, Greve J, Brehler R, Magerl M, Knipps LM, Knop J, Flemming A, Schubert T, Maurer M. 07/2022 European Journal of Dermatology.

BACKGROUND: Little is known about how many patients with hereditary angioedema due to C1 inhibitor deficiency (HAE-C1-INH) receive on-demand and/or prophylactic treatment and what their clinical features are. Here, we estimated, using Delphi-based consensus, prevalence and treatment patterns in Germany as well as patient features linked to long-term prophylaxis.

MATERIALS & METHODS: Eight experts, who together treat approximately 75% of all German HAE-C1-INH patients, participated in a classic, two-round Delphi survey. Consensus was defined as agreement between at least 75% of participants.

RESULTS: Experts agreed that an estimated 1,350 patients in Germany have HAE-C1-INH, i.e. 1.62 per 100,000. One in four patients was estimated to receive long-term prophylaxis. Patient features linked to the use of prophylactic treatment included reduced quality of life, frequent swellings and swellings that affect the upper airways, and >two attacks per month.

CONCLUSION: The rate of prophylactic treatment in Germany is low, but is expected to increase. The level of disease activity and its impact and control are and should be considered in the choice for prophylactic treatment.

32(4):487-494

Available online at: jle.com/fr/revues/ejd/e-docs/patients_with_hereditary_angioedema_and_their_treatment_patterns_in_germany_a_delphi_consensus_study_323281/article.phtml?tab=texte

Pawaskar D, Chen X, Glassman F, May F, Roberts A, Biondo M, McKenzie A, Nolte MW, Jusko WJ, Tortorici M. 03/2022 Clinical and translational science.

Factor XII (FXII) is a serine protease involved in multiple cascades, including the kallikrein-kinin system. It may play a role in diseases in which the downstream cascades are dysregulated, such as hereditary angioedema. Garadacimab (CSL312) is a first-in-class, fully human, monoclonal antibody targeting activated FXII (FXIIa). We describe how translational pharmacokinetic (PK) and pharmacodynamic (PD) modeling enabled dose selection for the phase I, first-in-human trial of garadacimab. The PK/PD data used for modeling were derived from preclinical PK/PD and safety studies. Garadacimab plasma concentrations rose with increasing dose, and clear dose-related PD effects were observed (e.g., a mechanism-based prolongation of activated partial thromboplastin time). The PK/PD profile from cynomolgus monkeys was used to generate minimal physiologically-based pharmacokinetic (mPBPK) models with target-mediated drug disposition (TMDD) for data prediction in cynomolgus monkeys. These models were later adapted for prediction of human data to establish dose selection. Based on the final mPBPK model with TMDD and assuming a weight of 70 kg for an adult human, a minimal inhibition (<10%) of FXIIa with a starting dose of 0.1 mg/kg garadacimab and a near maximal inhibition (>95%) at 10 mg/kg garadacimab were predicted. The phase I study is complete, and data on exposure profiles and inhibition of FXIIa-mediated kallikrein activity observed in the trial support and validate these simulations. This emphasizes the utility and relevance of translational modeling and simulation in drug development. Copyright © 2021 CSL Behring LLC. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.

15(3):709-720

Available online at: dx.doi.org/10.1111/cts.13192

Duckworth EJ, Murugesan N, Li L, Rushbrooke LJ, Lee DK, De Donatis GM, Maetzel A, Yea CM, Hampton SL, Feener EP. 09/2022 Clinical & Experimental Allergy.

BACKGROUND: Hereditary angioedema (HAE) is a rare genetic disease that leads to recurrent episodes of swelling and pain caused by uncontrolled plasma kallikrein (PKa) activity. Current guidelines recommend ready availability of on-demand HAE treatments that can be administered early upon attack onset. This report describes the pharmacological and pharmacodynamic properties of the novel oral small-molecule PKa inhibitor KVD900 as a potential on-demand treatment for HAE.

METHODS: Pharmacological properties of KVD900 on PKa and closely related serine proteases were characterized using kinetic fluorogenic substrate activity assays. Effects of KVD900 on PKa activity and kallikrein kinin system activation in whole plasma were measured in the presence of dextran sulphate (DXS)-stimulation using a fluorogenic substrate and capillary immunoassays to quantify high molecular weight kininogen (HK), plasma prekallikrein and Factor XII cleavage. Pharmacodynamic effects of orally administered KVD900 were characterized in plasma samples from six healthy controls in a first in human phase 1 clinical trial and from 12 participants with HAE in a phase 2 clinical trial.

RESULTS: KVD900 is a selective, competitive and reversible inhibitor of human PKa enzyme with a Ki of 3.02 nM. The association constant (Kon ) of KVD900 for PKa is >10 x 106 M-1 s-1 . Oral administration of KVD900 in a first-in-human clinical trial achieved rapid and near complete inhibition of DXS-stimulated PKa enzyme activity and HK cleavage and reduced plasma prekallikrein and Factor XII activation in plasma. In individuals with HAE, orally administered KVD900 inhibited DXS-stimulated PKa activity in plasma by >=95% from 45 min to at least 4 h post-dose and provided rapid protection of HK from cleavage.

CONCLUSION: KVD900 is a fast-acting oral PKa inhibitor that rapidly inhibits PKa activity, kallikrein kinin system activation and HK cleavage in plasma. On-demand administration of KVD900 may provide an opportunity to halt the generation of bradykinin and reverse HAE attacks. Copyright © 2022 KalVista Pharmaceuticals, Inc. Clinical & Experimental Allergy published by John Wiley & Sons Ltd.

52(9):1059-1070

Available online at: dx.doi.org/10.1111/cea.14122

Mathis A, Sale M, Cornpropst M, Sheridan WP, Ma SC. 04/2022 Clinical and translational science.

Hereditary angioedema (HAE) is an autosomal dominant disorder characterized by recurrent episodes of swelling of the skin, larynx, gastrointestinal tract, genitals, and extremities that can be disruptive to patient quality of life. Dysregulation of plasma kallikrein activity leads to increased production and accumulation of bradykinin in HAE and causes attacks of angioedema. Plasma kallikrein is a serine protease essential for the formation of bradykinin. Berotralstat is a potent, highly selective, orally bioavailable small-molecule plasma kallikrein inhibitor that has been approved to prevent attacks of HAE in adults and children 12 years of age and older. Population pharmacokinetic (PK) analyses were conducted to describe the PK of berotralstat (BCX7353; Orladeyo TM ) and to evaluate the covariates that may explain variability in PK. The PK of berotralstat were characterized by population PK modeling of data from 13 clinical studies and a total of 771 healthy subjects and patients with HAE. The PK profile was well described by a three-compartment model with first-order absorption including an absorption lag time and linear elimination. Among the covariates tested, the effects of bilirubin and food were found not to be clinically significant and were removed from the model. Covariate analysis indicated significant effects of dose on bioavailability and weight on berotralstat clearance and volume. Despite the covariate effect of weight, simulations in adolescents and adults who were underweight, low weight, and overweight demonstrated similar predicted exposures to those observed at therapeutic doses in a clinical trial. Therefore, no dose adjustment is required in these HAE patient subpopulations. Copyright © 2022 BioCryst Pharmaceuticals, Inc. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.

15(4):1027-1035

Available online at: dx.doi.org/10.1111/cts.13233

Oztop N, Demir S, Toprak ID, Unal D, Gelincik A. 11/2022 Allergy & Asthma Proceedings.

BACKGROUND: There are some adverse effects with coronavirus disease 2019 (COVID-19) vaccines, but the impact of COVID-19 vaccination on attacks in hereditary angioedema (HAE) is not well defined.

OBJECTIVE: We aimed to investigate the influence of COVID-19 vaccination on the course of HAE.

METHOD: The COVID-19 vaccination status was determined in 140 adult patients with HAE. The number and severity of attacks recorded from patients' diaries were evaluated at four different periods, comprising 1 month before the first dose, the period between the first and the second doses of COVID-19 vaccine in all the patients, the period between the second dose and the third doses in those who received three doses, and 1 month after the last vaccination dose. The disease and attack severities were assessed with the disease severity score (DSS) and 10-point visual analog scale, respectively. The patients were divided into two main groups as group 1 (those who had at least two doses of COVID-19 vaccines [n = 114]) and group 2 (those who had no vaccination [n = 26]). Only Sinovac and Biontech, which were only approved in Turkey.

RESULTS: The mean +/- standard deviation DSS was significantly higher in the patients who experienced an attack after vaccination within 48 hours (6.61 +/- 1.88 versus 4.14 +/- 1.69; p < 0.001). Long-term prophylaxis was less common in the patients with an increased number of attacks (n = 5 (27.8%) versus n = 54 (56.3%); p = 0.027). The number of patients with less than a high school education was higher in group 2 (n = 23 [88.5%]) than in group 1 (n = 26 [3.1%]) (p < 0.001). The number of patients who had concerns about the triggering of a vaccine-induced HAE attack or about the possible vaccine adverse effects was higher in group 2 (n = 26 [100%]) than in group 1 (n = 74 [64.9%]).

CONCLUSION: It seems that COVID-19 vaccination does not increase HAE attacks regardless of the type of the vaccines. We recommend that HAE activity should be under control before COVID-19 vaccination, and the patients should be well informed about the safety of the vaccines.

43(6):546-554

Available online at: ncbi.nlm.nih.gov/pmc/articles/PMC9645734/

Craig T, Feuersenger H, Pragst I, Dang J. 05/2022 Allergy & Asthma Proceedings.

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.

43(3):202-208

Available online at: dx.doi.org/10.2500/aap.2022.43.220016 (small fee)

Craig T, Magerl M, Levy DS, Reshef A, Lumry WR, Martinez-Saguer I, Jacobs JS, Yang WH, Ritchie B, Aygoren-Pursun E, Keith PK, Busse P, Feuersenger H, Pawaskar D, Jacobs I, Pragst I, Doyle MK. 03/2022 Lancet.

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. Copyright © 2022 Elsevier Ltd. All rights reserved.

399(10328):945-955

Available online at: doi.org/10.1016/s0140-6736(21)02225-x (small fee)

Fijen LM, Levi M. 03/2022 Lancet.

Hereditary angioedema is a rare autosomal dominant genetic disorder characterised by recurrent, localised swellings in various tissues including the skin, genitals, abdomen, face, and oropharyngeal region. These attacks can be painful, debilitating, and life-threatening, substantially affecting quality of life. Inadequate control of the contact system, consisting of factor XII (FXII), plasma kallikrein, and high molecular weight kininogen, results in excessive bradykinin formation, which increases vascular permeability and thus causes angioedema attacks.

399(10328):889-890

Available online at: dx.doi.org/10.1016/S0140-6736(21)02436-3 (small fee)

Davie RL, Edwards HJ, Evans DM, Hodgson ST, Stocks MJ, Smith AJ, Rushbrooke LJ, Pethen SJ, Roe MB, Clark DE, McEwan PA, Hampton SL. 10/2022 Journal of Medicinal Chemistry.

Hereditary angioedema (HAE) is a rare genetic disorder in which patients experience sudden onset of swelling in various locations of the body. HAE is associated with uncontrolled plasma kallikrein (PKa) enzyme activity and generation of the potent inflammatory mediator, bradykinin, resulting in episodic attacks of angioedema. Herein, we disclose the discovery and optimization of novel small molecule PKa inhibitors. Starting from molecules containing highly basic P1 groups, which typically bind to an aspartic acid residue (Asp189) in the serine protease S1 pocket, we identified novel P1 binding groups likely to have greater potential for oral-drug-like properties. The optimization of P4 and the central core together with the particularly favorable properties of 3-fluoro-4-methoxypyridine P1 led to the development of sebetralstat, a potent, selective, orally bioavailable PKa inhibitor in phase 3 for on-demand treatment of HAE attacks.

65(20):13629-13644

Available online at: dx.doi.org/10.1021/acs.jmedchem.2c00921

Riedl MA, Neville D, Cloud B, Desai B, Bernstein JA. 09/2022 Allergy & Asthma Proceedings.

BACKGROUND: Hereditary angioedema (HAE) is a rare genetic disorder characterized by recurrent, localized episodes of edema. Current treatment guidelines highlight the importance of shared decision-making (SDM) during implementation of HAE management plans.

OBJECTIVE: To determine what constitutes a successful SDM approach in HAE management.

METHOD: Qualitative telephone interviews, which lasted ~1 hour, were conducted with four HAE physicians and four patients from the APeX-S trial. The physicians were asked to describe the structure and/or content of typical HAE prophylaxis consultations and factors to consider when selecting medications for long-term treatment. Insights from these interviews were used to develop an SDM process diagram. The patients were interviewed to assess how closely the diagram fit their perspectives on the HAE consultation and their involvement in decisions that concerned their care. Interview transcripts were assessed by the interviewer to determine the degree of SDM involvement in each consultation by using qualitative criteria from the literature.

RESULTS: Two physicians followed a high-SDM format, and one physician used a "blended" approach. The fourth physician followed a standard (low SDM) format. A successful SDM approach was found to require pre-visit planning, a commitment on behalf of the physician to use SDM methods to learn more about the patient, and empowerment of the patient to reflect on and vocalize his or her preferences and/or needs. Patients engaged in SDM were more likely to proactively request a treatment switch.

CONCLUSION: The adoption of validated HAE-specific treatment decision aids, as well as measures to change the mindsets of patients and physicians, may facilitate successful implementation of SDM in HAE. Clinical Trial Registration: The APeX-S trial was registered with clinicaltrials.gov (NCT03472040).

43(5):397-405

Available online at: dx.doi.org/10.2500/aap.2022.43.220050 (small fee)

Busse P, Kaplan A. 03/2022 The Journal of Allergy & Clinical Immunology in Practice.

Hereditary angioedema (HAE) is a rare, chronic, genetic disease that presents with nonpruritic angioedema of the face, extremities, airway (can be life-threatening), genitourinary system, and abdomen. These symptoms can significantly impair daily activities. Hereditary angioedema is classified into HAE owing to a deficiency of functional C1INH (HAE-C1INH) or HAE with normal C1INH (HAE-nl-C1INH). Both type I and II HAE-C1INH result from inherited or spontaneous mutations in the SERPING1 gene, which encodes for C1INH. These mutations result in C1INH dysfunction, leading to uncontrolled plasma kallikrein activity with excessive bradykinin production. Bradykinin receptor activation leads to vasodilation, increased vascular permeability, and smooth muscle contractions, resulting in submucosal angioedema through fluid extravasation. Hereditary angioedema nl-C1INH is caused by either a known or unknown genetic mutation. The underlying mechanism of HAE-nl-C1INH is less well understood but is thought to be related to bradykinin signaling. Plasma kallikrein inhibitors have been developed to inhibit the kallikrein-kinin pathway to prevent (prophylactic) and treat on-demand (acute) HAE attacks. Several of these medications are delivered through subcutaneous or intravenous injection, although new and emerging therapies include oral formulations. This article provides a historical review and describes the evolving landscape of available kallikrein inhibitors to treat HAE-C1INH. Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

10(3):716-722

Available online at: dx.doi.org/10.1016/j.jaip.2021.11.011

Maurer M, Aberer W, Caballero T, Bouillet L, Grumach AS, Botha J, Andresen I, Longhurst HJ. 09/2022 Clinical & Experimental Allergy.

In patients with hereditary angioedema (HAE), bradykinin causes swelling episodes by activating bradykinin B2 receptors. Icatibant, a selective bradykinin B2 receptor antagonist, is approved for on-demand treatment of HAE attacks. The Icatibant Outcome Survey (IOS; NCT01034969) is an ongoing observational registry initiated in 2009 to monitor the effectiveness/safety of icatibant in routine clinical practice. As of March 2019, 549 patients with HAE type 1 or 2 from the IOS registry had been treated of 5995 total attacks. This article reviews data published from IOS over time which have demonstrated that the effectiveness of icatibant in a real-world setting is comparable to efficacy in clinical trials; one dose is effective for the majority of attacks; early treatment (facilitated by self-administration) leads to faster resolution and shorter attack duration; effectiveness/safety of icatibant has been shown across a broad range of patient subgroups, including children/adolescents and patients with HAE with normal C1 inhibitor levels; and tolerability has been demonstrated in patients aged >=65 years. Additionally, this review highlights how IOS data have provided valuable insights into patients' diagnostic journeys and treatment behaviours across individual countries. Such findings have helped to inform clinical strategies and guidelines to optimise HAE management and limit disease burden. This research was sponsored by Takeda Development Center Americas, Inc. Takeda Development Center Americas, Inc., provided funding to Excel Medical Affairs for support in writing and editing this manuscript. Copyright © 2022 The Authors. Clinical & Experimental Allergy published by John Wiley & Sons Ltd.

52(9):1048-1058

Available online at: dx.doi.org/10.1111/cea.14206 (small fee)

Maurer M, Magerl M, Betschel S, Aberer W, Ansotegui IJ, Aygoren-Pursun E, Banerji A, Bara NA, Boccon-Gibod I, Bork K, Bouillet L, Boysen HB, Brodszki N, Busse PJ, Bygum A, Caballero T, Cancian M, Castaldo A, Cohn DM, Csuka D, Farkas H, Gompels M, Gower R, Grumach AS, Guidos-Fogelbach G, Hide M, Kang HR, Kaplan AP, Katelaris C, Kiani-Alikhan S, Lei WT, Lockey R, Longhurst H, Lumry WR, MacGinnitie A, Malbran A, Martinez Saguer I, Matta JJ, Nast A, Nguyen D, Nieto-Martinez SA, Pawankar R, Peter J, Porebski G, Prior N, Reshef A, Riedl M, Ritchie B, Rafique Sheikh F, Smith WB, Spaeth PJ, Stobiecki M, Toubi E, Varga LA, Weller K, Zanichelli A, Zhi Y, Zuraw B, Craig T. 07/2022 Allergy.

Hereditary angioedema (HAE) is a rare and disabling disease for which early diagnosis and effective therapy are critical. This revision and update of the global WAO/EAACI guideline on the diagnosis and management of HAE provides up-to-date guidance for the management of HAE. For this update and revision of the guideline, an international panel of experts reviewed the existing evidence, developed 28 recommendations, and established consensus by an online DELPHI process. The goal of these recommendations and guideline is to help physicians and their patients in making rational decisions in the management of HAE with deficient C1 inhibitor (type 1) and HAE with dysfunctional C1 inhibitor (type 2), by providing guidance on common and important clinical issues, such as: (1) How should HAE be diagnosed? (2) When should HAE patients receive prophylactic on top of on-demand treatment and what treatments should be used? (3) What are the goals of treatment? (4) Should HAE management be different for special HAE patient groups such as children or pregnant/breast-feeding women? and (5) How should HAE patients monitor their disease activity, impact, and control? It is also the intention of this guideline to help establish global standards for the management of HAE and to encourage and facilitate the use of recommended diagnostics and therapies for all patients. Copyright © 2022 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.

77(7):1961-1990

Available online at: dx.doi.org/10.1111/all.15214