Aulenbacher F, Gutsche A, Farkas H, Kohalmi KV, Kocaturk E, Aygoren-Pursun E, Martin L, Longhurst H, Staubach P, Zanichelli A, Aberer W, Bygum A, van den Elzen M, Buttgereit T, Magerl M

Nov/2025. Frontiers in immunology

Introduction: All angioedema (AE) presents with transient, localized swelling; however, the underlying causes, prognosis, and treatments vary significantly. Consequently, identifying a specific AE type is challenging. Methods: We aimed to apply a machine learning (ML) model to improve AE diagnosis. Random forest (RF) ML was used to create a prediction model for diagnosing correct AE types. Development comprised a literature search to establish AE's clinical characteristics, developing and translating questions in collaboration with 12 European AE centers, and selecting, testing, validating and optimizing the established ML model. Analysis included 342 specialist-diagnosed patients with one of six AE types. Results: The final optimized RF model correctly identified AE types with true positive rates of up to 94% in hereditary AE due to C1 inhibitor deficiency (C1INH), with a Percentage Accuracy of 89.2% and a Kappa value of 81.8% across the six AE types, with a high agreement with the diagnoses made by experts. Discussion: This is the first ever reported ML algorithm designed to pre-assess to aid AE diagnosis. Copyright © 2026 Aulenbacher, Gutsche, Farkas, Kohalmi, Kocaturk, Aygoren-Pursun, Martin, Longhurst, Staubach, Zanichelli, Aberer, Bygum, van den Elzen, Buttgereit and Magerl.

16:1697143

Available online at: https://dx.doi.org/10.3389/fimmu.2025.1697143

Bernatoniene J, Bourgoin-Heck M, Cancian M, Yang W, Hagin D, Pagnier A, Stobiecki M, Kinaciyan T, Phillips-Angles E, Gayet S, Bara NA, Hunter J, Mateescu E, DeSpirito M, Johnston D, Long D, Iocca H, Petroni D, Aygoren-Pursun E

Dec/2025. Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology

BACKGROUND: Hereditary angioedema (HAE) is a rare genetic disorder with symptoms often appearing during childhood. Current approved long-term prophylaxis (LTP) for children aged <12 years requires parenteral administration. Berotralstat is an oral, small-molecule plasma kallikrein inhibitor, approved as prophylaxis of HAE attacks in patients aged 12 years or older. OBJECTIVE: To evaluate oral berotralstat for the LTP of HAE in pediatric patients through APeX-P (NCT05453968), the largest trial of LTP in patients with HAE aged 2 to <12 years. METHODS: Before berotralstat initiation, patients received standard of care for 12 weeks. Pharmacokinetics, safety, and efficacy of berotralstat were assessed in a planned interim analysis. RESULTS: Median (range) age of patients (N = 29) was 8.0 (3-11) years, with 48.3% female. Median age at symptom onset was 2.0 years, and 82.8% of patients reported symptom onset before 6 years. Steady-state berotralstat median (range) Tmax was 3.9 (0.9-6.0) hours, geometric mean (coefficient of variation) Cmax was 204 ng/mL (40%), and AUC0-last was 915 ng*h/mL (42%). Most common treatment-emergent adverse events (AEs) were nasopharyngitis, upper respiratory tract infection, and headache. There were no drug-related grade 3/4 or serious AEs, deaths, or discontinuations related to AEs. Median (range) HAE attack rate during standard of care was 0.96 (0-5.0) attacks per 4-week period. Median (range) HAE attack rates for each 4-week period from day 1 to week 48 were 0 (week 4: 0-4.0; week 48: 0-1.7). CONCLUSION: Oral berotralstat was well tolerated and resulted in early and sustained reductions in HAE attack rates. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05453968 and ClinicalTrialsRegister.eu Identifier: EU CTN 2024-511257-22-00. Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.

135(6):681-688.e3

Available online at: https://dx.doi.org/10.1016/j.anai.2025.07.012

Bernstein JA, Betschel SD, Busse PJ, Banerji A, Wedner HJ, Manning M, Zaragoza-Urdaz RH, Anderson J, Gagnon R, Baptist AP, Soteres D, Lumry WR, Craig T, Petroni D, Hsu FI, Nova Estepan D, Juethner S, Watt M, Khutoryansky N, Zuraw BL

Aug/2025. Advances in therapy

INTRODUCTION: Lanadelumab is approved for long-term prophylaxis of hereditary angioedema (HAE) attacks in patients aged >= 2 years in the USA and aged >= 12 years in Canada. The EMPOWER Study (NCT03845400) evaluated the real-world effectiveness and safety of lanadelumab in male and female patients with HAE due to C1 inhibitor deficiency type 1 or 2 from the USA and Canada. Here, we report final, up to 36-month, data. METHODS: Patients aged >= 12 years were classified as newly treated with lanadelumab or established on lanadelumab (receiving < 4 and >= 4 lanadelumab doses at enrollment, respectively). The primary objective was effectiveness of lanadelumab as measured by HAE attack rate before and after lanadelumab initiation. Safety data were collected. RESULTS: A total of 109 patients received >= 1 lanadelumab dose and had >= 1 post-baseline safety assessment. Patients were 40.9 (17.4) years of age (mean [standard deviation (SD)]), majority (72/109; 66.1%) female, 37/109 (33.9%) male, and over 90% white. Patients newly treated with and established on lanadelumab received lanadelumab for 737.7 (374.5) (mean [SD]) and 907.1 (469.3) days, respectively, during the study. In patients newly treated with lanadelumab, the mean (95% confidence interval) observed attack rate (attacks/month) decreased by 85% after lanadelumab initiation, from 1.42 (0.34-2.50) pre-lanadelumab to 0.20 (0.02-0.38) post-lanadelumab initiation (cumulative period). Patients established on lanadelumab had an observed attack rate of 0.20 (0.10-0.30) during 36 months' follow-up. Of 154 treatment-emergent adverse events (TEAEs), no injection site reactions were reported and 6 (in 2 patients) were considered related to lanadelumab; no lanadelumab-related TEAEs were serious. CONCLUSION: Real-world data from EMPOWER showed marked HAE attack rate reduction up to 36 months after initiating lanadelumab in patients newly treated with lanadelumab and maintenance of low attack rates in patients established on lanadelumab. No new safety signals were identified. TRIAL REGISTRATION: ClinicalTrials.gov, identifier NCT03845400. Graphical abstract available for this article. Copyright © 2025. Takeda Development Center Americas Inc.

42(8):3882-3901

Available online at: https://dx.doi.org/10.1007/s12325-025-03226-3

Blair HA

Nov/2025. Drugs

Sebetralstat (EKTERLY R), an orally available plasma kallikrein inhibitor, is being developed by KalVista Pharmaceuticals for the on-demand treatment of acute attacks of hereditary angioedema (HAE). On 7 July 2025, sebetralstat received its first approval in the USA for the treatment of acute attacks of HAE in adult and pediatric patients aged 12 years and older. The drug has since been approved on 15 July 2025 in the UK for the treatment of HAE attacks in adults and adolescents aged 12 years and older. Sebetralstat has also received a positive opinion in the EU for the symptomatic treatment of acute attacks of HAE in adults and adolescents aged 12 years and older. This article summarizes the milestones in the development of sebetralstat leading to this first approval for HAE. Copyright © 2025. The Author(s), under exclusive licence to Springer Nature Switzerland AG.

85(11):1499-1505

Available online at: https://dx.doi.org/10.1007/s40265-025-02239-0

Bocquet A, Bouillet L, Hardy G, Boccon-Gibod I, Deroux A, Arnaud M, Pelletier F, Thanh AD, Ozanne N, Armengol G, Jeandel PY, Sailler L, Taquet MC, Launay D, Fain O, Gobert D

Dec/2025. Orphanet journal of rare diseases

BACKGROUND: The diagnosis of hereditary angioedema with a normal C1Inh was genetic. The two most frequent pathogenic variants are found in the FXII and PLG genes. Their management is similar to that of HAE patients with C1Inh deficiency but without evidence-based medicine. OBJECTIVE: The French Reference Centre for Angioedema (CREAK) Our center identified all patients with HAE with a normal C1Inh to evaluate their therapeutic management. METHODS: This was a national retrospective study conducted in our center the CREAK network. RESULTS: A total of 287 patients were identified with an F12 pathogenic variant (133 families), 38 with PLG (12 families) and one patient with KNG1. Among these patients, 111 patients with HAE-FXII and 19 patients with HAE-PLG were symptomatic. More women than men were symptomatic (86.3% vs. 30.8%, respectively) (p < 0,0001). The mean age at first attack was 24 +/- 12 years. 49% of patients with HAE-FXII were estrogen dependent (vs. 0% HAE-PLG, p < 0,01). 91% of patients with HAE-PLG needed to receive at least one attack of icatibant with 100% efficacy. 67% of patients with HAE-FXII were treated at least once: 56% with icatibant and 54% with C1Inh concentrate (during pregnancy). 12,6% of patients with HAE-FXII and 47,4% of patients with HAE-PLG required long-term prophylactic treatment: 66,7% of patients HAE-PLG who were taking tranexamic acid were attack-free (vs. 37,5 3% of HAE-FXII patients). 100% of patients with HAE-FXII treated with lanadelumab were completely asymptomatic (vs. 25% of patients with HAE-PLG). CONCLUSION: HAE patients with a normal C1inh have specific clinical features, including a later age at first attack than HAE patients with a normal C1inh, high sensitivity to estrogens of HAE-FXII and the location of the HAE-PLG on the tongue. The treatments used for HAE patients with C1Inh deficiency appear to be effective and safe. Low-dose progestin-only pills are good contraceptive options. Copyright © 2025. The Author(s).

21(1):5

Available online at: https://dx.doi.org/10.1186/s13023-025-04155-8

Christiansen S, O'Connor M, Craig T, Radojicic C, Wedner HJ, Danese S, Ulloa J, Desai V, Utter C, Andriotti T, Audhya P, Busse P

May/2025. Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology

BACKGROUND: Hereditary angioedema (HAE) is clinically characterized by recurrent attacks of subcutaneous and submucosal swelling. OBJECTIVE: To investigate real-world timing, potential barriers, and impact of delaying on-demand treatment (OD) of HAE attacks. METHODS: Patients with HAE (type I or II) aged 12 years or older with more than or equal to 1 treated (Treated Cohort) or untreated (Untreated Cohort) attack in the past 3 months were recruited by the US HAE Association. Respondents completed a 20-minute, self-reported, online survey about their last HAE attack. RESULTS: In the Treated Cohort (n = 94), of the 67% who reported treating their attack early, only 26% administered OD in less than 1 hour. Furthermore, 79% (n = 74) reported treatment-related anxiety, which correlated with treatment delay. Time to treatment paralleled changes in attack severity (33% mild attacks treated in <1 hour vs 67% in >=1 hour, progressed to moderate/severe) and mean duration (<1 hour: 0.7 day; >8 hours: 2.7 days). In the Untreated Cohort (n = 20), 50% of the respondents describing their last untreated attack as mild experienced progression to moderate or severe and 25% reported spread to another site including the larynx and face. Untreated attacks lasted a mean of 2.3 days. CONCLUSION: The disparity between survey respondents' perception of treating early and actual time to OD administration is striking. Treatment-related anxiety was a common reason for delaying OD. Increased treatment intervals translated into progression of HAE attack severity, duration, and spread to other sites. Suboptimal management of attacks intensifies the HAE disease burden, underscoring the need for improved treatment options, guidance, and removal of OD administration barriers. Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.

134(5):570-579.e4

Available online at: https://dx.doi.org/10.1016/j.anai.2024.12.012

Christiansen SC, Lopez-Gonzalez L, MacKnight SD, Laliberte F, Spencer C, Boudreau J, Nestler-Parr S, Johnston DT, Gillard P, Zuraw BL

Jun/2025. Journal of managed care & specialty pharmacy

BACKGROUND: Hereditary angioedema (HAE) is a rare disease characterized by unpredictable recurrent, debilitating, and potentially fatal attacks of subcutaneous and submucosal tissue swelling. OBJECTIVE: To evaluate all-cause, angioedema-related, and HAE attack-related medical visits and hospitalizations before and after initiation of berotralstat long-term prophylaxis (LTP) for patients with HAE in the United States. METHODS: This retrospective pre-post analysis used Komodo's Healthcare Map claims data to identify patients who initiated berotralstat (December 2020 to December 2022). The first entry for berotralstat dispensing was defined as the index date. Inclusion criteria comprised patients aged at least 12 years at index with at least 6 months of continuous insurance eligibility pre-index and evidence consistent with HAE pre-index (International Classification of Diseases, Tenth Revision, Clinical Modification diagnosis codes D84.1, D68.2, or T78.3x; medication use [on-demand or LTP]; or presence of diagnostic HAE laboratory tests). Rates of all-cause, angioedema-related, and HAE attack-related medical visits per person-year were compared post-index vs pre-index using rate ratios with 95% CIs and P values from generalized estimating equation Poisson regression models with robust SEs. Study limitations included the inability to distinguish HAE types and the uncertainty of whether a dispensed medication was consumed or taken as prescribed. RESULTS: The study population included 260 patients treated with berotralstat (mean age = 39.7 years; 74.2% female). After berotralstat initiation, there were significant decreases in the rates of all-cause health care resource utilization (HRU): all-cause inpatient (IP) visits decreased by 34% (P = 0.037) and all-cause outpatient/emergency department (OP/ED) visits decreased by 14% (P = 0.005). There were also significant decreases in rates of angioedema-related HRU (IP visits: 52%, P = 0.001; OP/ED visits: 44%, P < 0.001) as well as HAE attack-related HRU (IP visits: 60%, P < 0.001; OP/ED visits: 50%, P < 0.001). Use of on-demand medications decreased significantly after berotralstat initiation (32%, P = 0.002). Results were similar among subgroups of patients defined by HAE treatment history, including patients who were LTP-experienced (n = 126) and LTP-naive but on-demand treatment-experienced (n = 67). CONCLUSIONS: Prophylactic treatment of HAE with berotralstat was associated with significant reductions in all-cause HRU, including decreases to angioedema-related and HAE attack-related medical visits, hospitalizations, and administration of on-demand treatment.

31(6):578-589

Available online at: https://dx.doi.org/10.18553/jmcp.2025.31.6.578

Christiansen SC, Zuraw BL

Jan/2025. Allergy and asthma proceedings

Background: Idiopathic non-mast cell angioedema (INMA) is a rare disease typified by recurrent attacks of cutaneous and subcutaneous swelling. Every attack carries the potential for severe morbidity and, in the case of laryngeal involvement, mortality. Whereas therapies approved for hereditary angioedema (HAE) have been used in the care of patients with INMA, little is known with regard to their efficacy for the treatment of this disease. Objective: The objective was to gather evidence from global experts, ranking their assessment of on-demand therapy (ODT) and long-term prophylactic (LTP) treatment efficacy for INMA. Methods: A survey was developed and distributed to international experts invited to attend a 2023 symposium. INMA was diagnosed by standardized criteria. Linkert scales were used to rate the efficacy for ODT and LTP therapy. Enrollment was closed after 1 month and the data were analyzed. Results: Surveys were distributed to 31 experts from 16 countries with a 77% response rate (n = 24) reporting on 300 patients with INMA. Efficacy rankings of ODT were the following: icatibant (14 experts with 93 treated patients), 46.2% high and 38.7% moderate; and plasma-derived C1 inhibitor (C1INH) (13 experts with 31 treated patients), 32.3% moderate and 45.2% mild. Efficacy rankings of LTP were the following: antifibrinolytics (11 experts with 52 treated patients), 23.1% high and 38.5% moderate; lanadelumab (5 experts with 19 treated patients), 21% high and 79% moderate; and subcutaneous C1INH (3 experts with 19 treated patients), 21.1% moderate and 79.0% mild. LTP efficacy was also recorded for berotralstat and progestin. Conclusion: Icatibant (ODT) and either antifibrinolytics or lanadelumab (LTP) were ranked as the most efficacious treatments for the patients with INMA (among medications with at least five treated patients) by the expert physicians. Progestins, berotralstat, and plasma derived C1INH each demonstrated a favorable prophylactic effect; however, broader experience will be required to formulate overall recommendations.

46(1):38-44

Available online at: https://dx.doi.org/10.2500/aap.2025.46.240091

Cohn DM, Reshef A, Staubach P, Lumry WR, Feuersenger H, Jacobs I, Pragst I, Zuraw B, Bork K

Dec/2025. The Journal of allergy and clinical immunology

BACKGROUND: Hereditary angioedema (HAE) with normal C1 inhibitor (HAE-nC1INH), including HAE arising from F12 (HAE-FXII) or PLG (HAE-PLG) mutations, has a high unmet therapeutic need. OBJECTIVE: Our aim was to explore long-term prophylaxis with monthly subcutaneous garadacimab (anti-activated factor XII mAb) in patients with HAE-FXII or HAE-PLG. METHODS: Efficacy and safety were evaluated for HAE-FXII or HAE-PLG in open-label phase 2 (a 13-week treatment period [TP1] and subsequent >=44-week extension period [TP2]; 600 mg of garadacimab during each period) and ongoing phase 3 open-label extension (OLE; garadacimab dose 200 mg) studies. RESULTS: Patients 1 and 2 (HAE-FXII) completed phase 2 and then continued into OLE (total exposure time 42.9 and 40.2 months, respectively); patient 3 (HAE-FXII) discontinued TP1 (because of lack of efficacy). Patients 4 to 6 (HAE-PLG) completed TP1 only. Patients 1 and 2 (HAE-FXII) had a reduction in monthly attack rate (AR) of 88% or more versus run-in during phase 2 (TP1 AR = 0.4 and 0.0 and TP2 AR= 0.1 and 0.2, respectively; run-in = 3.2 for both) and were attack-free during the OLE. The AR was increased for patients 4 and 5 (HAE-PLG) and reduced for patient 6 (HAE-PLG). During TP1, 4 of 6 patients (HAE-FXII [n = 2]; HAE-PLG [n = 2]) experienced treatment-emergent adverse events (TEAEs): patient 1 (HAE-FXII) experienced a garadacimab-related TEAE (mild injection-site reaction), and patient 3 (HAE-FXII) experienced an unrelated serious TEAE (severe HAE attack). Patients 1 and 2 (HAE-FXII) collectively experienced 13 mild or moderate TEAEs during TP2 and 2 mild TEAEs during the OLE. CONCLUSIONS: Garadacimab showed a favorable safety profile in all 6 patients with HAE-nC1INH. Garadacimab also demonstrated efficacy in 2 of the 3 patients with HAE-FXII; a reduction in AR was observed in 1 of the 3 patients with HAE-PLG. Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.

156(6):1756-1760.e4

Available online at: https://dx.doi.org/10.1016/j.jaci.2025.08.005

Cohn DM, Soteres DF, Craig TJ, Lumry WR, Magerl M, Riedl MA, Audhya PK, Maurer M, Bernstein JA

Mar/2025. The Journal of allergy and clinical immunology

Over the past 2 decades, guidelines for the on-demand treatment of hereditary angioedema attacks have undergone significant evolution. Early treatment guidelines, such as the Canadian 2003 International Consensus Algorithm, often gated on-demand treatment by attack location and/or severity. Pivotal trials for on-demand injectable treatments (plasma-derived C1 esterase inhibitor, icatibant, ecallantide [United States only], and recombinant human C1 esterase inhibitor), which were approved in the United States and the European Union between 2008 and 2014, were designed accordingly. Subsequent post hoc analyses of clinical trial data alongside real-world evidence led to a paradigm shift. In 2013, the US Hereditary Angioedema Association guidelines recommended that all attacks, irrespective of location or severity, be considered for treatment as early as possible after onset to minimize morbidity and mortality. This approach remains the cornerstone of current treatment guidelines and has shaped the design of recent clinical trials, such as those for the investigational agents, oral plasma kallikrein inhibitor sebetralstat and oral bradykinin B2 receptor antagonist deucrictibant. This narrative review discusses the evolution of on-demand treatment guidelines, the clinical trial and real-world data that prompted significant revisions, and the subsequent changes to trial designs introduced to facilitate guideline compliance. Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.

155(3):726-739

Available online at: https://dx.doi.org/10.1016/j.jaci.2024.12.1079

Cohn DM, Gurugama P, Magerl M, Katelaris CH, Launay D, Bouillet L, Petersen RS, Lindsay K, Aygoren-Pursun E, Maag D, Butler JS, Shah MY, Golden A, Xu Y, Abdelhady AM, Lebwohl D, Longhurst HJ

Jan/2025. The New England journal of medicine

BACKGROUND: Hereditary angioedema is a rare genetic disease characterized by severe and unpredictable swelling attacks. NTLA-2002 is an in vivo gene-editing therapy that is based on clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein 9. NTLA-2002 targets the gene encoding kallikrein B1 (KLKB1). A single dose of NTLA-2002 may provide lifelong control of angioedema attacks. METHODS: In this phase 2 portion of a phase 1-2 trial, we randomly assigned adults with hereditary angioedema in a 2:2:1 ratio to receive NTLA-2002 in a single dose of 25 mg or 50 mg or placebo. The primary end point was the number of angioedema attacks per month (the monthly attack rate) from week 1 through week 16. Secondary end points included safety, pharmacokinetics, and pharmacodynamics (i.e., the change from baseline in total plasma kallikrein protein level); exploratory end points included patient-reported outcomes. RESULTS: Of the 27 patients who underwent randomization, 10 received 25 mg of NTLA-2002, 11 received 50 mg, and 6 received placebo. From week 1 through week 16, the estimated mean monthly attack rate was 0.70 (95% confidence interval [CI], 0.25 to 1.98) with 25 mg of NTLA-2002, 0.65 (95% CI, 0.24 to 1.76) with 50 mg, and 2.82 (95% CI, 0.80 to 9.89) with placebo; the difference in the estimated mean attack rate with NTLA-2002 as compared with placebo was -75% with 25 mg and -77% with 50 mg. Among patients who received NTLA-2002, 4 of the 10 patients who received 25 mg (40%) and 8 of the 11 who received 50 mg (73%) were attack-free with no additional treatment during the period from week 1 through week 16. The most common adverse events among patients who received NTLA-2002 were headache, fatigue, and nasopharyngitis. The mean percent change in total plasma kallikrein protein levels from baseline to week 16 was -55% with 25 mg and -86% with 50 mg; levels remained unchanged with placebo. CONCLUSIONS: NTLA-2002 administered in a single dose of 25 mg or 50 mg reduced angioedema attacks and led to robust and sustained reduction in total plasma kallikrein levels in patients with hereditary angioedema. These results support continued investigation in a larger phase 3 trial. (Funded by Intellia Therapeutics; ClinicalTrials.gov number, NCT05120830; EudraCT number, 2021-001693-33.). Copyright © 2024 Massachusetts Medical Society.

392(5):458-467

Available online at: https://dx.doi.org/10.1056/NEJMoa2405734

Costanzo G, Sambugaro G, Sartorio S, Zanichelli A, Firinu D

Jan/2025. Expert opinion on biological therapy

INTRODUCTION: Revolutionary drugs have been developed and approved in the last 5 years for the treatment of hereditary angioedema (HAE). Increased knowledge of HAE pathophysiology has led to the development of innovative drugs for self-administered on-demand therapy and for short- and long-term prophylaxis (LTP). This has rendered possible a personalized approach for patients, allowing greater control of symptoms, better quality of life and reduction in the incidence of adverse effects linked to old treatments. AREAS COVERED: In this review we have highlighted which treatments are currently approved for HAE and some of the promising future therapies under development. EXPERT OPINION: While the first generation of approved treatments improved disease control for most patients, innovative therapies may allow individualized action plans and reduce complexity of treatment. Switching therapies due to insufficient efficacy, patient preference or adverse events is becoming progressively feasible and common. New LTPs may lead to the achievement of attack-free remission, allowing us to hopefully reach complete disease control for all patients and further improving their quality of life. In particular, LTPs with longer administration intervals, and on-demand therapies administered via the oral route will have a key role and will set more prominent targets for the upcoming drugs.

25(1):79-91

Available online at: https://dx.doi.org/10.1080/14712598.2024.2441845

de Lange M, Petersen RS, Fijen LM, Cohn DM

Dec/2025. The Journal of allergy and clinical immunology

BACKGROUND: Angioedema due to acquired C1-inhibitor deficiency (AAE-C1INH) is a rare disorder characterized by recurrent episodes of angioedema due to excessive bradykinin release. Deucrictibant, an oral B2 receptor antagonist, is currently under development for long-term prophylactic and on-demand treatment in hereditary angioedema. In a recent small double-blind, placebo-controlled crossover trial (EudraCT no. 2021-000720-36), all 3 participants with AAE-C1INH had complete control of angioedema during 8 weeks of treatment with deucrictibant immediate-release capsule. OBJECTIVE: We investigated the long-term efficacy and safety of deucrictibant extended-release tablet as prophylactic treatment in patients with AAE-C1INH. METHODS: In this open-label, single-arm study, patients with AAE-C1INH received deucrictibant 40 mg extended-release tablet once daily. The primary end point was the time-normalized number of investigator-confirmed angioedema attacks per 28 days of exposure to deucrictibant compared to baseline. RESULTS: Four patients with AAE-C1INH were enrolled, 3 of whom were rolled over from the randomized controlled trial of immediate-release deucrictibant. The on-treatment follow-up duration in this study ranged from 563 to 612 days. The mean monthly attack rates at baseline were 1.2, 1.2, 0.9, and 2.1, respectively (mean, 1.35). One mild abdominal attack was reported by one patient 2 days after initiation of deucrictibant treatment; the remaining patients were attack-free during the treatment period. The mean monthly angioedema attack rate for all patients was 0.01. No treatment-related adverse events were reported. CONCLUSION: Deucrictibant extended-release tablet effectively prevented angioedema attacks in patients with AAE-C1INH, with no safety concerns. Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.

156(6):1650-1655

Available online at: https://dx.doi.org/10.1016/j.jaci.2025.07.033

De Maria B, Ranucci L, Gino C, Zulueta A, Parati M, Cesoni Marcelli A, Zingale LC, Sideri R, Dalla Vecchia LA, Perego F

Dec/2025. Frontiers in physiology

Background: Regulation of vascular permeability in hereditary angioedema due to C1 inhibitor deficiency (HAE-C1INH) is key to understanding the disease, but the role of the autonomic nervous system (ANS) in this mechanism remains unclear. Purpose: The aim of this study was to compare the cardiovascular autonomic response to the head-up tilt test (HUTT) in HAE-C1INH patients and matched healthy controls (HCs). Methods: HAE-C1INH patients were evaluated during a 1-week symptom-free period. Electrocardiogram (ECG) and beat-to-beat non-invasive arterial blood pressure (BP) were recorded in the supine position (REST) and during 70degree tilt (TILT). Heart rate and systolic BP (SBP) variability indices were derived. Variance (sigma2 SBP) and low-frequency power (LFSBP) of SBP variability were used as markers of sympathetic vascular control. Results: Twenty-five HAE-C1INH patients [13 male individuals, 44 (28.8-57.5) years] and 25 HCs [13 male individuals, 44 (30.8-54.3) years] were enrolled and divided into <45 and >=45 age groups. Eighteen patients were on long-term prophylaxis (LTP). In the younger group, LFSBP increased from REST to TILT in both groups, with no differences. In older subjects, HAE-C1INH patients showed higher sigma2 SBP [21.2 (9.3-59.2) vs. 7.5 (1.9-14.6) mmHg2] and a greater LFSBP increase [9.4 (4.6-22.4) vs. 0.9 (0.2-7.6) mmHg2] than HCs during TILT, suggesting sympathetic hyperactivation. No significant group differences in cardiac autonomic control were observed during REST or TILT, regardless of age. Findings in the LTP subgroup mirrored those of the full cohort. Conclusion: Older HAE-C1INH patients display altered vascular autonomic regulation, with an exaggerated sympathetic response during orthostatic stress. Further studies are needed to assess the role of LTP in these alterations. Clinical Trial Registration: https://clinicaltrials.gov/study/NCT06408805?cond=Hereditary%20Angioedema&term=autonomic&rank=1. Copyright © 2025 De Maria, Ranucci, Gino, Zulueta, Parati, Cesoni Marcelli, Zingale, Sideri, Dalla Vecchia and Perego.

16:1690915

Available online at: https://dx.doi.org/10.3389/fphys.2025.1690915

Demongeot J, Diallo AK, Hazgui H, Jelassi M, Kelloufi F, Ben Khalfallah H, Espinoza A, Montalva-Medel M

Dec/2025. International journal of molecular sciences

Many familial diseases are caused by genetic accidents, which affect the genome and its epigenetic environment, summarized as an interaction network between genes. We wish to study the existence or absence of robustness for such genetic interaction networks centered on the gene SP1 and involved in three familial diseases: familial angioedema, osteogenesis imperfecta, and biliary atresia. The updating of gene states at the vertices of the interaction graph of the genetic network (1 if a gene is activated, 0 if it is inhibited) can be performed in multiple ways that have been well-studied over the last 20 years: parallel, block-parallel, sequential, block-sequential, random, etc. We add to these classic updating modes two new ones, the intricate and the state-dependent. We have studied the robustness of three particular interaction graphs related to the familial diseases chosen as examples. The comparison of the interaction graphs and dynamics of the chosen familial diseases of different etiology shows common points in their interaction graphs and similarities in their dynamics according to their expression clock.

Available online at: https://dx.doi.org/10.3390/ijms262411976

Donadoni M, La Cava L, Bizzi E, Popescu Janu V, Meschia A, Cirigliano F, Cogliati C, Gidaro A

Oct/2025. Medicina (Kaunas, Lithuania)

Background and Objectives : Hereditary angioedema caused by C1 inhibitor deficiency (HAE-C1-INH) is a rare genetic condition characterized by recurrent, potentially life-threatening episodes of angioedema. Long-term prophylaxis (LTP) is essential for decreasing the frequency and severity of attacks. This study aims to compare the safety profiles of two first-line LTP therapies, both of which inhibit kallikrein: berotralstat (oral) and lanadelumab (subcutaneous), using data from the WHO's VigiBase pharmacovigilance database. Materials and Methods: The study employed a retrospective quantitative design, utilizing the World Health Organization's pharmacovigilance database, VigiAccess, which contains individual case safety reports of adverse drug reactions (ADRs) to identify cases of ADRs associated with HAE-C1-INH long-term prophylaxis. Results: A total of 644 reports for berotralstat and 3432 reports for lanadelumab were analyzed. Berotralstat was mainly associated with gastrointestinal adverse events (47.9%), while lanadelumab was linked to injection site reactions (45.9%), infections (23.3%), musculoskeletal and connective tissue disorders (10%), immune system disorders (5.3%), vascular disorders (4.7%), and metabolic issues (3.9%). Female patients were more frequently affected in both groups. Statistically significant differences were observed, reflecting the differences in administration methods and pharmacological profiles between the two drugs. Limitations include the self-reported nature of the data and the absence of detailed clinical information. Conclusions: The results confirmed the literature's data on the gastrointestinal adverse effects of berotralstat, as well as site reactions and infections associated with lanadelumab. Notably, musculoskeletal and connective tissue disorders, immune system disorders, vascular disorders, and metabolic issues occurred more frequently in patients using lanadelumab.

Available online at: https://dx.doi.org/10.3390/medicina61111897

Farkas H, Anderson J, Bouillet L, Caballero T, Cancian M, Craig T, Fukunaga A, Grivcheva-Panovska V, Guilarte M, Honda D, Kanarek H, Kiani-Alikhan S, Kinaciyan T, Leguevaques D, Longhurst HJ, Magerl M, Manning ME, Martinez-Saguer I, Melamed I, O'Connor ME, Peter J, Savic S, Soteres DF, Staevska M, Staubach P, Stobiecki M, Tachdjian R, Valerieva A, Yong PFK, Hao J, Iverson M, Smith MD, Yea CM, Audhya PK, Aygoren-Pursun E, Bernstein JA, Cohn DM, Lumry WR, Riedl MA, Zanichelli A, Maurer M

Nov/2025. The journal of allergy and clinical immunology. In practice

BACKGROUND: Poor compliance with hereditary angioedema guidelines for on-demand treatment is common due to challenges with parenteral administration. Sebetralstat, an oral plasma kallikrein inhibitor, demonstrated faster times to beginning of symptom relief, reduction in attack severity, and complete resolution than placebo in the phase 3 KONFIDENT trial (NCT05259917). OBJECTIVE: This analysis evaluated long-term safety and effectiveness of sebetralstat in KONFIDENT-S (NCT05505916), an ongoing, 2-year, open-label extension study. METHODS: Enrolled participants aged >=12 years with hereditary angioedema due to C1-inhibitor deficiency administered sebetralstat 600 mg for each attack, as early as possible, regardless of severity or location. The primary outcome was incidence of treatment-emergent adverse events (TEAEs). Secondary outcomes were times to beginning of symptom relief, reduction in severity, and complete resolution. RESULTS: At data cutoff (January 31, 2024), 84 participants (mean age: 35.9 years; 14.3% <18 years; 64.3% female) treated 640 attacks with sebetralstat (84% of total attacks); the median (interquartile range [IQR]) number of attacks per participant was 5 (2-8). The median (IQR) time from attack onset to treatment was 9 (1-69) minutes. Baseline severity was as follows: 30.0% mild, 43.3% moderate, and 25.0% severe or very severe. Treatment-related TEAEs occurred in 8 participants (9.5%); none were serious. The median time to beginning of symptom relief (allowing for missing data entries between consecutive time points) was 1.68 (0.79-3.89) hours, to reduction in severity 6.57 (1.61 to >12) hours, and to complete attack resolution 21.02 (7.22 to >24) hours. No evidence of a diminished response over repeated treatments of attacks was observed. CONCLUSIONS: Oral sebetralstat enabled compliance with treatment guidelines. No new safety signals were observed, and effectiveness for repeated attacks was consistent with the KONFIDENT trial results. Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.

13(11):3094-3103.e5

Available online at: https://dx.doi.org/10.1016/j.jaip.2025.08.020

Farkas H, Peter JG, Stobiecki M, Anderson J, Aygoren-Pursun E, Hagin D, Jesenak M, Kessel A, Kiani-Alikhan S, Kinaciyan T, Manning M, Reshef A, Wu A, Iocca HA, Johnston DT, Noble L, Tomita D, Banerji A

Sep/2025. Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology

BACKGROUND: Berotralstat is a once-daily oral medication for the prophylaxis of hereditary angioedema (HAE) attacks in patients aged 12 years and older. OBJECTIVE: To assess the long-term safety and efficacy of berotralstat in patients with HAE caused by C1 inhibitor deficiency. METHODS: APeX-S was a global, open-label phase 2 study (NCT03472040) assessing berotralstat 150 and 110 mg for up to 96 weeks in the United States and 240 weeks elsewhere. The primary objective was long-term safety and tolerability; secondary objectives included efficacy and impact on quality of life (QoL) of berotralstat. Safety was evaluated by means of treatment-emergent adverse events and laboratory analyses. Efficacy was assessed using the number and rate of HAE attacks, durability of response, and number and proportion of days with angioedema symptoms. QoL was evaluated using the Angioedema Quality of Life Questionnaire. RESULTS: In APeX-S, 387 patients were enrolled and received berotralstat 150 mg (n = 287) or 110 mg (n = 100) from day 1. A total of 70 patients on berotralstat 110 mg crossed over to berotralstat 150 mg after a median (range) of 48 (46-71) weeks. Treatment-emergent adverse events up to 240 weeks were reported by 334 patients (86.3%); the most common being nasopharyngitis (23.8%), headache (14.7%), diarrhea (14.5%), upper respiratory tract infection (12.9%), and abdominal pain (11.1%). Treatment with berotralstat led to improvements in HAE attack rates and Angioedema Quality of Life Questionnaire scores up to week 96, with greater improvements observed in patients who received berotralstat 150 mg from day 1. CONCLUSION: This study supports the long-term safety of berotralstat and its efficacy in preventing HAE attacks and improving QoL. CLINICAL TRIAL REGISTRATION: This trial was registered at ClinicalTrials.gov as NCT03472040 (https://clinicaltrials.gov/study/NCT03472040). Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.

135(3):311-319.e6

Available online at: https://dx.doi.org/10.1016/j.anai.2025.06.004

Ferriani MPL, Seneda Lemos JE, Arruda LK, Nunes FL, Dias MM, Kolarik ML, Roxo-Junior P, Ferraro MF, Zanetti MET, Serpa FS, Chong-Neto HJ, Minafra FG, Valle SOR, Campos RA, da Silva J, Mansour E, Goncalves RF, Toledo EC, Marcelino FC, Moreira IF, Azoubel-Antunes A, Ferreira JFS, Dias GAC, Aun MV, Castro APBM, Oliva-Alonso ML, Batigalia VA, Tavares CLTSV, Capelo AV, Moyses TR, Rosario Filho NA, Jannuzzi LNP, Fragnan NTML, Figueiredo JP, Fonseca JT, Teixeira AJR, Nasser NMF, Ferraroni NR, Mendonca LO, Iwashita MT, Prado AIF, Tumelero MT, Machado JA, Kamoi TO, Ferrel LM, Barbosa AMSC, de Moraes CGFB, Kruk T, Figueiredo MR, Moraes MSY, Moreno AS, Maia LSM, Traina F, Ruy PC, Pesquero JB, Bork K, Cichon S, Aragon DC, Giavina-Bianchi P, Grumach AS

Nov/2025. The journal of allergy and clinical immunology. In practice

BACKGROUND: Hereditary angioedema (HAE) is a rare autosomal dominant disorder with a prevalence of 1:50,000 individuals. Delayed diagnosis and deaths from asphyxia still occur. OBJECTIVE: To identify knowledge and management gaps regarding clinical, genetic, and therapeutic aspects of HAE in Brazil, aiming to improve patient care and outcomes. METHODS: A Brazilian multicenter HAE registry was established, with patients' data included by treating physicians using the REDCap (Research Electronic Data Capture) platform. RESULTS: Of the 820 patients with HAE enrolled, 68.8% were female. Most (72.4%) experienced HAE due to C1 inhibitor deficiency (HAE-C1INH), whereas 19.4% had HAE with normal C1INH caused by variants in the F12 gene (HAE-FXII). Onset of symptoms occurred earlier in HAE-C1INH as compared with HAE-FXII (mean 11.2 years vs 19.4 years, respectively), and time for diagnosis was shorter in patients younger than 18 years, as compared with those 18 years and older (mean 1.8 years vs 14.5 years, respectively). Regarding treatment, 52.8% received first-line on-demand therapies (icatibant or plasma-derived C1INH [pdC1INH]). Only 4.8% used first-line options for long-term prophylaxis (LTP), such as lanadelumab or subcutaneous/intravenous pdC1INH. Attenuated androgens were used for LTP in 52% of patients, with adverse effects reported for 34.8%. CONCLUSIONS: Brazilian patients with HAE share common aspects with global patients, including predominance in women, and HAE-C1INH as the most common subtype. Available genetic testing allowed for identification of a notable proportion of HAE-FXII (19.4% of the patients). Despite recent advances, access to first-line therapies for LTP of HAE attacks remains limited. Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.

13(11):3104-3117

Available online at: https://dx.doi.org/10.1016/j.jaip.2025.08.026

Fisch SA, Rundle AG, Neugut AI, Freedberg DE

Dec/2025. International archives of allergy and immunology

INTRODUCTION: Hereditary angioedema (HAE) is a rare disease caused by dysfunction or lack of the C1 esterase inhibitor (C1-INH) protein. The true prevalence of HAE and whether this prevalence differs across regions is uncertain. METHODS: To estimate the prevalence of HAE worldwide, a systematic review and meta-analysis were performed. The pooled prevalence of HAE was calculated using a random-effects model, and heterogeneity across studies was assessed. RESULTS: Twenty-four studies from 2000 to 2024 were included in the analysis, describing 11,245 cases of HAE. The pooled prevalence of HAE was 1.22 cases per 100,000 people (95% confidence interval [CI]: 0.91, 1.53), with lower prevalences reported in Asia and Africa compared to Europe and North America. HAE type 1 made up most of the cases, with a slight female predominance. CONCLUSION: HAE is a rare condition which affects 1-2 individuals per 100,000 people worldwide. A true estimate of the prevalence of HAE will inform care for the condition, especially as new treatment options become available. Copyright © 2025 S. Karger AG, Basel.

186(8):802-810

Available online at: https://dx.doi.org/10.1159/000543321

Fung S

Jun/2025. Drugs

Garadacimab (Andembry R) is a fully human IgG4/lambda recombinant monoclonal anti-activated Factor XII antibody being developed by CSL Behring for the prevention of hereditary angioedema attacks. In January 2025, garadacimab received its first approval in Australia and the UK for prevention of hereditary angioedema attacks in adult and adolescent patients aged >= 12 years. Additionally, in February 2025, garadacimab was approved for the same indication in the EU, Japan and Switzerland. In the USA and Canada, regulatory review of garadacimab is currently underway. This article summarizes the milestones in the development of garadacimab leading to this first approval for prevention of recurrent hereditary angioedema attacks in adult and adolescent patients aged >= 12 years. Copyright © 2025. The Author(s), under exclusive licence to Springer Nature Switzerland AG.

85(6):827-832

Available online at: https://dx.doi.org/10.1007/s40265-025-02180-2

Gao H, Zhao Y, Chen S, Zhang Z, Yang F, Chen Z, Wang L, Yang J, He S, Tang C, Zheng S, Guan C, Xu Y, Tang L, Zhang A, Maurer M, Lee D, Ma L, Luo X

Aug/2025. Journal of clinical immunology

Hereditary angioedema with normal C1 inhibitor (HAE-nC1-INH) is a rare and genetically heterogeneous disorder with an incomplete molecular understanding. This study aimed to identify novel genetic variants associated with HAE-nC1-INH, characterize their clinical manifestations, and evaluate real-world treatment responses. Whole-exome sequencing of 27 HAE patients, including eight with HAE-nC1-INH, identified four previously unreported MYOF variants and additional pathogenic variants in KNG1 and HS3ST6, expanding the genetic spectrum of the disease. MYOF variants were associated with recurrent edema episodes, often with prolonged duration. The HS3ST6 variant was linked to refractory angioedema with non-resolving lower extremity involvement, highlighting atypical, persistent clinical phenotypes beyond the classical self-limiting presentation of HAE. Lanadelumab effectively reduced attack frequency in most patients; however, the variability in treatment response, particularly in MYOF and HS3ST6 carriers, highlights the need for individualized therapeutic approaches. These findings provide new insights into the genetic and clinical complexity of HAE-nC1-INH and emphasize the importance of genetic testing in refining diagnosis and optimizing treatment strategies, contributing to a more precise understanding of hereditary angioedema. Copyright © 2025. The Author(s).

45(1):124

Available online at: https://dx.doi.org/10.1007/s10875-025-01912-z

Garcia R, Cheng S, Glassman F, Sharma A, De Miguel-Lillo B, Wiens M, Johnston C, Lawo JP, Pragst I, French J, Polhamus D, Nandy P

May/2025. CPT: pharmacometrics & systems pharmacology

Hereditary angioedema (HAE) is a rare genetic disease that manifests as recurrent, unpredictable, and potentially life-threatening attacks of angioedema. Garadacimab is a first-in-class, fully human, monoclonal antibody targeting activated factor XII (FXIIa) that is under clinical development for the long-term prophylaxis of HAE attacks. We developed population pharmacokinetic (PK)/pharmacodynamic (PD)/exposure-response (ER) models using pooled data across clinical studies to quantify the relationship between garadacimab concentration and the relative risk of HAE attacks and to support the rationale for 200 mg once-monthly dosing. The PK of garadacimab was adequately characterized by a two-compartment model with first-order absorption and elimination. The PD, as analyzed by FXIIa-mediated kallikrein activity, was adequately characterized by a direct inhibitory response model. PK/PD parameters were generally consistent across multiple covariates. ER analysis based on a repeated-time-to-event model showed that administration of garadacimab 200 mg subcutaneously (SC) once monthly results in 75% of patients reaching the target therapeutic threshold (90% reduction in relative risk of attack vs. run-in). Use of a loading dose (two 200 mg SC injections) as the first administration achieved steady-state PK exposures and PD response, with 85% of patients having exposures surpassing the therapeutic threshold. The models support the use of garadacimab 200 mg SC once-monthly dosing in patients aged >= 12 years, with no need for dose adjustments, and indicate that, due to the achievement of garadacimab steady-state exposures after the first administration, the use of a loading dose may facilitate the early onset of protection against HAE attacks, as observed in clinical studies. Copyright © 2025 The Author(s). CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.

14(5):954-963

Available online at: https://dx.doi.org/10.1002/psp4.70009

Ghosh D, Anderson J, Singh U, Bernstein CK, Bernstein JA

May/2025. The Journal of allergy and clinical immunology

BACKGROUND: Approximately 85% of hereditary angioedema (HAE) attacks are associated with prodromal symptoms. OBJECTIVE: We investigated the clinical effect of treating HAE C1-esterase inhibitor (HAE-C1-INH) type 1 patients with recombinant human C1-INH (rhC1-INH) during their prodrome versus an active swelling episode and associated changes in blood transcriptomic genes and pathways before and after treatment. METHODS: A 2-center, unblinded, case-crossover study randomly assigned 5 HAE-C1-INH type 1 patients to prodrome or attack treatment groups; after a patient was treated for either 2 prodromes or 2 HAE attacks, they were crossed over to be treated for 2 HAE attacks or 2 prodromes. All patients were treated during the prodrome or acute attack with rhC1-INH; (conestat alfa, 50 IU/kg body weight, maximum 4200 IU for body weight >=85 kg). Blood samples for analysis by RNA sequencing were obtained (1) at baseline, (2) during the prodrome before and after treatment, and (3) during an attack before and after treatment. Differentially expressed genes and pathways were elucidated by Ingenuity Pathway Analysis (IPA; Qiagen). RESULTS: Treatment during the HAE prodrome with rhC1-INH was as effective at preventing progression to a swelling episode as treatment of an acute attack. HAE prodromes were associated with upregulation of multiple inflammatory extracellular matrix genes, neuropeptide, and inflammasome member genes (eg, SPARCL1, AGRP, NLRP9; log2 fold change = 4.1, 3.9, and 3.0, respectively). TNF-alpha and IL-10 were 2 major hub genes in prodrome-associated enriched gene networks. rhC1-INH treatment resulted in reversal of the disease signature in HAE-associated dysregulated pathways. Approximately 42% of prodrome-associated differentially expressed genes were also associated with HAE attacks. The enriched gene networks with hub genes for prodrome (ERK and VEGF) and for acute attack (insulin and SERPINA1) stages of HAE were identified. The major enriched pathways shared between HAE prodrome and attack were associated with neutrophil function and prostaglandin metabolism. CONCLUSION: Treatment of HAE-C1-INH type 1 patients who have a well-defined prodrome that historically results in an acute attack may be justified clinically and mechanistically. This approach would represent a paradigm shift for management of HAE on-demand treatment. Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

155(3):947-955

Available online at: https://dx.doi.org/10.1016/j.jaci.2024.11.035

Glassman F, Lawo JP, Bica MA, Roberts A, Pawaskar D, Akama H, Jain M, Goodson S

Apr/2025. Journal of clinical pharmacology

Garadacimab, an activated factor XII (FXIIa) inhibitor monoclonal antibody, is being evaluated for the long-term prophylaxis of hereditary angioedema. Here, we report the results from a two-part, phase 1, open-label, single ascending dose study assessing the pharmacokinetics (PK), pharmacodynamics, safety, and tolerability after subcutaneous (SC) and intravenous (IV) administration of garadacimab in healthy Japanese and White participants. Part 1 assessed garadacimab PK after SC administration of a 200 mg dose in weight-matched White and Japanese participants, and 600 mg dose in Japanese participants. Part 2 assessed 3 and 10 mg/kg IV doses in Japanese participants. Follow-up for safety was over 84 days post-dose. Overall, 37 participants received garadacimab dosing and 36 completed the study, with one participant lost to follow-up. Following SC administration, time to maximum plasma concentration (tmax) occurred at 7 days post-dose, and garadacimab exposure, based on maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC), increased less than 3-fold when tripling the dose. PK was comparable between Japanese and White participants, with geometric mean ratios for Cmax and AUC close to 100%. Following IV administration, tmax occurred at the end of infusion, and garadacimab exposure increased in a dose-proportional manner. Inhibition of FXIIa-mediated kallikrein activity versus baseline was observed in all participants receiving the SC and IV doses. No anti-drug antibodies against garadacimab were reported. Consistent with pivotal phase 3 (VANGUARD) outcomes, no safety concerns and no difference in the safety profile of garadacimab were observed between healthy Japanese and White participants. Copyright © 2024 The Author(s). The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.

65(4):466-477

Available online at: https://dx.doi.org/10.1002/jcph.6162

Gokmen NM, Gumusburun R, Camyar A, Ozgul S, Ozisik M, Turk T, Sin AZ

Jul/2025. BMC oral health

BACKGROUND: The factors causing acute attacks during dental and gingival procedures in patients with hereditary angioedema due to C1 inhibitor (HAE-C1INH) deficiency remain unclear. Our aim is to investigate the patients and dental/gingival procedure characteristics influencing acute attack risk. METHODS: A retrospective review of 638 dental interventions in 40 HAE-C1INH patients was conducted between June and September 2023 using questionnaires, diaries, and medical charts. Data included demographics, clinical details, intervention history, and types of procedures, aiming to understand acute attack patterns. RESULTS: A total of 40 HAE-C1INH patients (36 type 1; 23 female; median age 41.5 (30.8-53.5) years; median disease onset age 10.5 (5.0-15.0) years; median annual attack frequency 24.5 (12.0-52.0) were analyzed. Facial and laryngeal edema history were found in 82.5% and 67.5% of patients, respectively. Treatment-naive median serum C4 level, C1 inhibitor (C1INH) function and C1INH antigenic level (for type 1 HAE) were 6 mg/dL (IQR: 5-6; normal range: 10-40 mg/dL), 13.2% (IQR: 7.2-18.8; normal range: 70-130%), and 5.6 mg/dL (IQR: 3-7; normal range: 0.21-0.39 g/L), respectively. Acute angioedema attacks were observed in 72 out of 638 procedures. Before HAE-C1INH diagnosis, per-person attack frequency and per-procedure attack frequency were found to be 26.5% (9/34), and 15.74% (95% CI:12.28-19.71), respectively. Higher annual attack frequency (p = 0.038), lower C1INH function (p = 0.044), and female gender (p = 0.047) related to acute attacks due to dental interventions in pre-diagnosis period. Prophylactic HAE treatment significantly reduced the frequency of acute attacks following dental procedures. The attack frequency per procedure was 14.6% (95% CI: 11.48-18.20) among untreated patients and 3.23% (95% CI: 1.19-6.89) among those receiving prophylactic medication, post-diagnosis. Tooth extraction, wisdom teeth extraction and challenging surgical tooth extraction were found to be more risky. CONCLUSION: Prophylactic HAE treatment significantly reduced the frequency of acute attacks, compared to the untreated group. Pre-procedural prophylactic treatment is particularly important for safer dental care in HAE patients with higher annual attack frequency, lower C1INH function, and female gender, especially during high-risk procedures such as tooth extraction, wisdom teeth extraction, and challenging surgical tooth extractions. Copyright © 2025. The Author(s).

25(1):1017

Available online at: https://dx.doi.org/10.1186/s12903-025-06359-7

Guilarte M, Lumry WR, Magerl M, Martinez Saguer I, Reshef A, Sobotkova M, Braverman J, Lawo JP, Wieman L, Nenci C, Katelaris CH

May/2025. Allergy and asthma proceedings

Background: Hereditary angioedema (HAE) attacks substantially impair health-related quality of life (HRQoL). Current World Allergy Organization and the European Academy of Allergy and Clinical Immunology guidelines goals include complete control and normalization of patients' lives. Garadacimab (anti-activated factor XII monoclonal antibody) reduced the mean attack rate after first administration in the pivotal phase III (VANGUARD; NCT04656418) and ongoing long-term phase III open-label extension (OLE) (NCT04739059) studies. Objective: To report exploratory HRQoL data from the interim analysis of the phase III OLE study (data cutoff February 13, 2023). Methods: Patients ages >=12 years and with HAE received garadacimab 200 mg subcutaneously once monthly in the OLE study. The patient population comprised patients who were garadacimab naive (received placebo in the previous phase III study and newly enrolled patients) and patients who received garadacimab in previous phase II/III studies. The Angioedema Quality of Life (AE-QoL) questionnaire, Treatment Satisfaction Questionnaire for Medication version II (TSQM II), and Work Productivity and Activity Impairment: General Health (WPAI:GH) questionnaire were administered at baseline and every 3 months during the OLE study. AE-QoL and TSQM II scores were evaluated in comparison with minimal clinically important differences (MCID). Results: Overall, 90 patients who were garadacimab naive and 71 patients with previous garadacimab exposure received garadacimab in the phase III OLE study. The mean +/- standard deviation AE-QoL total score improved by 34.2 +/- 18.8 points in patients who were garadacimab naive and by 2.3 +/- 13.1 points further to the reduction experienced in patients with previous garadacimab exposure. The AE-QoL MCID was met by 92.1% of patients who were garadacimab naive; 81.6% of patients with previous garadacimab exposure experienced stable AE-QoL scores or further improvements per MCID. TSQM II scores were improved from day 1 with garadacimab and sustained to month 12. Improvements in WPAI:GH scores were consistent with AE-QoL and TSQM II. Conclusion: Garadacimab elicited clinically meaningful long-term improvements in HRQoL, work productivity, and treatment satisfaction in patients with HAE, which brought them closer to complete disease control and normalization of life.Clinical trial NCT04739059, <ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="http://clinicaltrials.gov">clinicaltrials.gov.

46(3):192-199

Available online at: https://dx.doi.org/10.2500/aap.2025.46.250027

Horvath HR, Visy B, Kohalmi KV, Balla Z, Andrasi N, Czaller I, Zotter Z, Farkas H

Oct/2025. Clinical immunology (Orlando, Fla.)

BACKGROUND: Hereditary angioedema (HAE) imposes a significant burden on patients due to the unpredictability of attacks. Long-term prophylaxis (LTP) aims to prevent these episodes and improve quality of life. Over the past five decades, LTP options have evolved from non-specific treatments (fresh frozen plasma, attenuated androgens, antifibrinolytics) to more targeted therapies (intravenous or subcutaneous C1 inhibitor (C1INH), lanadelumab, berotralstat). OBJECTIVE: To assess the use, efficacy, and safety of various LTP therapies among Hungarian HAE patients. METHODS: Data from the Hungarian HAE Registry (1979-2023) were analysed, including LTP usage, attack rates, side effects, and laboratory parameters. RESULTS: Danazol and tranexamic acid use increased over the first 30 years but has declined in the last decade. Conversely, the use of modern LTP therapies and the proportion of patients relying solely on on-demand medication have significantly increased over the past decade. Danazol and tranexamic acid reduced attack rates in 60 % of patients without significant changes in the laboratory parameters at the lowest effective doses. Furthermore, 100 % of patients on subcutaneous C1INH, lanadelumab, and berotralstat experienced fewer attacks and improved quality of life compared to pre-treatment periods, with no serious side effects or significant laboratory abnormalities. CONCLUSION: Modern prophylaxis usage is increasing among Hungarian HAE-C1INH patients, following the global trends. Both modern and traditional LTP options proved safe and effective in our patient population when used with appropriate monitoring. Copyright © 2024. Published by Elsevier Inc.

279:110542

Available online at: https://dx.doi.org/10.1016/j.clim.2025.110542

Johnson F, Hofauer B

Sep/2025. Frontiers in immunology

Bradykinin-mediated angioedema comprises rare but potentially life-threatening disorders, most notably hereditary angioedema (HAE) due to C1 inhibitor (C1-INH) deficiency or dysfunction. Diagnosis is often difficult, as these conditions can resemble urticaria variants, leading to misdiagnosis and delays in care. Distinguishing features are critical, since bradykinin-mediated forms do not respond to antihistamines or corticosteroids. This review summarizes the differential diagnoses of angioedema, including urticaria variants, cheilitis granulomatosa, and hypocomplementemic urticarial vasculitis, highlighting clinical and diagnostic clues. Particular focus is given to HAE-its subtypes (Type I, Type II, and normal C1-INH), pathophysiology, presentation, and genetic basis. Acquired angioedema and drug-induced forms, such as ACE inhibitor-associated angioedema, are also discussed. The therapeutic landscape is rapidly evolving, spanning acute and prophylactic approaches. Options include C1-INH concentrate, kallikrein inhibitors, bradykinin receptor antagonists, and factor XII inhibitors. While these advances expand treatment opportunities, they also complicate decision-making for patients and physicians. Furthermore, emerging CRISPR-based gene editing therapies represent innovative approaches that pose complex ethical dilemmas, and their long-term safety and efficacy have yet to be established. Although novel therapies reduce attack frequency, their true impact on quality of life is not fully established. Comparative effectiveness data are limited, long-term safety-particularly of gene-based therapies-is unknown, and the real-world utility of new oral on-demand agents for acute therapy is uncertain, especially in severe pharyngeal or laryngeal attacks that may hinder swallowing. Current guidelines remain unclear on the need for short-term prophylaxis in patients already receiving effective long-term prophylactic therapy. In conclusion, despite major therapeutic advances, persistent challenges and unanswered questions underscore the need for pragmatic, patient-centered, long-term studies to optimize care. Copyright © 2025 Johnson and Hofauer.

16:1681763

Available online at: https://dx.doi.org/10.3389/fimmu.2025.1681763

Kayikci H, Kayikci H, Damadoglu E, Cihanbeylerden M, Tuccar C, Ustaoglu AP, Karakaya G, Kalyoncu AF

Feb/2025. International archives of allergy and immunology

INTRODUCTION: Surgical interventions can trigger angioedema attacks in hereditary angioedema (HAE). The aim of this study was to assess the incidence of perioperative angioedema and identify associated risk factors. METHODS: This retrospective study included HAE patients diagnosed between 1999 and 2024 at a tertiary adult allergy clinic. Data on surgical procedures and perioperative angioedema were analyzed. RESULTS: Of 102 HAE patients, 28 were excluded due to incomplete data, leaving 74 patients (46 female, 62.2%). Fifty-three patients underwent 94 surgeries, with the most common being gynecological (27, 28.7%), abdominal (27, 28.7%), and otorhinolaryngological (16, 17.0%). Of the 54 surgeries before HAE diagnosis, 23 (42.5%) were abdominal. Among 27 abdominal surgeries, 17 (62.9%) occurred in patients with gastrointestinal angioedema prior to diagnosis. Of the 40 surgeries after diagnosis, 31 (77.5%) received preoperative short-term prophylaxis (STP), mostly plasma-derived C1 esterase inhibitor concentrate (27, 87.1%). Perioperative angioedema occurred in 28 (29.8%) surgeries, with a median recovery of 48 h. In surgeries after diagnosis, attacks occurred in 7 out of 31 surgeries (22.6%) with STP and 2 out of 9 (22.2%) without. Among gynecological surgeries, 22 cesarean sections were performed. No significant difference in attack frequency was found between cesarean sections with STP (3, 27.3%) and without (2, 18.2%, p = 0.611). CONCLUSION: Our study found that abdominal attacks before HAE diagnosis are consistent with the literature, underscoring their importance for early diagnosis. The angioedema rate was similar with or without STP before cesarean section, suggesting STP may not be necessary. Further research is needed to optimize HAE management in surgery. Copyright © 2025 S. Karger AG, Basel.

186(11):1079-1085

Available online at: https://dx.doi.org/10.1159/000544822

Liu H, Deng Y, Liu J, Wang Z, Hu XQ, Duan Y, Chen Y, Xie Z

Oct/2025. Journal of medicinal chemistry

Plasma kallikrein (PKal) is a pivotal serine protease involved in the regulation of the kallikrein-kinin system, the complement system, and several other biological pathways. Inhibition of PKal has become a key therapeutic strategy for hereditary angioedema, with four PKal-targeting agents approved by the U.S. FDA. The therapeutic potential of PKal inhibition is also being actively explored in other conditions, such as diabetic macular edema and COVID-19, through ongoing clinical trials. Here, we provide a comprehensive analysis of the biological functions of PKal across diverse signaling pathways, PKal-associated diseases, and recent clinical advancements of PKal-targeting agents. Furthermore, we spotlight the optimization strategies and key structure-activity relationships underlying the discovery and development of small-molecule PKal inhibitors, offering insights that may inform future PKal drug development for hereditary angioedema and other PKal-related diseases.

68(20):21012-21034

Available online at: https://dx.doi.org/10.1021/acs.jmedchem.5c02234

Lumry W, Gunsior M, Cohen T, Bernard K, Gustafson P, Chung JK, Morabito C

Jul/2025. Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology

BACKGROUND: Hereditary angioedema (HAE) is a rare, autosomal-dominant disorder characterized by bradykinin-mediated episodic, localized swelling that can be fatal. Currently approved long-term prophylactic therapies for HAE attacks incur substantial treatment burden through frequent dosing. Navenibart (STAR-0215) is a monoclonal antibody inhibitor of plasma kallikrein modified to extend circulating half-life and is under investigation for HAE prophylaxis. OBJECTIVE: To evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of a single dose of navenibart in healthy adults and to assess the feasibility of every 3- and 6-month dosing. METHODS: In this phase 1a study, participants were randomized 3:1 to receive placebo or navenibart in escalating (100-1200 mg) dosing cohorts. Safety outcomes, including treatment-emergent adverse events (TEAEs) and serious AEs, were monitored until the end of the study (day 224). Additional end points included pharmacokinetic parameters and inhibition of plasma kallikrein activity. RESULTS: In total, 31 participants received navenibart and 10 received placebo. The median age of the participants was 36 years; 53.7% were male; 51.2% were Black or African American. Rates of TEAEs were similar between navenibart and placebo, and no serious AEs were reported. Navenibart-related TEAEs included injection site reactions, inclusive of erythema, pruritus, and swelling, which resolved without intervention. For all doses more than or equal to 300 mg, navenibart mean half-life ranged from 82 to 105 days and inhibition of factor XIIa-induced plasma kallikrein activity vs placebo was statistically significant (P < .05). Statistically significant inhibition of factor XIIa-induced plasma kallikrein activity vs placebo (P < .05) was observed with all doses of navenibart. CONCLUSION: In this first-in-human study, up to 1200 mg of navenibart was well tolerated and demonstrated an extended half-life with durable plasma kallikrein inhibition. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05477160. Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.

135(1):103-111.e2

Available online at: https://dx.doi.org/10.1016/j.anai.2025.03.016

Lumry WR, Grumach AS, Betschel SD, Radojicic C, van Kooten S, Heckmann M, Danese S, Malloy N, Goga L, Guilarte M

Jan/2025. Allergy and asthma proceedings

Background: Despite the use of long-term prophylaxis (LTP) for hereditary angioedema (HAE), the risk of having an attack remains and patients with HAE and on LTP may still experience attacks that can be life threatening. However, the behavioral patterns and perspectives surrounding HAE attack management by patients on LTP are not fully understood. Objective: This survey aimed to better understand and compare the behavioral patterns and perspectives, including attitudes and perceptions associated with on-demand treatment among patients on LTP versus those using on-demand therapy only. Methods: People living with HAE were recruited by the US Hereditary Angioedema Association to complete a 20-minute online survey between September 6 and October 19, 2022. Participants were stratified by treatment (50% using LTP [+on-demand therapy], 50% on-demand therapy only). Results: Respondents included 107 patients with HAE (mean age, 41 years [range, 16-83 years]). Patients using LTP reported treating a mean +/- standard deviation 84.8% +/- 23.8% of their HAE attacks compared with a mean +/- standard deviation 75.6% +/- 27.5% for patients with on-demand only treatment. Similar percentages of patients on LTP versus patients on-demand only reported always carrying on-demand treatment when away from home (35% versus 38%) and modifying their daily lives to minimize the occurrence of HAE attacks, which included avoiding potential triggers (42.9% versus 45.5%). Conclusion: Although patients on LTP treat a higher percentage of their attacks compared with patients with on-demand only treatment, both groups reported similar behaviors in terms of carrying on-demand treatment when away from home and modifying their daily lives to minimize the occurrence of HAE attacks. These findings highlight the importance of understanding patient perspectives and behaviors in the management of HAE.

46(1):32-37

Available online at: https://dx.doi.org/10.2500/aap.2025.46.240096

Magerl M, Bouillet L, Martinez-Saguer I, Gavini F, Bent-Ennakhil N, Sayegh L, Andresen I

Feb/2025. The journal of allergy and clinical immunology. In practice

BACKGROUND: Hereditary angioedema (HAE) is a rare genetic disease characterized by recurrent episodes of cutaneous or subcutaneous edema. There is clinical need for treatments that reduce the rate of HAE attacks in patients. OBJECTIVES: Primary objectives were to evaluate the effectiveness of lanadelumab on attack-free rate (AFR; proportion of patients who had zero HAE attacks), and of every 2-week and every 4-week adjustments on AFR. METHODS: A retrospective medical chart review study was conducted in 19 HAE centers and included data from patients with type I or II HAE treated with lanadelumab (index treatment) in Germany, France, Greece, and Austria who were aged 12 years or older (ClinicalTrials.gov identifier: NCT04861090). Data abstraction occurred September 15, 2021, to June 29, 2022. Analyses were primarily descriptive. RESULTS: Data from 198 patients were collected (61.6% female, 91.9% with type I HAE). Lanadelumab treatment patterns varied between countries. Cumulative AFR improved from 0% (preindex) to 54.4% (12 months postindex) and 39.4% (postindex; median duration, 28.8 months). Monthly AFRs varied from 16.2% to 28.3% preindex (17.7% AFR in the month before index date), and from 82.7% (month 1) to more than 95% at multiple time points between 26 and 43 months postindex. Patients with interval increases (n = 144 [72.7%]) showed improved cumulative AFR (0% preindex to 50.0% postindex). CONCLUSIONS: This real-world study demonstrates that lanadelumab long-term prophylaxis is effective in improving AFR in patients with type I/II HAE on every 2-week dosing and dose interval increases. Effectiveness with lanadelumab is rapid and was observed starting from the first month of starting therapy. Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.

13(2):378-387.e2

Available online at: https://dx.doi.org/10.1016/j.jaip.2024.12.008

Maurer M, Cimbollek S, Kelly M, Rodney K, Elliott J, LoboGuerrero E, Magerl M

May/2025. Frontiers in immunology

Hereditary angioedema (HAE) types 1/2 are rare genetic disorders leading to C1 inhibitor (C1INH) deficiency/dysfunction. Guidelines recommend long-term prophylaxis (LTP) to prevent HAE attacks. Subcutaneous (SC) C1INH replacement therapy is approved for LTP in patients with HAE (age indication varies between countries). There is little real-world data on the outcomes of patients who switch to C1INH SC in Europe, particularly those who switch from C1INH IV. This retrospective patient chart analysis captured real-world evidence of the effectiveness of C1INH SC LTP in patients with HAE in Germany (n=69) and Spain (n=37). The primary endpoint was change in annualized attack rate (AAR) in patients who used C1INH IV LTP during a 6-month baseline period and switched to C1INH SC LTP for >=6 months. Switching to C1INH SC LTP from C1INH IV LTP was associated with a 73.2% reduction in AAR (n=48; P<0.001) compared to baseline. Emergency Room (ER) visits and rescue medication use were also significantly reduced after switching to C1INH SC LTP from C1INH IV LTP. A similar reduction in AAR (68.9%), ER visits (49.8%), and rescue medication use (61.9%) was observed in the overall population (n=105), regardless of treatment at baseline. Similar changes from baseline were seen in patients from Germany and Spain. Copyright © 2025 Maurer, Cimbollek, Kelly, Rodney, Elliott, LoboGuerrero and Magerl.

16:1576235

Available online at: https://dx.doi.org/10.3389/fimmu.2025.1576235

Nadasan V, Kiss KO, Borka-Balas R, Bara NA

Mar/2025. Oral health & preventive dentistry

PURPOSE: To evaluate hereditary angioedema (HAE) attack frequency associated with dental procedures, determine whether patients with post-dental procedural attacks receive more appropriate treatment after their condition is diagnosed, and investigate the potential impact of perceived risk on patients seeking dental care and dental professionals providing it. MATERIALS AND METHODS: The observational study included all the eligible adults from the Romanian Hereditary Angioedema Registry who provided informed consent. The impact of dental procedures on the HAE attacks was measured using a structured questionnaire including 20 questions administered via telephone. RESULTS: Patients experienced dental procedure-related symptoms suggestive of HAE both before (47.6%) and after their condition was diagnosed (51.9%). Before the HAE diagnosis, 86.2% of the patients received glucocorticoids and antihistamines for post-procedural swelling. After diagnosis, 85.3% of the patients were given Icatibant and C1-INH. More than half (55.3%) of the patients reported not seeking dental interventions because of fear of HAE attacks or anticipation of refusal, and 24.7% of them declared they had been denied dental care by dental health professionals at least once. CONCLUSION: Swelling related to dental procedures was common among the studied HAE patients. Unwarranted medications used before HAE diagnosis for dental post-procedural symptoms were replaced by adequate HAE-specific medications in most patients with established HAE diagnosis. A statistically significant proportion of patients refrained from undergoing dental interventions, and some of them were refused dental care by oral health professionals due to fear of HAE attacks.

23:173-182

Available online at: https://dx.doi.org/10.3290/j.ohpd.c_1907

Nishad M, Verma S, Maqsood R, Pal RS

Oct/2025. Reviews on recent clinical trials

Angioedema is a health issue that affects parts of the body like the upper pulmonary and gastric pathways and is identified by abrupt, nonpitting enlargement of the skin, mucous membranes, or both. The swelling usually lasts a few hours to 72 hours and may appear as non-puritic, subcutaneous, or submucosal organ edema. It is characterized by localized swelling brought on by the release of histamine. Itching is rare, and usual areas of appearance include the hands, feet, face, and genitalia, with periorbital swelling being the most often. The main objective of this review article is to study in brief the classifications, etiology, pathophysiology, and clinical trial data by describing the recent advancement in the treatment of angioedema. Various research articles obtained from different journals indexed under Scopus and SCI were used to prepare the review article and for illustrative work software such as Biorender and Microsoft Word was used. Histaminemediated angioedema, linked to allergic reactions, coexists with urticaria. Bradykinin-mediated angioedema, exemplified by hereditary angioedema and acquired forms, lacks urticaria. Idiopathic angioedema, with uncertain etiology. Imitated angioedema results from non-IgE-mediated reactions, often induced by medications. It is a complicated medical condition with a variety of causes and mechanisms. Over time, outcomes for patients have been greatly improved by a growing understanding of its etiology, pathophysiology, and available treatments. The field of medical treatment for this difficult problem is always changing, and this is partly due to clinical trials. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.

20(2):79-95

Available online at: https://dx.doi.org/10.2174/0115748871307432240930051749

Princic N, Evans KA, Shah CH, Sing K, Juethner S, Schultz BG

Apr/2025. Journal of comparative effectiveness research

Aim: Hereditary angioedema (HAE) is a rare and chronic genetic condition. Lanadelumab and berotralstat, two plasma kallikrein inhibitors, have both been approved for long-term prophylaxis in patients with HAE; however, real-world data comparing costs and healthcare resource utilization (HCRU) are lacking. Materials & methods: This retrospective study used administrative healthcare insurance claims data (Merative TM MarketScan R Commercial, Medicare and Early View Research Databases; 1 July 2017-31 July 2023) to identify patients with HAE who initiated lanadelumab or berotralstat and were persistent for >=18 months or 6 months, respectively. Sex, baseline healthcare costs and baseline number of on-demand treatment/short-term prophylaxis medication claims were used to calculate covariate balancing propensity scores for inverse probability of treatment weighting. Following weighting, outcomes during the 6-month follow-up period in patients receiving berotralstat were compared with those during months 0-6, 7-12 and 13-18 in lanadelumab-treated patients. Results: Fifty-seven lanadelumab- and 32 berotralstat-treated patients were included. After weighting, more berotralstat-treated patients had an all-cause inpatient admission (berotralstat, 9.4%; lanadelumab, months 0-6, 4.0%, 7-12, 1.8%, months 13-18, 2.0%) and emergency room visit (berotralstat, 21.9%; lanadelumab, months 0-6, 14.0%, 7-12, 8.0%, months 13-18, 17.9%). Total HAE treatment costs were similar during months 0-6 (lanadelumab, $377,326 vs berotralstat, $373,010), but decreased in months 7-12 ($319,967) and 13-18 ($283,241) of lanadelumab. On-demand treatment/short-term prophylaxis costs were lower for lanadelumab across the three follow-up periods than for berotralstat during months 0-6 (berotralstat, $60,451; lanadelumab, months 0-6, $46,336, months 7-12, $37,578, months 13-18, $23,968). The proportion of lanadelumab-treated patients who reduced dosing frequency was 24.8% during months 7-12 and 21.6% during months 13-18. Conclusion: Patients with HAE initiating lanadelumab versus berotralstat may require less on-demand and supportive HAE treatments and incur lower treatment-related and total healthcare costs. The ability to reduce lanadelumab dosing frequency after an attack-free period may be key in treatment selection, given the combination of cost savings and lower healthcare resource utilization.

14(4):e240205

Available online at: https://dx.doi.org/10.57264/cer-2024-0205

Reshef A, Hsu C, Katelaris CH, Li PH, Magerl M, Yamagami K, Guilarte M, Keith PK, Bernstein JA, Lawo JP, Shetty H, Pollen M, Wieman L, Craig TJ

Feb/2025. Allergy

BACKGROUND: Hereditary angioedema (HAE) is a chronic, unpredictable disease. Long-term prophylactic treatments that offer durable efficacy, safety, and convenience are required to assist patients in achieving complete disease control, per international guidelines. We report an interim analysis of an ongoing phase 3 (VANGUARD) open-label extension (OLE) study evaluating the long-term safety and efficacy of garadacimab for HAE prophylaxis. METHODS: Adults and adolescents aged >=12 years with HAE previously participating in phase 2 and pivotal phase 3 (VANGUARD) studies were rolled over to an OLE, alongside newly enrolled patients. Patients received garadacimab 200 mg subcutaneously, once monthly for >=12 months. The primary endpoint was treatment-emergent adverse events (TEAEs) in patients with C1 inhibitor deficiency/dysfunction. RESULTS: At data cut-off (February 13, 2023; N = 161), median (interquartile range) exposure was 13.8 months (11.9-16.3). For the primary endpoint, 133/159 patients experienced >=1 TEAE (524 events), equivalent to 0.23 events/administration and 2.84 events/patient-year. Garadacimab-related TEAEs (13% of patients, 52 events) were most commonly injection-site reactions (ISRs). No deaths occurred. One patient discontinued treatment due to garadacimab-related moderate ISR. Most TEAEs were mild/moderate; three events were serious (COVID-19, two events; abdominal HAE attack, one event) and not garadacimab related. No abnormal bleeding, thromboembolic, severe hypersensitivity, or anaphylactic events were observed. Mean HAE attack rate decreased by 95% from the run-in period; 60% of patients were attack-free. Almost all patients (93%) rated their response to garadacimab as "good" or "excellent." CONCLUSION: Garadacimab has a favorable safety profile suitable for long-term use and provides durable protection against HAE attacks. Copyright © 2024 The Author(s). Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.

80(2):545-556

Available online at: https://dx.doi.org/10.1111/all.16351

Riedl MA, Bernstein JA, Jacobs JS, Craig T, Banerji A, Perego F, Lumry WR, Wedner HJ, Gierer S, Manning ME, Bordone L, Treadwell S, Lin T, Newman KB, Yarlas A, Cohn DM

Sep/2025. The journal of allergy and clinical immunology. In practice

BACKGROUND: Hereditary angioedema (HAE) is a rare, potentially life-threatening disorder characterized by episodes of tissue swelling. Donidalorsen, an investigational ligand-conjugated antisense oligonucleotide, reduces plasma prekallikrein production. OBJECTIVE: We report an interim analysis on safety, efficacy, quality of life (QoL), and treatment preference and satisfaction from an ongoing open-label phase 3 study (OASISplus Switch cohort, NCT05392114). METHODS: Patients with HAE receiving stable doses (>=12 weeks) of lanadelumab, complement protein 1 inhibitor, or berotralstat switched to donidalorsen 80 mg subcutaneously every 4 weeks, using a predefined algorithm. The primary end point was the incidence and severity of treatment-emergent adverse events. Other end points included change in HAE attack rate, angioedema-QoL score, disease control (>=10 points on the Angioedema Control Test), and treatment preference and satisfaction at week 16, compared with baseline on prior treatment. RESULTS: A total of 65 patients were enrolled; 32 switched from lanadelumab, 22 from complement protein 1 inhibitor, and 11 from berotralstat. At cutoff, 58 were ongoing in the study (89%). Forty-five patients (70%) reported treatment-emergent adverse events; 62% were unrelated to donidalorsen. At week 16, total HAE attack rates had decreased by 62%. Hereditary angioedema attack rates decreased by 65%, 41%, and 73%, and mean angioedema-QoL scores improved by 8.4, 9.6, and 17.1 points for patients switching from lanadelumab, C1INH, and berotralstat, respectively. More patients reported well-controlled disease (93% vs 67%), and most patients preferred donidalorsen over their prior treatment, with improved treatment satisfaction. CONCLUSIONS: Donidalorsen was well tolerated, decreased HAE attack rate, and improved QoL and disease control. Most patients preferred donidalorsen over their prior treatment. Further analyses are planned at week 52. Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.

13(9):2381-2389.e3

Available online at: https://dx.doi.org/10.1016/j.jaip.2025.06.018

Riedl MA, Yarlas A, Bordone L, Treadwell S, Wang S, Newman KB, Cohn DM

Aug/2025. Allergy

BACKGROUND: Hereditary angioedema (HAE) is a rare disease characterized by unpredictable, frequently severe swelling that negatively impacts patients' quality of life (QoL). In the phase III OASIS-HAE study (NCT05139810), donidalorsen reduced HAE attack rate, increased disease control, and improved QoL. Here, we report further analysis of donidalorsen's impact on QoL and other patient-reported outcomes (PROs). METHODS: This double-blind, placebo-controlled study randomized patients with HAE to donidalorsen 80 mg or placebo once every 4 (Q4W) or 8 weeks (Q8W) over 24 weeks. PROs included Angioedema (AE)-QoL Questionnaire, Angioedema Control Test (AECT), Patient Global Impression of Severity (PGIS), and Work Productivity and Activity Impairment Questionnaire plus Classroom Impairment Questions (WPAI+CIQ). RESULTS: Ninety patients received donidalorsen Q4W (n = 45), donidalorsen Q8W (n = 23), or placebo (n = 22). A larger percentage of the donidalorsen Q4W group (88%) achieved clinically meaningful improvement (>= 6-point reduction) in AE-QoL total score vs. placebo (45%). Both donidalorsen groups reported larger least-squares mean (LSM) changes from baseline to week 24 vs. placebo in AE-QoL functioning (difference: Q4W, -24.5; Q8W, -16.1), fears/shame (Q4W, -23.9; Q8W, -20.1), and nutrition (Q4W, -15.7; Q8W, -10.7) domains. Donidalorsen improved AECT scores vs. placebo (difference: Q4W, 6.0; Q8W, 4.1). A greater proportion of the donidalorsen Q4W group reported decreased disease severity vs. the placebo group (PGIS; 82% vs. 44%). Donidalorsen Q4W showed benefits vs. placebo in the presenteeism, overall work/school impairment, and activity impairment domains of the WPAI+CIQ. CONCLUSIONS: Donidalorsen significantly improved QoL and other PROs vs. placebo in patients with HAE. Copyright © 2025 The Author(s). Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.

80(8):2361-2368

Available online at: https://dx.doi.org/10.1111/all.16563

Singh P, Witjes H, Kleijn HJ, Diep JK, Bordone L, Newman KB, Gao X, Cohn DM

Nov/2025. Clinical and translational science

Hereditary angioedema (HAE) is characterized by recurrent attacks of severe tissue swelling. In the OASIS-HAE phase 3 study (NCT05139810), donidalorsen, an RNA-targeted antisense oligonucleotide that reduces prekallikrein production in the liver, significantly reduced HAE attack rates. To characterize the relationship between prekallikrein concentrations and HAE attack rates following donidalorsen and predict the efficacy of potential dosing regimens, an exposure-response model was developed using data from OASIS-HAE. Simulations were conducted to evaluate the following regimens: 80 mg once every 4 weeks (Q4W), 8 weeks (Q8W), 1 month (Q1M), and 2 months (Q2M), and a switch to Q2M dosing for patients who were attack-free for 3 months on the Q1M regimen. The relationship between prekallikrein concentrations and HAE attack rates was well characterized by a sigmoidal Emax (maximum effect) model with baseline attack rate and baseline prekallikrein concentration included as covariates. The average prekallikrein concentration estimated to result in a 90% reduction in attack rate (EC10) was 47.1 mg/L. Predicted percent reductions in attack rates at steady state were similar for Q4W (84.1%) vs. Q1M (82.9%) and Q8W (72.6%) vs. Q2M (70.2%) dosing. Predicted reductions in attack rate remained similar and clinically meaningful in patients who switched from Q1M to Q2M dosing (94.0% in month 1 and 91.3% in month 2 of the 2-month dosing interval at steady state). Overall, exposure-response analyses supported the efficacy of Q1M and Q2M dosing and indicated that switching to Q2M dosing could be a viable approach for patients who are attack-free on the Q1M regimen. Copyright © 2025 The Author(s). Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.

18(11):e70388

Available online at: https://dx.doi.org/10.1111/cts.70388

Sivananthan S, Seto T, Tehrani NC, Bhakta V, Sheffield WP

Mar/2025. BMC biotechnology

BACKGROUND: The naturally occurring variant Alpha-1 Antitrypsin M358R (AAT M358R), modified at the P1 position of the reactive center loop (RCL), shifts its inhibitory protease target from neutrophil elastase to multiple coagulation and contact proteases, including activated plasma kallikrein (Pka; KLKB1). Our aim was to increase the specificity of AAT M358R for Pka as a potential novel therapeutic agent to treat pathological swelling arising from elevated Pka levels in patients with Hereditary Angioedema. RESULTS: Two AAT M358R T7Select phage display libraries randomized at RCL positions P7-P3 and P2-P3' were iteratively probed with Pka. The most abundant Pka-inhibitory motifs from phage display were P7-P3, QLIPS; and P2-P3', VRRAY (mutated residues in bold). AAT variants expressing these motifs, alone or in combination, as well as six less-mutated P7-P3 revertant proteins were expressed, purified, and characterized kinetically. Variants AAT M358R (QLIPS) (designated 7-QLIPS-3) and 7-FLEPS-3 exhibited significantly enhanced selectivity for Pka (over factor XIa) by factors of 6.9 and 9.2, respectively, without increasing the stoichiometry of inhibition (SI) or decreasing the inhibition rate relative to AAT M358R. No other variants matched this profile. CONCLUSIONS: Pro substitution at P4 was found to be important for enhanced inhibition of Pka by AAT M358R. Two novel variants with this substitution are more rapid and selective inhibitors of Pka than AAT M358R and may provide better control of Pka in vivo than existing HAE therapeutics. Copyright © 2025. The Author(s).

25(1):22

Available online at: https://dx.doi.org/10.1186/s12896-025-00956-8

Staubach P, Craig TJ, Fukuda T, Aygoren-Pursun E, Hakl R, Braverman J, Lawo JP, Pollen M, Nenci C, Li PH, Farkas H

May/2025. Allergy and asthma proceedings

Background: Hereditary angioedema (HAE) is associated with substantial health-related quality of life (HRQoL) impairments. Complete disease control and life normalization are key treatment goals. In previous studies, garadacimab prevented HAE attacks with a favorable safety profile and HRQoL improvements. Objective: HRQoL was evaluated in patients with HAE receiving garadacimab stratified by attack-free status. Methods: In the pivotal phase III study (NCT04656418), 39 patients received garadacimab 200 mg subcutaneously once monthly and 25 volume-matched placebo. In the phase III open-label extension (OLE), 90 patients in the garadacimab-naive group (received placebo in previous studies or newly enrolled) and 71 patients in the previous garadacimab exposure group (received garadacimab in previous studies) received garadacimab (NCT04739059). Patients ages >= 18 years completed the Angioedema Quality of Life (AE-QoL) questionnaire in both studies; scores were evaluated post hoc by attack-free status. Results: In the pivotal phase III and phase III OLE studies, 62% and 60% of patients, respectively, were attack-free. In the pivotal phase III study, the mean AE-QoL total score improved with garadacimab, from 38.8 (day 1) to 6.6 (month 6) for attack-free patients (n = 19) and to 18.4 for patients with one or more attacks (n = 14) versus a change in mean AE-QoL total score from 43.7 to 40.5 with placebo (n = 20). In the phase III OLE study, the mean AE-QoL total score for patients who were garadacimab naive decreased from 46.2 (day 1) to 8.6 (month 12) for attack-free patients (n = 34) and from 54.5 to 23.5 for patients with one or more attacks (n = 30). For the previous garadacimab exposure group, AE-QoL improvements were maintained from previous studies, regardless of attack-free status. Conclusion: Garadacimab was associated with HRQoL improvement versus run-in in all groups. After garadacimab exposure in previous studies, improvements were maintained in the phase III OLE study. Attack-free patients had the greatest HRQoL improvements, bringing them closer to complete disease control and life normalization.Clinical trials NCT04656418, NCT04739059, <ext-link xmlns:xlink="http://www.w3.org/1999/xlink" ext-link-type="uri" xlink:href="http://www.clinicaltrials.gov">www.clinicaltrials.gov.

46(3):200-208

Available online at: https://dx.doi.org/10.2500/aap.2025.46.250026

Tachdjian R, Banerji A, Busse PJ, Agmon-Levin N, Anderson J, Cancian M, Spadaro G, Enciu C, Estepan DN, Khutoryansky N, Jain S, Recke A

Apr/2025. Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology

BACKGROUND: Symptoms of hereditary angioedema (HAE) typically first present during childhood, but the frequency/severity of attacks often increases at puberty. Real-world data on long-term HAE prophylaxis in adolescents are limited. We report pooled data from adolescent patients enrolled in two Phase 4 studies (EMPOWER, ENABLE) evaluating the effectiveness/safety of lanadelumab (monoclonal antibody directed against plasma kallikrein) for the prevention of HAE attacks. METHODS: Adolescent patients (aged 12 to <18 years) with HAE-C1INH enrolled in EMPOWER and ENABLE received open-label lanadelumab 300 mg once every 2 weeks. Effectiveness outcomes were based on patient-reported assessments of on-treatment HAE attacks. Safety was assessed through the recording of treatment-emergent adverse events (TEAEs) and serious adverse events. This analysis categorized patients as "new" or "established" lanadelumab patients. RESULTS: Thirteen new and seven established patients on lanadelumab were included. The observed monthly attack rate in new patients fell from 3.8 (mean) and 2.8 (median) during the pre-enrollment period to 0.65 (mean) and 0.21 (median) during the cumulative study period after lanadelumab initiation (84.2% and 92.9% reductions, respectively). In established patients, mean (SD) HAE attack rate (as treated) during the overall study period was 0.04 (0.03) attacks/month. Most HAE attacks were of mild/moderate severity. Nine new patients reported 42 TEAEs, mostly mild/moderate in severity, with 3 TEAEs reported as serious. Seven established patients reported 12 TEAEs (all mild/moderate and non-serious). No TEAEs were related to lanadelumab. CONCLUSION: These data support lanadelumab's effectiveness/safety in adolescents with HAE, consistent with results from Phase 3 lanadelumab studies in mixed adult/adolescent populations. CLINICAL TRIAL IDENTIFIERS: NCT03845400 (EMPOWER) and NCT04130191 (ENABLE). Copyright © 2025 Takeda Development Center Americas, Inc. Pediatric Allergy and Immunology published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.

36(4):e70072

Available online at: https://dx.doi.org/10.1111/pai.70072

Walsh S, Haltner A, Bartlett M, Sears J, Li Y, Kelly M, Gavata-Steiger S, Nenci C, Jacobs I, Pragst I, Ray N, Samjoo IA

Aug/2025. Journal of comparative effectiveness research

Aim: This study aimed to estimate the relative efficacy between garadacimab 200 mg once monthly (200 QM) and two dosing regimens of lanadelumab (300 mg once every 2 weeks [300 Q2W] and 300 mg once every 4 weeks [300 Q4W]) in adolescent/adult patients with hereditary angioedema (HAE) using matching-adjusted indirect comparisons (MAICs), in the absence of head-to-head randomized controlled trials. Materials & methods: Individual patient data were available from the phase II (NCT03712228) and the phase III VANGUARD (NCT04656418) trials investigating garadacimab, and published summary-level data from the phase III HELP trial investigating lanadelumab (NCT02586805). The primary outcome was time-normalized number of HAE attacks. Secondary efficacy outcomes included time-normalized number of HAE attacks requiring on-demand treatment, time-normalized number of moderate and/or severe HAE attacks, and proportion of attack-free patients. Quality of life (QoL) was also assessed via change from baseline in AE-QoL total score. Results: Compared with lanadelumab 300 Q2W, garadacimab 200 QM statistically significantly reduced number of moderate and/or severe HAE attacks (rate ratio [RR]; 95% confidence interval: 0.25; 0.07, 0.84) and improved AE-QoL score (mean difference: -17.38; -33.67, -1.08). Compared with lanadelumab 300 Q4W, garadacimab 200 QM showed statistically significant improvements in all outcomes: HAE attacks (RR: 0.29; 0.13, 0.63), attacks requiring on-demand treatment (RR: 0.29; 0.13, 0.66), moderate and/or severe HAE attacks (RR: 0.15; 0.05, 0.49), proportion of attack-free patients (hazard ratio: 3.25; 1.45, 7.29), and AE-QoL score (mean difference: -21.29; -37.39, -5.18). Conclusion: These MAICs showed improved efficacy and QoL with garadacimab compared with lanadelumab across multiple endpoints. These findings demonstrate that garadacimab may provide improved therapeutic benefit compared with lanadelumab in the long-term prophylactic treatment of patients with HAE.

14(8):e240237

Available online at: https://dx.doi.org/10.57264/cer-2024-0237

Walsh S, Bartlett M, Salvo-Halloran EM, Sears J, Li Y, Kelly M, Gavata-Steiger S, Nenci C, Jacobs I, Pragst I, Ray N, Samjoo IA

Jun/2025. Drugs in R&D

BACKGROUND AND OBJECTIVES: Several treatments for long-term prophylaxis (LTP) of hereditary angioedema (HAE) are in clinical use, such as garadacimab, lanadelumab, subcutaneous C1 esterase inhibitor (C1INH), and berotralstat. In the absence of head-to-head comparative evidence, indirect comparison methods are needed to compare LTP treatments in patients with HAE. The objective of this analysis was to estimate the comparative efficacy, safety, and impact on quality of life of LTP treatments for patients with HAE through NMAs. METHODS: A systematic literature review was conducted to identify randomized controlled trials (RCTs) investigating LTP treatments in patients (at least 12 years old) with HAE (PROSPERO protocol #CRD42022359207). A network meta-analysis (NMA) feasibility assessment evaluated trial suitability and Bayesian NMAs were conducted for evaluable efficacy, safety, and quality of life (QoL) outcomes. RESULTS: The results of these NMAs show improved efficacy, QoL, and reduced rate of adverse events with garadacimab (200 mg once monthly), lanadelumab (300 mg every two or four weeks), subcutaneous C1INH (60 IU/kg twice weekly), and berotralstat (150 mg once daily) compared to placebo in the treatment of patients with HAE. For the primary outcome of time-normalized number of HAE attacks, garadacimab statistically significantly reduced the rate of attacks compared to lanadelumab Q4W and berotralstat. A similar statistically significant reduction was shown for HAE attacks treated with on-demand treatment. Garadacimab showed statistically significant reduction in the rate of moderate and/or severe HAE attacks compared to lanadelumab Q2W. Garadacimab also showed statistical improvements in change from baseline in AE-QoL total score as compared to berotralstat. CONCLUSIONS: Overall, garadacimab ranked as the most probable effective treatment among all comparators assessed, with lanadelumab Q2W or subcutaneous C1INH ranking second, across most outcomes. Copyright © 2025. The Author(s).

25(2):161-178

Available online at: https://dx.doi.org/10.1007/s40268-025-00511-y

Wang W, Zhang Y, Fang Y, Gao J, Thuku RC, Yang J, Na C, Lu Q, Fang M

Jun/2025. European journal of pharmacology

The contact-kinin system plays a central role in the thromboinflammatory pathology of ischemic stroke. Modulating this pathway represents a promising strategy for the prevention and treatment of ischemic stroke. Based on our recent findings demonstrating that the short peptide SD6 (SLGASD), derived from a specific influenza-related immunoglobulin heavy chain junction region sequence, exhibits anti-coagulant properties, we designed a cyclized version, cycloSD6, and evaluated its anti-ischemic stroke potential. Notably, cycloSD6 showed enhanced inhibition of activated coagulation factor XII (FXIIa; with an inhibition constant (Ki) of 41.27 mcM) and plasma kallikrein (PKa; Ki: 28.54 mcM), two key enzymes in the contact-kinin system, surpassing the inhibitory effects of its linear form. In vitro, 4-100 mcM of CycloSD6 inhibited LPS-induced inflammation. And CycloSD6 at doses of 1 and 4 mg/kg displayed significant anti-thrombotic functions in several mouse models, including carrageenan-induced tail thrombosis, FeCl3-induced arterial thrombosis, and cortical photothrombosis models, and did not affect mouse tail bleeding time. The peptide also exerted comparable anti-ischemic stroke effects to those of ecallantide (DX-88), a kallikrein inhibitor approved for the treatment of hereditary angioedema, in a mouse model of transient middle cerebral artery occlusion. Thus, this short peptide CycloSD6, which dual targets FXII and PKa, harbors anti-thromboinflammation and anti-stroke properties with low bleeding risk. And these findings suggest that cycloSD6 may serve as a potential therapeutic candidate or template for the development of agents targeting ischemic stroke. Copyright © 2025 The Authors. Published by Elsevier B.V. All rights reserved.

998:177497

Available online at: https://dx.doi.org/10.1016/j.ejphar.2025.177497

Watt M, Goldgrub R, Malmenas M, Haeussler K

Feb/2025. Journal of comparative effectiveness research

Aim: To compare the efficacy and safety of lanadelumab versus other approved long-term prophylaxis (LTP) treatments in patients with pediatric hereditary angioedema (HAE) aged <12 years. Materials & methods: A systematic literature review was conducted to identify studies of LTP in patients with HAE aged <12 years. Two studies met the inclusion criteria in an indirect treatment comparison of efficacy and safety data in pediatric HAE patients. These were for lanadelumab (SPRING, NCT04070326) and intravenous-C1-esterase inhibitor (C1-INH[IV], NCT02052141). A propensity score analysis used individual patient-level data from both studies in a logistic regression model to estimate inverse probability weights. To avoid convergence issues and an underpowered analysis due to the small sample size (n = 29), the base case was defined as Poisson regression analyses on monthly attack rate adjusting for one covariate (baseline attack rate). Model selection among unadjusted, adjusted and weighted regression models was conducted through the Akaike and Bayesian Information Criteria. Results: Lanadelumab 150 mg every 2 weeks (Q2W) reduced the monthly HAE attack rate by 82.1% versus C1-INH(IV) 1000 IU twice weekly (every 3-4 days [BIW]; rate ratio [RR], 0.1792 [95% CI: 0.0296-1.0853]) and by 88.9% versus C1-INH(IV) 500 IU BIW (RR: 0.1107 [95% CI: 0.0234-0.5239]). Treatment with lanadelumab Q2W reduced the risk of total adverse events by 56.2% versus C1-INH(IV) 1000 IU BIW (RR:0.4377 [95% CI: 0.1536-1.2469]) and by 66.0% versus C1-INH(IV) 500 IU BIW (RR: 0.3401 [95% CI: 0.1234-0.9371]). Conclusion: This exploratory analysis suggested a trend toward greater efficacy and fewer adverse events with lanadelumab 150 mg Q2W compared with C1-INH(IV) BIW 1000 IU and 500 IU in pediatric patients with HAE. Future studies could potentially assess larger samples over longer periods of time for the long-term preventative efficacy, safety and tolerability of lanadelumab and C1-INH(IV).

14(2):e240110

Available online at: https://dx.doi.org/10.57264/cer-2024-0110

Xu Y, Guo Y

Aug/2025. Orphanet journal of rare diseases

BACKGROUND: Hereditary angioedema (HAE) is a rare monogenic disease, and there are few reports on its clinical characteristics, particularly its drug efficacy, in China. The objective of this study was to gain insight into the clinical characteristics of HAE in Chinese patients, and the efficacy and safety of prophylactic treatment with lanadelumab. RESULTS: The cohort included 22 patients with a median age of 35.0 years (IQR: 27.0-48.3 years). The male-to-female ratio was 1:1.75. The median age at onset was 15.5 years (IQR: 10.0-21.3 years), with a median diagnostic delay of 18.5 years. A significant positive correlation was found between patient age and the duration of diagnostic delay (r = 0.750; p = 0.000). In the cohort, 18 patients (81.8%) had Type I HAE, whereas 4 patients (18.2%) had Type II HAE. The average monthly frequency of attacks was 1.0 (IQR: 0.3, 1.3). Ten patients (45.5%) experienced onset following minor trauma/local bumps/pressure/heat exposure, which was the most common precipitating factor; 7 patients (31.8%) experienced spontaneous onset without apparent precipitating factors. A family history was reported for 16 patients (72.7%). Six patients (27.3%) had concomitant diseases involving various positive autoantibodies or confirmed autoimmune diseases. Eleven patients (50.0%) in this cohort were either currently receiving or had previously received lanadelumab treatment, with a median treatment duration of 7 months (IQR: 3-10 months). Nine patients reached the steady-state period of treatment (> 70 days). Eight patients experienced no oedema attack during treatment. There was a significant reduction in the frequency of attacks and a significant improvement in quality of life by Day 30 (D30) posttreatment, with a decrease of 91.5% in the average monthly frequency of attacks. The average monthly frequency of attacks decreased by 94.6% and 96.2% after 3 months of treatment and at the time of the last injection, respectively, with no life-threatening laryngeal oedema attacks. Only 5 patients (45.5%) experienced local adverse reactions during treatment, and no severe adverse reactions were reported. CONCLUSION: (1) The median age at onset, diagnostic delay, and precipitating factors in this cohort were consistent with previously reported data from domestic studies. However, the proportion of Type 2 patients was greater than that in prior domestic reports, and a trend towards earlier diagnosis in younger patients was observed; notably, this cohort identified a high proportion (27.3%) of patients with positive autoantibodies or confirmed autoimmune diseases for the first time in China. (2) After treatment with lanadelumab, patients experienced significant improvements in symptoms, quality of life, and anxiety/depression levels. Symptom control was achieved by D30 prior to the drug steady state-period and was maintained throughout the entire treatment period. No serious adverse reactions were observed during the treatment, indicating a high safety profile for the medication. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR2500098307, 2025/03/05. Copyright © 2025. The Author(s).

20(1):441

Available online at: https://dx.doi.org/10.1186/s13023-025-03988-7

Yao W, Diao R, Yang B, Wang Y, Li B, Li T, Ge L, Yu Y, Zhu R, Wang H

Oct/2025. International archives of allergy and immunology

INTRODUCTION: Hereditary angioedema (HAE) is a rare genetic disorder caused by deficiency or dysfunction of C1-esterase inhibitor that is characterized by recurrent episodes of bradykinin-mediated edema. Lanadelumab has been the only available first-line therapy for long-term prophylaxis (LTP) of HAE in China since its approval in 2020. The present study aimed to investigate the clinical efficacy and safety of lanadelumab for LTP in Chinese patients. METHODS: A retrospective clinical data were collected for the 6 patients and used to examine the frequency of attack symptoms, disease-related loss of work days, and quality of life before and after LTP with lanadelumab. Health-related quality of life was assessed using the Dermatology Life Quality Index (DLQI) and the Angioedema Quality of Life Questionnaire (AE-QoL). RESULTS: Lanadelumab led to reductions of 97.8% and 98.5% in the attack rate and treated attack rate, respectively. All patients exhibited significant improvements in AE-QoL and DLQI scores (100% reduction rates) during the early treatment period (4 weeks and 2 weeks, respectively) and in missed work days/year (98.9% reduction rate). The efficacy of lanadelumab remained stable during COVID-19 vaccination and infection. No serious/severe treatment-emergent adverse events occurred during lanadelumab treatment. CONCLUSION: This study is the first report that demonstrates the clinical efficacy of lanadelumab and safety of LTP in HAE patients from Chinese mainland. A reasonable dosage plan can ensure a quick and long-lasting protective role of lanadelumab against HAE attacks, during COVID-19 pandemic period. Copyright © 2024 S. Karger AG, Basel.

186(3):221-231

Available online at: https://dx.doi.org/10.1159/000541242

Zanichelli A, Wuillemin WA, Aygoren-Pursun E, Banerji A, Busse PJ, Betschel SD, Cancian M, Gagnon R, Goodyear MD, Kinaciyan T, Kessel A, Magerl M, Recke A, Wedner HJ, Estepan DN, Watt M, Andresen I, Juethner S, Khutoryansky N, Martinez-Saguer I

Nov/2025. Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology

BACKGROUND: Real-world clinical data support effectiveness and safety of lanadelumab in patients with hereditary angioedema (HAE); however, disease activity between patients can vary substantially in the absence of long-term prophylactic treatment. OBJECTIVE: To assess the effectiveness of lanadelumab in patients with HAE by baseline HAE attack frequency. METHODS: Patients with HAE from the phase 4 EMPOWER (NCT03845400) and ENABLE (NCT04130191) studies with available baseline attack rate data were included in this post hoc analysis. Disease activity subgroups were defined per pre-enrollment/lanadelumab (baseline) HAE attack rate (low, <1; moderate, >=1 to <2; high, >=2 to <3; very high, >=3 attacks/mo). RESULTS: The analysis included 152 patients (low disease activity, n = 29; moderate, n = 29; high, n = 15; very high, n = 79). In all 4 subgroups, mean and median HAE attack rates after lanadelumab initiation were low (0.0-0.5 attacks/mo). Clinically meaningful improvements (>=6-point decreases) in mean Angioedema Quality of Life total scores were observed regardless of pre-lanadelumab attack rates. From month 1 after lanadelumab initiation to the end of follow-up, mean Angioedema Control Test Scores were 10 or more (indicating patient perception of well-controlled disease) in all 4 subgroups. CONCLUSION: In these real-world data sets, on-treatment lanadelumab attack rates were low regardless of baseline disease activity. Patients from all 4 subgroups experienced improvements in health-related quality of life and disease control. Overall, these findings support long-term prophylaxis with lanadelumab across disease activity levels. TRIAL REGISTRATION: EMPOWER: ClinicalTrials.gov Identifier: NCT03845400; ENABLE: ClinicalTrials.gov Identifier: NCT04130191. Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.

135(5):560-569.e2

Available online at: https://dx.doi.org/10.1016/j.anai.2025.07.025

Zanichelli A, De Angeli G, Baroni I, Mansi M, Caravella G, Caruso R

Jul/2025. Expert opinion on pharmacotherapy

INTRODUCTION: Hereditary angioedema (HAE) is a genetic rare condition characterized by recurrent attacks of swelling that might be potentially life-threatening. Recurrence and severity of attacks may impact psychological life, expectations and productivity. We aim to review the state-of-the-art of HAE preventive and on-demand treatment of non-biologic drugs, providing a perspective of their personalized use and development. AREAS COVERED: This literature analysis integrates international guidelines and clinical trial data on on-demand therapies and short-/long-term prophylaxis. Modern medications should be considered and personalized for HAE patients to provide benefits compatible with patients' lifestyles, preferences, and experiences. Accordingly, a new era toward oral formulations has begun starting from berotralstat, with a consistent number of drugs under development. EXPERT OPINION: All HAE patients should have an effective on-demand treatment available in case of attacks. Long-term prophylaxis (LTP) should be considered and individualized for all patients at every visit, following a shared decision-making approach to optimize disease control while limiting side effects. Parenteral administration of LTP is associated with treatment complexities and barriers. Oral treatment could address practical needs for HAE patients both in preventive and on-demand setting, avoiding injection-related side effects, reducing treatment burden, and improving quality of life. In the next future, significant advances in HAE therapeutics could result from gene therapy.

26(10):1221-1228

Available online at: https://dx.doi.org/10.1080/14656566.2025.2509782

Zuraw BL, Lopez-Gonzalez L, Manjelievskaia J, Winer I, Dean A, Wall S, Nelson J, Nestler-Parr S, Gillard P, Christiansen SC

May/2025. Allergy and asthma proceedings

Introduction: Real-world evidence that compares the treatment patterns of targeted long-term prophylaxis (LTP) for hereditary angioedema (HAE), including berotralstat, lanadelumab, and subcutaneous (SC) plasma-derived C1 inhibitor (pdC1-INH) is limited. Objective: The study aimed to assess adherence and persistence after initiation of berotralstat, lanadelumab, or SC-pdC1-INH. Methods: Electronic health records linked to claims data was used to select patients ages >= 12 years, initiating one of three LTPs between June 22, 2017, and September 12, 2023, with mutually exclusive cohorts assigned hierarchically in reverse order of their U.S. Food and Drug Administration approval date. Patients were required to have >= 12 months of continuous enrollment before and after the LTP initiation date. Demographics and baseline clinical characteristics were captured. Primary study measures were adherence, defined as the mean proportion of days covered (PDC), and persistence, defined as having no gap in treatment >= 45 days after the LTP initiation date. A subgroup analysis was conducted among patients with two or more claims for their index LTP. A sensitivity analysis was performed by reassigning cohorts based on the first claim for qualifying LTP after June 22, 2017. Results: The main analysis included 357 patients (90 on berotralstat, 189 lanadelumab, and 78 SC-pdC1-INH). Overall, 46% to 51% of the patients had LTP experience. Adherence (mean PDC) was similar between treatments at 0.73, 0.78, and 0.74 for berotralstat, lanadelumab, and SC-pdC1-INH, respectively. Proportions of patients persistent on index LTP after 12 months were similar across LTPs: 61%, 58%, and 53% for berotralstat, lanadelumab, and SC-pdC1-INH, respectively. The findings of the subgroup and sensitivity analyses supported the main analysis. Conclusion: Adherence and persistence rates for all three LTP treatments were uniformly high. Berotralstat adherence and persistence were comparable with those observed after lanadelumab or SC-pdC1-INH initiation in the main analysis, among patients with two or more claims for their index LTP, and among cohorts assigned based on the first claim for qualifying LTP.

46(3):209-217

Available online at: https://dx.doi.org/10.2500/aap.2025.46.250029