Long-term Safety and Effectiveness of Sebetralstat: Interim Analysis of KONFIDENT-S Open-label Extension.

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.

Lanadelumab's impact on hereditary angioedema control and quality of life across disease activity subgroups: Real-world evidence.

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.

Hereditary angioedema treatment beyond biologics: current state of preventive and on-demand approaches and new perspectives.

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.

Diagnostic testing for chronic spontaneous urticaria with or without angioedema: The do's, don't and maybe's.

Chronic spontaneous urticaria (CSU), with or without angioedema, is heterogeneous and comprised of different endotypes and phenotypes. Because acute urticaria will mostly resolve spontaneously, routine testing and laboratory evaluation is not required unless supported by the clinical history or physical examination. With the advent of omalizumab, there has been a surge of interest in identifying biomarkers that could predict response to this treatment.

Hereditary angioedema diagnosis: Reflecting on the past, envisioning the future.

Individuals with hereditary angioedema (HAE), a rare disease most frequently associated with deficiency (HAE-C1INH-Type1) or dysfunction (HAE-C1INH-Type2) of C1 inhibitor (C1INH), continue to experience frequent misdiagnoses and long delays in diagnosis, preventing appropriate management strategies and placing the patients at continued risk of inappropriate management of painful, debilitating, and potentially fatal swelling attacks. Physician education to increase HAE awareness is important to initiate diagnostic testing for patients who may be at risk of HAE. Standard tests for diagnosing HAE-C1INH-Type1 and HAE-C1INH-Type2 include measurements of antigenic C4 level, antigenic C1INH level, and C1INH function; in contrast, known subtypes of HAE due to normal C1INH can only be confirmed through genetic testing.

Lanadelumab for prevention of attacks of non-histaminergic normal C1 inhibitor angioedema: results from the randomized, double-blind CASPIAN Study and CASPIAN open-label extension.

Background: Randomized controlled trial data for non-histaminergic normal C1 inhibitor (nC1INH) angioedema prevention are lacking.

Methods: Patients aged ≥12 years with investigator-confirmed non-histaminergic nC1INH angioedema were enrolled in phase III, multicenter, randomized, placebo-controlled, double-blind CASPIAN Study (NCT04206605). Patients with ≥1 investigator-confirmed angioedema attack/4 weeks during observation period were randomized 2:1 to lanadelumab 300 mg every 2 weeks or placebo.

Assessment of potential drug-drug interactions in patients with hereditary angioedema from the ITACA cohort: simulations from a real-life dataset considering danazol versus berotralstat.

Background: Danazol is regularly used as a prophylactic treatment in patients with Hereditary angioedema due to C1-inhibitor deficiency (HAE-C1INH). However, this drug is characterized by a risk of drug-drug interactions (DDIs). Berotralstat, the first oral kallikrein inhibitor, has been recently approved for the prevention of HAE attacks.

Hereditary Angioedema with Normal C1 Inhibitor: an Updated International Consensus Paper on Diagnosis, Pathophysiology, and Treatment.

Hereditary angioedema (HAE) has been recognized for almost 150 years. The newest form of HAE, where C1 inhibitor levels are normal (HAE-nC1INH), was first described in 2000. Over the last two decades, new types of apparent non-mast cell-mediated angioedema with normal quantity and activity of C1INH have been described, in some cases with proven genetic pathogenic variants that co-segregate with angioedema expression within families.

A COSMIN systematic review of instruments for evaluating health-related quality of life in people with Hereditary Angioedema.

Background: Hereditary angioedema (HAE) adversely affects health-related quality of life (HRQoL). HAE often compromises the HRQoL due to the impact on functional capacity caused by edema, pain, other symptoms, and psychosocial factors. Patient-Reported Outcome Measures (PROMs) focus on HRQoL and are crucial tools for evaluating the burden of the disease and choosing the most appropriate interventions for this population.

Patterns of C1-Inhibitor Plasma Levels and Kinin-Kallikrein System Activation in Relation to COVID-19 Severity.

Background: Although more than four years have passed since the pandemic began, SARS-CoV-2 continues to be of concern. Therefore, research into the underlying mechanisms that contribute to the development of the disease, especially in more severe forms, remains a priority. Sustained activation of the complement (CS), contact (CAS), and fibrinolytic and kinin-kallikrein systems (KKS) has been shown to play a central role in the pathogenesis of the disease.

DAB2IP associates with hereditary angioedema: Insights into the role of VEGF signaling in HAE pathophysiology.

Background: In the recent years, there was an important improvement in the understanding of the pathogenesis of hereditary angioedema (HAE). Notwithstanding, in a large portion of patients with unknown mutation (HAE-UNK) the genetic cause remains to be identified.

Objectives: To identify new genetic targets associated with HAE, a large Argentine family with HAE-UNK spanning 3 generations was studied.

Comorbidities in Angioedema Due to C1-Inhibitor Deficiency: An Italian Survey.

Background: Hereditary angioedema (HAE) due to C1-inhibitor (C1-INH) deficiency is characterized by unpredictable recurrent episodes of swelling affecting the skin and the mucosa tissues, including gastrointestinal tract and/or oropharyngeal-laryngeal mucosae. Long-term prophylaxis (LTP) is used to prevent attacks.

Objective: Because C1-INH plays a pivotal role in several biological pathways, we investigated the possible association of comorbidities with C1-INH deficiency and the use of LTP with attenuated androgens (AA) or tranexamic acid (TXA).

Evaluation of patient-reported outcome measures for on-demand treatment of hereditary angioedema attacks and design of KONFIDENT, a phase 3 trial of sebetralstat.

Background: Hereditary angioedema (HAE) with C1-inhibitor deficiency (HAE-C1-INH) is characterized by recurrent, debilitating episodes of swelling. Sebetralstat, an investigational oral plasma kallikrein inhibitor, demonstrated promising efficacy for on-demand treatment of HAE-C1-INH in a phase 2 trial. We describe the multipronged approach informing the design of KONFIDENT, a phase 3 randomized, placebo-controlled, three-way crossover trial evaluating the efficacy and safety of sebetralstat in patients aged ≥12 years with HAE-C1-INH.

Multicentric Observational Study on Safety and Tolerability of COVID-19 Vaccines in Patients with Angioedema with C1 Inhibitor Deficiency: Data from Italian Network on Hereditary and Acquired Angioedema (ITACA).

Angioedema due to C1 inhibitor deficiency (AE-C1-INH) is a rare disease characterized by recurrent and unpredictable attacks of angioedema. Multiple trigger factors, including trauma, emotional stress, infectious diseases, and drugs, could elicit angioedema attacks. The aim of this study was to collect data on the safety and tolerability of COVID-19 vaccines in a population of patients affected by AE-C1-INH.

An investigational oral plasma kallikrein inhibitor for on-demand treatment of hereditary angioedema: a two-part, randomised, double-blind, placebo-controlled, crossover phase 2 trial.

Background: Guidelines recommend effective on-demand therapy for all individuals with hereditary angioedema. We aimed to assess the novel oral plasma kallikrein inhibitor, sebetralstat, which is in development, for on-demand treatment of hereditary angioedema attacks.

Methods: In this two-part phase 2 trial, individuals with type 1 or 2 hereditary angioedema aged 18 years or older were recruited from 25 sites, consisting of specialty outpatient centres, across nine countries in Europe and the USA.

Real-Life Experience With Subcutaneous Plasma-Derived C1-Inhibitor for Long-Term Prophylaxis in Patients With Hereditary Angioedema: A Case Series.

Hereditary angioedema due to C1-inhibitor deficiency (C1-INH-HAE) is characterized by swelling attacks that may be even life-threatening. To reduce the frequency of attacks, some patients need a long-term prophylaxis (LTP). In addition to the intravenous administration, plasma-derived C1-inhibitor (pdC1-INH) has been proved effective also if administered subcutaneously at the dose of 120 IU/kg/week.

Emerging drugs for the treatment of hereditary angioedema due to C1-inhibitor deficiency.

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

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

The international WAO/EAACI guideline for the management of hereditary angioedema - The 2021 revision and update.

Hereditary Angioedema (HAE) is a rare and disabling disease for which early diagnosis and effective therapy are critical. This revision and update of the global WAO/EAACI guideline on the diagnosis and management of HAE provides up-to-date guidance for the management of HAE. For this update and revision of the guideline, an international panel of experts reviewed the existing evidence, developed 28 recommendations, and established consensus by an online DELPHI process.