Background:Clinical trial designs evaluating on-demand therapies for hereditary angioedema attacks have evolved in response to changes in treatment guidelines. Sebetralstat, an oral plasma kallikrein inhibitor, was evaluated in 2 randomized, placebo-controlled clinical trials, which instructed early treatment of attacks with no minimum severity requirement. Objective:Characterize the efficacy and safety of sebetralstat by pooling data from phase 2 and 3 trials. Methods:This pooled analysis included participants (phase 2, aged ≥18 years; phase 3, aged ≥12 years) who received ≥1 dose of study drug (phase 2, sebetralstat 600 mg or placebo; phase 3, sebetralstat 300 mg or 600 mg, or placebo). Efficacy outcomes included times to beginning of symptom relief within 12 h, reduction in severity within 12 h, and complete attack resolution within 24 h. P values were not adjusted for multiplicity. Results:377 attacks were treated: 87 with sebetralstat 300 mg; 151 with sebetralstat 600 mg; 139 with placebo. Median (interquartile range) time to treatment was 32.5 min (8.0-94.0). Baseline severity was rated as "Mild" (46.2%), "Moderate" (40.6%), or "Severe"/"Very Severe" (12.7%). Compared with placebo, time to beginning of symptom relief was faster with sebetralstat (300 mg; 600 mg [P = 0.0001; P < 0.0001]), as was reduction in severity (P = 0.0038; P < 0.0001) and complete attack resolution (P = 0.0021; P < 0.0001). Median time to beginning of symptom relief was 1.6 h (0.8-7.0) and 1.8 h (1.0-4.3) with sebetralstat 300 mg and 600 mg, respectively, and 8.3 h (1.5 to >12) with placebo. Sebetralstat had a safety profile comparable to placebo. Conclusion:Across phase 2 and 3 clinical trials, sebetralstat enabled early treatment, provided effective symptom relief versus placebo, and was well tolerated, regardless of attack location or baseline severity. Clinical trial registration:ClinicalTrials.gov Identifier NCT04208412, registered on 2019-07-02; ClinicalTrials.gov Identifier NCT05259917 (KONFIDENT), registered on 2022-02-22.

ABSTRACT Background Lanadelumab has been approved for hereditary angioedema (HAE) long‐term prophylaxis since 2018. The Phase 4, prospective ENABLE Study (NCT04130191) evaluated the long‐term effectiveness and safety of lanadelumab in clinical practice across Europe and the Middle East. Methods Patients with HAE aged ≥ 12 years initiating lanadelumab treatment (300 mg every 2 weeks) per approved product labeling were recruited from Austria, Germany, Israel, Italy, Kuwait, Spain, and Switzerland and followed for up to 36 months (± 30 days). The primary objective was to evaluate lanadelumab effectiveness for HAE attack prevention. Safety and patient‐reported health‐related quality of life (HRQoL) were also evaluated. Results Outcomes were analyzed in 138 patients (mean [range] age: 41.0 [14–79] years; 62.3% female; 92.0% HAE‐C1INH‐Type1), of whom > 60% extended dosing intervals by Month 12. Over a mean ± SD treatment duration of 28.6 ± 9.8 months, mean ± SD patient‐reported HAE attack rate decreased from 3.88 ± 3.43 attacks/month pre‐lanadelumab to 0.30 ± 0.53 attacks/month (mean decrease, 84% [median 96%]). The incidence‐rate ratio was 0.07 (95% CI: 0.06–0.10), reflecting a 93% reduction from modeled pre‐lanadelumab rates. Overall, 95/138 patients reported treatment‐emergent adverse events (TEAEs); most were unrelated to lanadelumab (82.3%). Of the 17.7% of TEAEs considered treatment‐related, injection‐site reactions, headache, fatigue, and asthenia occurred in > 1 patient. Before lanadelumab initiation, most patients reported moderate‐to‐large HRQoL impairments; clinically meaningful improvements were observed 1 month after lanadelumab initiation and sustained throughout the study. Conclusions Real‐world data from ENABLE demonstrated long‐term effectiveness of lanadelumab in patients with HAE aged ≥ 12 years and a safety profile consistent with previous clinical studies.

CSU AE and CSU W+AE patients show similar rates of autoimmune and autoallergic endotypes. The study supports the current CSU definition and recommendations in the global urticaria guideline.

BACKGROUND:Hereditary angioedema is a bradykinin-mediated, rare condition characterised by recurrent and potentially life-threatening attacks of subcutaneous and submucosal swelling. Bradykinin B2 receptor antagonism is a proven mechanism for on-demand treatment of attacks, but no evidence exists on its effects when used prophylactically. Deucrictibant is an investigational orally bioavailable bradykinin B2 receptor antagonist. We aimed to evaluate the efficacy, safety, and tolerability of two dose regimens of oral deucrictibant administered as prophylaxis against hereditary angioedema attacks. METHODS:CHAPTER-1 was a multicentre, double-blind, placebo-controlled, randomised, phase 2 trial conducted in two parts, a double-blind placebo controlled first part and an open-label second part, with only part 1 reported here. Part 1 recruited adults (aged 18-75 years) with hereditary angioedema type 1 or 2 from 37 sites (university hospitals and accredited angioedema centres) across North America, Europe, and Israel. Patients required a documented history of three or more attacks within the last 3 consecutive months before screening or two or more during the screening period (up to 8 weeks) to be eligible. An interactive response technology system randomised eligible patients 1:1:1 to receive oral deucrictibant 20 mg daily, 40 mg daily, or matching placebo for 12 weeks. Randomisation to treatment groups was stratified by the baseline attack rate. Patients, investigators, site personnel, and the sponsor were blinded to treatment assignment. Masking was achieved with identically appearing deucrictibant and placebo capsules. The primary endpoint was the time-normalised number of investigator-confirmed attacks per 4 weeks (monthly attack rate) from weeks 1 to 12 and was assessed using the intention-to-treat set. The endpoint was analysed by comparing each deucrictibant group with the placebo group using a Poisson generalised linear model with a log link function and Pearson's χ2 scaling of SEs to account for potential dispersion. The safety analysis set included all patients who were randomly assigned and who received one or more doses of study drug (deucrictibant or placebo). CHAPTER-1 is registered with ClinicalTrials.gov (NCT05047185) and is now complete. FINDINGS:Between March 9, 2022, and June 19, 2023, 44 patients were screened. Of 34 patients who were randomly assigned, 11 patients received deucrictibant 20 mg, 12 patients received deucrictibant 40 mg, and 11 patients received the placebo, with a median follow-up of 85·0 days (IQR 84·0-86·0). 21 (62%) patients were female, 13 (38%) were male, and 34 (100%) patients were White. The least squares mean monthly attack rate (primary analysis) was 0·40 (95% CI 0·18-0·92) for deucrictibant 20 mg, 0·30 (0·11-0·81) for deucrictibant 40 mg, and 1·93 (1·30-2·88) for placebo; percent reduction in attack rate compared with placebo was 79·2% (95% CI 47·2-91·8) for deucrictibant 20 mg (p=0·0010) and 84·5% (95% CI 53·8-94·8) for deucrictibant 40 mg (p=0·0008). Treatment-related treatment-emergent adverse events were experienced by two (18%) patients receiving deucrictibant 20 mg, one (8%) patient receiving deucrictibant 40 mg, and one (9%) patient receiving the placebo; all were mild in severity (grade 1) and did not require dosing modification of the study drug. There were no serious adverse events or deaths in any treatment group. INTERPRETATION:To the best of our knowledge, this trial provides the first clinical evidence and proof-of-concept for bradykinin B2 receptor antagonism as a therapeutic approach for the prevention of hereditary angioedema attacks and supports further investigation of oral deucrictibant for bradykinin-mediated angioedema. FUNDING:Pharvaris.

Hereditary angioedema (HAE) with C1 inhibitor deficiency is a rare disease characterized by unpredictable episodes of tissue swelling (angioedema), which, in most cases, occur first under the age of 18 years, and entail a significant burden of disease not only for the patients but also for their families. Clinical symptoms of HAE are not specific, which may cause difficulties in differential diagnosis. Additionally, if not appropriately treated, HAE attacks can be life-threatening. The international HAE guidelines published so far have focused mainly on adults. A guideline that refers to the age-specific characteristics of pediatric patients, both in terms of diagnosis and management, was therefore needed. The International Steering Committee and Taskforce developed recommendations and provided evidence-based grading based on expert opinion and strength of evidence. Recommendations were presented to, discussed, and electronically voted by healthcare professionals during the 14th C1 Inhibitor Deficiency and Angioedema Workshop in Budapest, Hungary, 2025. This international guideline will ensure early diagnosis, standardized and up-to-date treatment, and promote the availability of effective therapies for all pediatric patients affected with this rare disease. It also draws attention to the importance of establishing HAE centers and registries, which solicit specialist care and research of the disease.

Garadacimab (monoclonal antibody inhibiting activated factor XII [FXIIa]) is approved for long-term prophylaxis (LTP) against hereditary angioedema (HAE) attacks. Due to the novelty of FXIIa inhibition and the lifelong need for HAE LTP, long-term evaluation of garadacimab is important. Pooling data from multiple studies can provide valuable insights into treatment effects over longer durations. We report the integrated summary of safety (ISS) and efficacy (ISE) of garadacimab LTP across the HAE clinical development program. The ISS comprised data from phase 2 (13-week placebo-controlled period, 75/200/600 mg monthly or 400 mg every 2 weeks; ≥ 44-week open-label period, 200/600 mg monthly; NCT03712228), pivotal phase 3 (6 months; 200 mg monthly; NCT04656418), and ≥ 12-month phase 3 open-label extension (OLE) studies (200 mg monthly; NCT04739059). The ISE comprised data from phase 3 studies. Endpoints included treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), adverse events of special interest (AESIs) per protocol, and efficacy. At data cutoff (June 15, 2024), median garadacimab exposure (ISS: any dose, n = 172) was 2.5 (range 0.2–5.5) years. Overall rates of TEAEs and garadacimab-related TEAEs were 2.8/patient-year and 0.2/patient-year, respectively. No deaths occurred; four TEAEs led to treatment discontinuation. Eleven patients experienced SAEs (0 garadacimab-related). No garadacimab-related AESIs were reported; one unrelated AESI was observed with garadacimab 600 mg (epistaxis; mild; resolved). The most common garadacimab-related TEAEs were mild/moderate injection-site reactions. In the ISE (median exposure 2.5 [range 0.3–3.2] years), the mean (95

Bradykinin is a nonapeptide of the kinin family with vasoactive and proinflammatory activities. While generation of kinins is mainly driven by activation of the contact system and plasma or tissue kallikreins, additional independent cascades contribute to their formation. Kinins mediate their effects through the constitutively expressed bradykinin B2 receptor and the inducible bradykinin B1 receptor. Bradykinin is the most studied kinin peptide mainly due to its potential role in the vascular system and exerts its effects mainly via the bradykinin B2 receptor. Kinins have been implicated in the pathogenesis of multiple types of angioedema as well as of various conditions, such as allergic mast cell-mediated skin diseases, cardiovascular and respiratory pathologies. This review summarizes our current knowledge of the biology, regulation, and functions of kinins and their receptors as well the emerging evidence on the various mechanisms involved in bradykinin formation and their relevance in disease pathogenesis. The review focuses on the clinical evidence on the roles of bradykinin and of the bradykinin B2 receptor in various conditions, and the potential to develop novel strategies targeting the bradykinin B2 receptor for management of bradykinin-mediated diseases.

This update to the 2019 Canadian Hereditary Angioedema (HAE) Guideline broadens its focus to include the management of patients with HAE worldwide, building on its established international framework. It has been developed through a collaboration of Canadian and international HAE experts and patient groups, coordinated by the Canadian Hereditary Angioedema Network. The objective is to provide evidence-based recommendations, using the Grading of Recommendations Assessment, Development and Evaluation system, for the management of patients with HAE. These include recommendations for the treatment of attacks, short-term prophylaxis, and long-term prophylaxis, as well as recommendations for self-administration, individualized therapy, health-related quality of life, and comprehensive care. New to the 2024 edition are specific recommendations for the treatment of angioedema attacks in individuals with HAE who are breastfeeding/lactating, as well as a dedicated section on shared decision-making. HAE results in spontaneous and often unpredictable attacks of painful swelling, typically affecting the extremities, bowel mucosa, genitals, face, and upper airway. These attacks are associated with significant functional impairment, reduced health-related quality of life, and in the case of laryngeal attacks, a high risk of mortality. Managing HAE is complex, and patient care in Canada, similar to many other countries, remains inconsistent and suboptimal. Care delivery lags behind nations that have implemented more structured management models for HAE, and offer broader access to a wider range of approved therapies. This guideline is intended to be used to optimize HAE management, highlight the importance of individualized care, and provide guidance to healthcare providers, policymakers, patients, and advocates. Primary target users include healthcare providers who are managing patients with HAE, as well as emergency and intensive care physicians, primary care physicians, gastroenterologists, dentists, otolaryngologists, pediatricians, hematologists, dermatologists, and gynecologists who will encounter patients with HAE and need to be aware of this condition. Hospital administrators, insurers and policy makers may also find this guideline helpful.

Abstract Introduction Hereditary angioedema (HAE), characterized by unpredictable attacks of subcutaneous or submucosal edema, can significantly impact patient quality of life (QoL). Despite advances in long-term prophylaxis (LTP), achieving complete control of HAE is challenging, making shared decision-making (SDM) critical for tailored HAE management. This investigation explores the dynamics of healthcare professional (HCP)–patient conversations concerning HAE management, and identifies barriers to SDM, LTP initiation and strategies that may overcome these to optimize patient QoL. Methods The investigation was conducted in Germany. HCPs managing patients with HAE participated in 60 min interviews and led simulated patient consultations. 30 min interviews with patients with HAE were also conducted. Results Ten HCPs and eight patients with HAE were interviewed. In the simulated consultations, most HCPs recommended LTP based on high attack frequency and substantial impact on QoL. Interviews revealed that HCPs typically initiate discussions on LTP by assessing disease burden, focusing on attack frequency and QoL. These treatment discussions also highlighted the need for improved communication with patients about the LTP treatments that are available to them. However, many HCPs lacked awareness of updated treatment guidelines and faced challenges in reassuring patients about the long-term safety and efficacy of newer LTP options. All patients who were initiated on LTP experienced positive results, including improved QoL and reduced fear of attacks. Those who declined LTP cited low attack frequency on their acute treatment and concerns about burden of treatment and long-term effects. Key barriers to effective SDM included time constraints during routine consultations, absence of clear SDM guidance, and a lack of jargon-free information to foster proactive patient engagement. Conclusion This research highlights opportunities to enhance HCP–patient conversations concerning the management of HAE. Inconsistencies between positive patient experiences with LTP and real-world prescription rates emphasize the need for improved SDM practices. Enhancing HCP awareness of patient perspectives, managing time constraints in consultations, and providing unbiased, patient-friendly information may help bridge these gaps and improve communication and ultimately patient QoL. The findings underscore the importance of further research to develop guidelines that prioritize SDM and patient empowerment in HAE management.

BACKGROUND:Hereditary angioedema (HAE) is a rare, potentially life-threatening disease caused in most cases by C1 inhibitor deficiency. Lanadelumab, a monoclonal antibody targeting plasma kallikrein, is an effective long-term prophylactic (LTP) treatment for HAE. However, consensus on best practices remains lacking. OBJECTIVES:This study aimed to report consensus statements on key principles on long-term lanadelumab therapy for HAE in Germany developed at an HAE LTP Expert Meeting in the year 2024 in Frankfurt, Germany. MATERIALS AND METHODS:A multidisciplinary panel of seven German HAE experts participated in a consensus process to align current guidelines with real-world clinical practice. Following literature review and debate, keynotes were drafted, refined, and voted on. Consensus was defined as ≥ 70% agreement. Key domains included: shared decision-making; flexibility in initiating or adjusting prophylaxis; structured patient education; self-administration; individualized dosing; emergency medication availability; and proactive follow-up, including specific guidance for women of childbearing age. RESULTS:Ten core consensus statements were developed, achieving unanimous (100%, n = 9/10 statements) or strong (≥ 85%, n = 1/10 statements) agreement. It is recommended that the decision to initiate long-term prophylaxis be made through shared decision-making and that the decision made can and should be adjusted again in the further course of treatment. It is advisable to train patients in the technique of self-injection and to start therapy with lanadelumab with a 2-week injection interval in accordance with the product information. The injection interval should be adjusted to the individual patient, and all well-controlled patients should be offered the option of extending the interval without compromising the goal of complete disease control. Even and especially when the prophylaxis is well tolerated, emergency medication must not be neglected. CONCLUSION:These consensus statements provide a practical, expert-endorsed framework for implementing lanadelumab LTP in clinical practice emphasizing individualized treatment aligned with international guidelines and patient needs.

Zusammenfassung Das hereditäre Angioödem ( Hereditary angioedema , HAE), eine seltene und belastende Erkrankung, die durch rezidivierende und spontane Gewebeschwellungsattacken gekennzeichnet ist, weist einen hohen ungedeckten therapeutischen Bedarf auf, da Patienten unter aktuellen prophylaktischen Behandlungen eine unzureichende Krankheitskontrolle erfahren. Das Ziel der HAE‐Behandlung gemäß den Leitlinien ist das Erreichen einer vollständigen Krankheitskontrolle und die Normalisierung des Lebens der Patienten. Faktor XII (FXII), der Hauptinitiator des Kontaktsystems, reguliert letztlich das Kallikrein‐Kinin‐System. Der aktivierte Faktor XII (FXIIa) wandelt Plasma‐Präkallikrein in Plasma‐Kallikrein um, welches das hochmolekulare Kininogen spaltet, um das vasoaktive Peptid Bradykinin zu erzeugen. In der Pathophysiologie des HAE führt eine Dysregulation des Kallikrein‐Kinin‐Systems zu einer übermäßigen Bradykininproduktion. Der monoklonale Anti‐FXIIa‐Antikörper Garadacimab ist zur Langzeitprophylaxe von HAE‐Attacken zugelassen. In der zulassungsrelevanten Phase‐III‐Studie (VANGUARD) und den laufenden offenen Phase‐III‐Erweiterungsstudien zeigte Garadacimab bei subkutaner Verabreichung (Aufdosierung mit 2 × 200 mg, gefolgt von 200 mg einmal monatlich) eine dauerhafte Wirksamkeit mit frühem Schutzbeginn und ein günstiges Langzeit‐Sicherheitsprofil. Basierend auf diesen und früheren klinischen Daten hat Garadacimab das Potenzial, Patienten den leitliniengemäßen Zielen der Krankheitskontrolle und Normalisierung des Lebens näherzubringen. Hier geben wir einen Überblick über die Ergebnisse des klinischen Entwicklungsprogramms von Garadacimab.

IntroductionAll angioedema (AE) presents with transient, localized swelling; however, the underlying causes, prognosis, and treatments vary significantly. Consequently, identifying a specific AE type is challenging.MethodsWe 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.ResultsThe 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.DiscussionThis is the first ever reported ML algorithm designed to pre-assess to aid AE diagnosis.