Efficacy, pharmacokinetics, and safety of subcutaneous C1-esterase inhibitor as prophylaxis in Japanese patients with hereditary angioedema: Results of a Phase 3 study.

BACKGROUND: Hereditary angioedema (HAE) is a rare and potentially life-threatening genetic disorder characterized by recurrent attacks of angioedema. HAE types I and II result from deficient or dysfunctional C1-esterase inhibitor (C1-INH). This Phase 3 study assessed the efficacy, pharmacokinetics (PK), and safety of subcutaneous (SC) C1-INH in Japanese patients with HAE. METHODS: The prospective, open-label, multicenter, single-arm Phase 3 study recruited patients with HAE types I or II to an initial run-in period, followed by a 16-week treatment period where patients received 60 IU/kg C1-INH (SC) twice weekly. The two primary endpoints were the time-normalized number of HAE attacks per month and C1-INH functional activity at Week 16. RESULTS: Nine patients entered the treatment period and completed the study. Treatment with C1-INH (SC) significantly reduced the mean monthly attack rate from 3.7 during the run-in period to 0.3 during treatment (exploratory p value of within-patient comparison = 0.004). After the last dose of C1-INH (SC) at Week 16, the mean trough concentration of C1-INH was 59.8%, and the mean area under the plasma concentration-time curve to the end of the dosing period and to the last sample were 5317.1 and 13,091.5 h•%, respectively. During the study, there were no deaths, serious adverse events, or adverse events leading to study discontinuation. CONCLUSIONS: C1-INH (SC) (60 IU/kg twice weekly) was efficacious and well tolerated as a prophylaxis against HAE attacks in Japanese patients with HAE types I or II, which was supported by the increased and maintained C1-INH functional activity. EudraCT Number 2019-003921-99; JapicCTI-205273.

Hereditary angioedema and Allergic bronchopulmonary aspergillosis: an unexpected association / Angioedema hereditário e Aspergilose broncopulmonar alérgica: uma associação inesperada

Hereditary angioedema (HAE) is a rare autosomal dominant disorder, Allergic bronchopulmonary aspergillosis (ABPA) is a lung disease involving hypersensitivity to the fungi Aspergillus fumigatus which occur in susceptible patient with asthma or cystic fibrosis, also considered a rare disease. We report a case of HAE and ABPA in a single patient. HAE diagnosis was confirmed: C4 = 3 mg/dL, C1INH < 2.8 mg/dL - nephelometry. Former lung function showed elevation RV and RV/FVC, suggesting small airways lung disease. Positive skin prick test to Aspergillus fumigatus (03 mm); total serum IgE level 3,100 IU/mL (nephelometry - BNII Siemens), eosinophilia 11% (528/mm3) and specific A. fumigatus IgG antibodies 6,8 mgA/L (FEIA - fluorenzymeimmunoassay - ThermoFisher) and Chest CT showed mucoid impaction of the bronchi, consistent to current ABPA. Controlling ABPA could prevent and reduce angioedema attacks, and lung structural damage. Early diagnosis and treatment of both diseases should be emphasized to reduce mortality and morbidity

Angioedema hereditário (AEH) é uma doença autossômica dominante; aspergilose broncopulmonar alérgica (ABPA) é uma doença de hipersensibilidade pulmonar relacionada ao esporo de Aspergillus fumigatus, mais suscetível em pacientes com asma e fibrose cística, ambas são consideradas doenças raras. Apresentamos um caso de AEH e ABPA em um paciente. O diagnóstico de AEH foi confirmado com exames laboratoriais: C4 = 3 mg/dL, C1INH < 2,8 mg/dL - nefelometria. Prova de função pulmonar evidenciou aumento de VR e VR/CVF, sugerindo doenças de pequenas vias aéreas. Teste de puntura positivo para A. fumigatus (03 mm); IgE total = 3.100 IU/mL (nefelometria - BNII Siemens), eosinofilia 11% (528/mm3) e IgG específica para A. fumigatus 6,8 mgA/L (FEIA - ThermoFisher), TC de tórax evidenciou impactação mucoide, consistente com ABPA. Controlar ABPA pode prevenir e reduzir as crises de angioedema e os danos ao tecido pulmonar. O diagnóstico precoce de ambas as doenças deve ser enfatizado para reduzir a morbimortalidade.

Angioedema hereditário inaugural na idade pediátrica / Hereditary angioedema in a child with no family history of disease

O angioedema hereditário por défice de C1-inibidor é uma doença rara autossômica dominante com uma prevalência estimada em 1:50.000. Habitualmente a história familiar aponta para este diagnóstico. No entanto, a apresentação atípica com história familiar negativa pode atrasar o diagnóstico de meses a anos. Os autores apresentam o caso de uma criança de 6 anos sem antecedentes pessoais ou familiares relevantes que recorreu ao Serviço de Urgência pediátrico por edema, calor e rubor do cotovelo, joelho e maléolos direitos com 12h de evolução, sem fatores associados. Ao exame objetivo: edema do cotovelo, joelho e maléolos direitos, exantema não pruriginoso maleolar homolateral com discreto desconforto à palpação. Sem elevação dos parâmetros infeciosos ou inflamatórios. Foi iniciada corticoterapia sistêmica, com melhoria lenta do quadro. Teve alta, referenciada à consulta de Imunoalergologia. Na anamnese foram apurados quatro episódios de edema periarticular nos doze meses prévios. A avaliação analítica da criança revelou C1 inibidor 62 mg/dL, C1 inibidor funcional 29%, confirmada em duas determinações, e a dos pais e dos dois irmãos foi normal. No estudo genético não foram identificadas mutações nos genes SERPING. O angioedema hereditário por défice de função do C1-inibidor - tipo II - representa 15 a 20% dos casos. Embora a história familiar seja o maior sinal de alerta para o diagnóstico desta patologia, em 20-25% dos casos ocorre mutação espontânea. Nestes casos um elevado grau de suspeição é necessário e um atraso no diagnóstico pode levar a consequências graves. As opções terapêuticas em crianças menores de 12 anos são ainda limitadas.

Hereditary angioedema with C1-inhibitor deficiency is a rare autosomal dominant disease with an estimated prevalence of 1:50 000. Usually, family history points to this diagnosis. However, atypical presentation with negative family history may delay diagnosis in months to years. The authors describe the case of a 6-year-old girl with apparently no significant family or past medical history, presenting to the emergency department for edema, warmth, and redness of the right elbow, knee, and ankle, which started 12 hours earlier, without associated factors. On physical examination, edema of the right elbow, knee, and ankle, and nonpruritic rash on the right ankle with a slight discomfort on palpation were found. Laboratory infection or inflammation markers were not elevated. Systemic corticosteroids were started, with slow improvement. She was discharged and referred to an immunoallergology outpatient clinic. On medical history taking, four episodes of periarticular edema in the past 12 months were identified. Laboratory evaluation revealed C1-inhibitor at 62 mg/dL and functional C1-inhibitor at 29%, confirmed in two samples; the parents and two siblings were normal. On genetic testing, there were no mutations on the SERPING genes. Hereditary angioedema with C1-inhibitor deficiency ­ ie, type II ­ accounts for 15 to 20% of cases. Even though family history is the major indicator for diagnosis of this condition, a de novo mutation occurs in 20 to 25% of cases. In these cases, a high suspicion is necessary, and a delayed diagnosis could have severe implications. Therapeutic options in children under the age of 12 are limited.

First administration of ecallantide in Peru: a case report of a Peruvian patient with hereditary angioedema with normal C1-inhibitor / Primeira administração de ecalantida no Peru: relato de caso de paciente peruano com angioedema hereditário com inibidor de C1 normal

Ecallantide is a specific treatment currently indicated for acute crisis of hereditary angioedema (HAE) due to C1-inhibitor deficiency. Our objective is to report the first administration of ecallantide (Kalbitor®) in Peru, where the treatment was used in an HAE patient with normal C1-inhibitor and no F12 gene alteration. We report the case of a 32-year-old postpartum patient with HAE with normal C1-inhibitor who belongs to the Peruvian Association of Patients with Hereditary Angioedema. During pregnancy, she had increased frequency and intensity of abdominal pain and facial edema crisis and received maintenance treatment with tranexamic acid and spasmolytics, with moderate response. One month postpartum, the patient showed respiratory symptoms and tested positive for coronavirus disease (COVID-19) in a polymerase chain reaction (PCR) test, without any HAE crisis during the infectious process. Three months postpartum, she had an acute laryngeal edema crisis with difficulty breathing and speaking, nausea, and vomiting, triggered by nonsteroidal anti-inflammatory drugs (NSAIDs). The patient then received treatment with antihistamines, corticosteroids, and adrenaline, without improvement; for that reason, the allergist administered ecallantide (Kalbitor®) with good response within the first 15 minutes of administration. Some Peruvian HAE patients have developed mild-to-moderate facial and peripheral edema crisis after NSAID intake, without improvement after administration of allergy treatment. In our patient, HAE crisis was not triggered by COVID-19. The patient showed worsening HAE crisis during pregnancy. The first administration of ecallantide (Kalbitor®) in Peru had good response and tolerance to the treatment as shown in this report.

Ecallantide é um tratamento específico totalmente indicado na crise aguda de deficiência de inibidor de C1 HAE. Nosso objetivo é relatar a primeira administração de Ecallantide (Kalbitor®) no Peru, um caso de paciente peruano com EH com inibidor C1 normal sem alteração genética F12. Relatamos o caso de uma paciente de 32 anos, pós-parto, com HAE inibidor de C1 normal, pertencente à Associação Peruana de Angioedema Hereditário de Pacientes. Durante a gravidez, a paciente apresentou aumento na frequência e intensidade das crises de edema abdominal e facial e recebeu tratamento de manutenção com ácido tranexâmico e espasmolítico, com resposta moderada. Um mês após o parto, a paciente apresentou quadro respiratório e teste de PCR molecular positivo para Doença do Coronavírus (COVID-19), sem crise de AEH durante o processo infeccioso. Três meses após o parto, a paciente apresentou crise de edema agudo de laringe com dificuldade para respirar e falar, náuseas e vômitos, desencadeado por AINH. A paciente recebeu tratamento com anti-histamínicos, corticosteroides e adrenalina sem melhora, por isso o alergista administrou Ecallantide (Kalbitor®) com boa resposta nos primeiros 15 minutos após o início da administração. Alguns pacientes peruanos com AEH desenvolveram crises de edema facial e periférico leve a moderado após a ingestão de AINEs, sem melhora após a administração de tratamento para alergia. Em nossa paciente, a crise de AEH não foi desencadeada por infecção aguda por COVID-19. A paciente apresentou agravamento da crise de AEH durante a gravidez. Apresentamos a primeira administração de Ecallantide (Kalbitor®) no Peru, com boa resposta e tolerância ao tratamento.

[EFFICACY, PHARMACOKINETICS, PHARMACODYNAMICS, AND SAFETY OF INTRAVENOUS C1 INHIBITOR FOR LONG-TERM PROPHYLAXIS AND TREATMENT OF BREAKTHROUGH ATTACKS IN JAPANESE SUBJECTS WITH HEREDITARY ANGIOEDEMA: A PHASE 3 OPEN-LABEL STUDY].

BACKGROUND: Hereditary angioedema (HAE) is associated with recurrent, painful, and potentially lifethreatening attacks characterized by swelling of subcutaneous or submucosal tissues. PURPOSE: To investigate the efficacy, safety, pharmacokinetics, and pharmacodynamics of repeat-use C1 inhibitor (C1-INH) replacement therapy for long-term prophylaxis and treatment of breakthrough attacks in the management of Japanese patients with HAE type I or II. METHODS: An open-label, single-arm, Phase 3 study was conducted in Japanese patients with HAE (NCT02865720). For patients 6 years of age or older, 1000U were administered biweekly (by a healthcare professional or self-administered) via intravenous infusion. RESULTS: In 8 enrolled patients, the mean number of attacks normalized per month was lower during C1-INH treatment than during the 3 months prior (1.826 vs. 3.375). Clinically meaningful mean change from baseline in the angioedema-quality of life (AE-QoL) total score was shown during treatment with C1-INH. Pharmacokinetic data showed markedly higher and enduring post-baseline plasma levels of C1-INH functional activity and C1-INH antigen concentration, starting from 0.5h after first dose of C1-INH and lasting up to 72 hours. C1-INH was well tolerated with no new safety signals identified in this population of Japanese patients with HAE. CONCLUSION: C1-INH was effective for long-term prophylaxis and treatment of breakthrough attacks with favourable safety profile in Japanese patients with HAE.

Efficacy, pharmacokinetics, and safety of icatibant for the treatment of Japanese patients with an acute attack of hereditary angioedema: A phase 3 open-label study.

BACKGROUND: Hereditary angioedema (HAE) is a genetic disease characterized by recurrent swelling episodes affecting the skin, gastrointestinal mucosa, and upper respiratory tract. METHODS: A phase 3, single-arm, open-label study was performed to evaluate a selective bradykinin B2 receptor antagonist, icatibant, for the treatment of acute attacks in Japanese patients with HAE Type I or II. After the onset of an acute attack, icatibant 30 mg was administered by the patient or a healthcare professional via subcutaneous injection in the abdomen. RESULTS: Eight patients who had an attack affecting the skin (n = 4), abdomen (n = 3), or larynx (n = 1) were treated with icatibant (3 of the injections were self-administered). The median time to onset of symptom relief was 1.75 h (95% confidence interval, 1.00-2.50), and all patients had symptom relief within 5 h after administration. The time to maximum plasma concentration of icatibant was 1.79 h, and the maximum plasma concentration was 405 ng/ml. Seven patients experienced an injection site reaction, and 3 patients had adverse events (2 patients had a worsening or repeat HAE attack 29.0 and 18.3 h after icatibant administration, respectively, and 1 had headache). CONCLUSIONS: Although the number of patients is small, the efficacy and tolerability of icatibant for acute attacks were demonstrated in Japanese patients with HAE, regardless of self-administration or administration by healthcare professional.

HEREDITARY ANGIOEDEMA DUE TO C1-INHIBITOR DEFICIENCY IN PEDIATRIC PATIENTS IN CROATIA - FIRST NATIONAL STUDY, DIAGNOSTIC AND PROPHYLACTIC CHALLENGES.

Hereditary angioedema (HAE) is a rare autosomal dominant disease with deficiency (type I) or dysfunction (type II) of C1 inhibitor, caused by mutations in the C1-INH gene, characterized by recurrent submucosal or subcutaneous edemas including skin swelling, abdominal pain and life-threatening episodes of upper airway obstruction. The aim of this study was to investigate healthcare experiences in children with HAE due to C1 inhibitor deficiency (C1-INH-HAE) in Croatia in order to estimate the number of affected children and to recommend management protocols for diagnosis, short-term prophylaxis and acute treatment. Patients were recruited during a 4-year period at five hospitals in Croatia. Complement testing was performed in patients with a positive family history. This pilot study revealed nine pediatric patients positive for C1-INH- HAE type I, aged 1-16 years, four of them asymptomatic. Before the age of one year, C1-INH levels may be lower than in adults; it is advisable to confirm C1-INH-HAE after the age of one year. Plasma-derived C1-INH is recommended as acute and short-term prophylactic treatment. Recombinant C1-INH and icatibant are licensed for the acute treatment of pediatric patients. In Croatia, HAE is still underdiagnosed in pediatric population.

Clinical Features of Hereditary Angioedema in Korean Patients: A Nationwide Multicenter Study.

BACKGROUND: Hereditary angioedema (HAE) is a genetically heterogeneous autosomal dominant disorder characterized by recurrent episodes of nonpruritic, nonpitting edema increasing after puberty. It can be fatal due to laryngeal or gastrointestinal (GI) involvement with varied and changing frequency of mortality according to studies published from the Western countries. Epidemiological and clinical data of HAE in Asian countries are sparse. We sought to examine the clinical characteristics of HAE patients in Korea. METHODS: Patients diagnosed with HAE at 15 tertiary hospitals across the country until 2016 were retrospectively reviewed. RESULTS: A total of 65 patients diagnosed with HAE by 2016 were identified. The prevalence of HAE was estimated at 1.3/1,000,000 in Korea. Of the 65 patients, 21 (32.3%) were males. A total of 90.8% patients had type I HAE, while the remaining 9.2% patients had type II HAE. The first symptom developed after 20 years in 73.8% of patients, with a mean age 28.4 ± 14.1 years. The age at diagnosis was 36.5 ± 15.8 years, with a mean time delay of 7.8 ± 10.5 years. While the face (82.3%) and extremities (upper 71.0%, lower 62.9%) were the most frequently involved, the GI tract was affected in 40.5% of Korean HAE patients. Prophylaxis was maintained in 62.5% of patients. There was no reported case of death from HAE so far. CONCLUSIONS: The clinical manifestation and severity of HAE may vary according to ethnicity. HAE is more infrequent and GI involvement is less likely in Korea compared with Western countries.

[EFFICACY, PHARMACOKINETICS, AND SAFETY OF ICATIBANT FOR THE TREATMENT OF JAPANESE PATIENTS WITH AN ACUTE ATTACK OF HEREDITARY ANGIOEDEMA: A PHASE 3 OPEN-LABEL STUDY].

BACKGROUND: Hereditary angioedema (HAE) is characterized by paroxysmal edema of the skin, gastrointestinal mucosa, and upper respiratory tract. PURPOSE: This study investigated icatibant, a selective bradykinin B2 receptor antagonist, as treatment for Japanese patients with an acute HAE attack. METHODS: This was an open-label, single-arm, Phase 3 study of Japanese adults with HAE type I or II. Icatibant (30 mg) was administered (by a healthcare professional [HCP] or self-administered) as a subcutaneous injection in the abdomen. RESULTS: Eight patients (4 cutaneous, 3 abdominal, 1 laryngeal) were treated with icatibant (all single injection; 3 self-administered, 5 HCP-administered). The median time to onset of symptom relief was 1.75 hours (95% confidence interval, 1.00 to 2.50); all patients had onset of relief within 5 hours. The estimated time to maximum icatibant concentration in the circulation was 1.79 hours and the maximum concentration was 405 ng/mL. There were 3 patients who experienced 3 adverse events (2 HAE attacks and 1 headache); 7 patients experienced an injection site reaction. CONCLUSION: Although our study was limited by the small number of patients, we found that icatibant was an effective and well-tolerated treatment for Japanese patients with acute HAE attacks, regardless of whether it was administered by a HCP or self-administered.

Outcomes of long term treatments of type I hereditary angioedema in a Turkish family

Abstract: Background: Hereditary angioedema is a rare autosomal dominantly inherited immunodeficiency disorder characterized by potentially life-threatening angioedema attacks. Objective: We aimed to investigate the clinical and genetic features of a family with angioedema attacks. Methods: The medical history, clinical features and C1-INH gene mutation of a Turkish family were investigated and outcomes of long-term treatments were described. Results: Five members had experienced recurrent swellings on the face and extremities triggered by trauma. They were all misdiagnosed as familial Mediterranean fever (FMF) depending on frequent abdominal pain and were on colchicine therapy for a long time. They had low C4 and C1-INH protein concentrations and functions. A mutation (c.1247T>A) in C1-INH gene was detected. They were diagnosed as having hereditary angioedema with C1-INH deficiency (C1-INH hereditary angioedema) for the first time. Three of them benefited from danazol treatment without any significant adverse events and one received weekly C1 esterase replacement treatment instead of danazol since she had a medical history of thromboembolic stroke. Study limitations: Small sample size of participants. Conclusion: Patients with C1-INH hereditary angioedema may be misdiagnosed as having familial Mediterranean fever in regions where the disorder is endemic. Medical history, suspicion of hereditary angioedema and laboratory evaluations of patients and their family members lead the correct diagnoses of hereditary angioedema. Danazol and C1 replacement treatments provide significant reduction in hereditary angioedema attacks.

Hereditary Angioedema as a Metabolic Liver Disorder: Novel Therapeutic Options and Prospects for Cure.

Hereditary angioedema (HAE) is a rare autosomal dominant disorder caused by mutations of the SERPING1 or the Factor 12 genes. It is potentially fatal, particularly if not identified at an early stage. Apart from androgens, which are contraindicated in children and in pregnant women, a range of effective, albeit very expensive treatments have recently become available for HAE patients. The cost of these new treatments is beyond the reach of most developing countries. At this time, there is no cure for the disorder. In spite of mutations of the SERPING1 gene, autoimmunity and infections are not prominent features of the condition. Here, we present the argument that HAE should be viewed primarily as a metabolic liver disorder. This conceptual paradigm shift will stimulate basic research and may facilitate new therapeutic approaches to HAE outlined in this paper. We suggest several novel potential treatment options for HAE from the perspectives of clinical immunology, molecular biology, and liver transplantation. Many of these offer the prospect of curing the disorder. The effectiveness of these options is rapidly improving in many cases, and their risks are decreasing. Given the very high costs of treating HAE, some of these curative options may become feasible in the next decade.

Angioedema hereditario en Medellín, Colombia: evaluación clínica y de la calidad de vida / Hereditary angioedema in Medellín (Colombia): Clinical evaluation and quality of life appraisal

Introducción. El angioedema hereditario es una inmunodeficiencia primaria de carácter autosómico dominante, debida a un déficit en la proteína inhibidora del factor C1 y caracterizada por episodios recurrentes de edema subcutáneo y de las mucosas. Las impredecibles y frecuentes crisis de angioedema afectan la calidad de vida de los individuos que las padecen. Objetivo. Analizar las características clínicas de una familia con un caso índice de angioedema hereditario y determinar el impacto de la enfermedad en la calidad de vida. Materiales y métodos. En el estudio se incluyeron 26 miembros de la familia, a 25 de los cuales se les midieron los niveles sanguíneos del factor C4 del complemento y del inhibidor de C1 antigénico y funcional. Se utilizaron dos instrumentos, el SF-36 para evaluar la salud del adulto y el KIDSCREEN-27 para la calidad de vida de niños y adolescentes. Resultados. El 83 % de los individuos que reportaron síntomas cumplían con los criterios serológicos del angioedema hereditario de tipo I: valores bajos del factor C4 del complemento y del inhibidor de C1 cuantitativo (antigénico) y cualitativo (funcional). Se encontró que la calidad de vida en cuanto al bienestar psicológico y el desempeño emocional de los pacientes, se veía considerablemente afectada por los síntomas de la enfermedad. Conclusión. Este estudio provee información sobre la primera familia caracterizada con angioedema hereditario de tipo 1 en el Valle de Aburrá, Colombia. Aunque para ello se usó un instrumento genérico, se confirmó, además, el efecto negativo de la enfermedad en la calidad de vida de los individuos que la padecen.

Introduction: Hereditary angioedema is an autosomal dominant primary immunodeficiency caused by a deficiency of the C1 inhibitor protein and characterized by recurrent episodes of subcutaneous and mucosal edema. Unpredictable and frequent crisis of angioedema affect the quality of life of individuals suffering this kind of disorder. Objective: To analyze the clinical characteristics of a family with an index case of hereditary angioedema and to determine the impact of this disease on their quality of life. Materials and methods: Twenty six members of the family were included in the trial; 25 of them were analyzed for C4 complement and antigenic and functional C1 inhibitor blood levels. Two instruments (SF-365 and KIDSCREEN-27) were used to evaluate adult health quality and children and teenagers quality of life, respectively. Results: Eighty three percent (83%) of individuals reporting symptoms of the condition exhibited serological criteria of hereditary angioedema type I: low levels of both C4 complement and quantitative (antigenic) and qualitative (functional) C1 inhibitor. In relation to patients' psychological and emotional performance, their quality of life was significantly affected by the symptoms of hereditary angioedema. Conclusion: This study provides evidence of the first family in Valle de Aburrá (Colombia) characterized as having hereditary angioedema type I. Despite the use of a generic instrument, the negative impact on the quality of life of individuals suffering this disease was also confirmed.