Hereditary angioedema is a bradykinin-mediated disorder characterised by recurrent painful swelling attacks. Treatment relies on medications to prevent attacks and on-demand therapies for attack manifestations. Parenteral administration associated with most available on-demand therapies often leads to treatment being delayed or forgone. Deucrictibant is an orally bioavailable bradykinin B2 receptor antagonist under development for prophylaxis and on-demand treatment of hereditary angioedema attacks. We aimed to investigate the efficacy and safety of deucrictibant for the on-demand treatment of hereditary angioedema attacks. RAPIDe-1 was a double-blind, randomised, placebo-controlled, crossover, dose-ranging, phase 2 trial that recruited adults aged 18-75 years with hereditary angioedema type 1 or 2 from 38 sites (eg, university hospitals and accredited angioedema centres) across North America, Europe, and Israel. Participants were required to have experienced two or more attacks within the past 2 months or three or more attacks within the past 4 months before screening. An interactive response technology system randomly assigned eligible patients (1:1:1) to receive a blinded dose of oral deucrictibant (immediate-release capsule) 10 mg, 20 mg, or 30 mg during an attack-free period to assess pharmacokinetics and safety in the part 1 of the study; and, subsequently, to receive a crossover treatment sequence of two administrations of the same deucrictibant dose (10 mg, 20 mg, or 30 mg) and one of placebo to treat three investigator-confirmed angioedema attacks in the part 2. Randomisation was stratified by whether the participant was willing to participate in full pharmacokinetic sampling. Participants, investigators, site personnel, and the sponsor were masked to treatment assignment and capsules of deucrictibant and placebo were identical. For each attack, patients self-administered the oral study drug within 3 h after at least one symptom (skin pain, skin swelling, or abdominal pain) reached a visual analog scale (VAS) individual score of 30 or more out of 100 and within 6 h from symptom onset. The primary endpoint was change in the patient-reported composite VAS-3 score measuring severity of attack manifestations from before treatment to 4 h post-treatment and assessed in the modified intention-to-treat and per-protocol populations. Safety was assessed in all patients who received any dose of study drug. RAPIDe-1 is registered with ClinicalTrials.gov (NCT04618211) and is completed. Between Feb 3, 2021, and June 23, 2022, 89 patients were screened, of whom 74 were randomly assigned between Feb 23, 2021, and July 26, 2022. For the primary analysis set, the median follow-up was 130·0 (IQR 92·5 to 212·5) days for the deucrictibant 10 mg group, 166·5 (80·0 to 275·0) days for the deucrictibant 20 mg group, and 172·0 (65·0 to 242·0) days for the deucrictibant 30 mg group. The primary efficacy analysis included 147 attacks in 62 patients, of whom 42 (68%) were female and 60 (97%) were White. Least squares mean differences of change in VAS-3 score between deucrictibant and placebo was -16·75 (95% CI -21·52 to -11·97) for 10 mg, -15·02 (-20·22 to -9·81; p<0·0001) for 20 mg, and -16·28 (-21·27 to -11·29; p<0·0001) for 30 mg. In part 1, all treatment-emergent adverse events were grades 1-2, with the most common in two or more patients being headache (two [8%] of 25) and nasopharyngitis (two [8%] of 25) in the deucrictibant 30 mg group. In part 2, no single treatment-emergent adverse event was reported by two or more patients in any treatment group. Most adverse events were considered unrelated to the study drug and there were no grade 3 or worse adverse events. Deucrictibant significantly reduced the severity of hereditary angioedema attacks compared with placebo; these results support continued investigation of antagonism of the bradykinin B2 receptor with an orally available agent as a potentially effective approach, with a safety profile similar to placebo, for on-demand treatment. Pharvaris.

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. 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. 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. 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. Pharvaris.

Hereditary angioedema (HAE) is a rare disease characterized by episodes of cutaneous and submucosal inflammation. Its global prevalence ranges from 1:50,000 to 1:100,000 individuals and is often underdiagnosed. It is classified into three main types based on C1 inhibitor (C1-INH) levels and functionality. Type 1 is the most common (85% of cases). It is characterized by low plasma concentrations of functional C1-INH as a result of mutations in the SERPING1 gene. We present the case of a 20-year-old male resident of Guadalajara with HAE type 1 diagnosed at age 12 and a history of drug use. He was admitted with edema in the left posterior thoracic region, which progressed to the neck, causing respiratory distress. During ambulance transport, the patient suffered cardiorespiratory arrest, requiring cardiopulmonary resuscitation. He was administered a bradykinin type 2 receptor antagonist and systemic steroid without success, and was admitted to the emergency department under advanced airway management. Laboratory tests and a CT scan revealed no significant findings. Given the persistence of facial edema, a human C1 esterase inhibitor was administered, and the patient was admitted to the intensive care unit for monitoring. Based on laboratory and CT results, substance abuse was suspected as a triggering factor. The literature reports that individuals with cocaine dependence present a persistent proinflammatory state characterized by reduced baseline levels of the anti-inflammatory interleukin IL-10 and a significant increase in the proinflammatory cytokine TNF-α after exposure to stressful stimuli or use. Although the evidence in the medical literature is limited, the use of psychoactive substances could act as a triggering factor for seizures in patients with hereditary angioedema type 1. This case underscores the importance of identifying potential less-studied aggravating factors and suggests the need for a targeted history of psychoactive substance use in patients with HAE. This could be explained by their effects on vasodilation, the release of inflammatory mediators, and increased vascular permeability, mechanisms that promote bradykinin accumulation. Given the potential risk, it is essential to consider drug use in the comprehensive evaluation of precipitating factors in these patients. el angioedema hereditario (AEH) es una enfermedad poco común, caracterizada por episodios de inflamación cutánea y submucosa. Su prevalencia global es de 1:50,000 a 1:100,000 personas y suele estar subdiagnosticada. Se clasifica en tres tipos principales según los niveles y funcionalidad del inhibidor de C1 (C1-INH), siendo el tipo 1 el más frecuente en el 85% de los casos, el cual se caracteriza por concentraciones plasmáticas bajas de C1-INH funcional, como consecuencia de mutaciones en el gen SERPING1. se presenta el caso de un masculino de 20 años, residente en Guadalajara, con AEH tipo 1 diagnosticado a los 12 años y antecedente de uso de drogas. Ingresó con edema en la región torácica posterior izquierda, que progresó a cuello, causando dificultad respiratoria. Durante el traslado en ambulancia presentó paro cardiorrespiratorio, requiriendo reanimación cardiopulmonar. Se le administró un antagonista del receptor de la bradicinina tipo 2 y esteroide sistémico sin éxito, por lo que fue recibido en urgencias bajo manejo avanzado de la vía aérea. Los análisis de laboratorio y la tomografía no mostraron hallazgos significativos. Ante la persistencia del edema facial, se administró inhibidor de C1 esterasa humana y el paciente ingresó a la unidad de cuidados intensivos para vigilancia. Por los resultados de laboratorio y tomografía se sospechó el uso de toxicomanías como factor desencadenante. La bibliografía reporta que individuos con dependencia a la cocaína presentan un estado proinflamatorio persistente caracterizado por niveles basales reducidos de la interleucina antiinflamatoria IL-10 y un aumento significativo de la citocina proinflamatoria TNF-α tras exposición a estímulos de estrés o consumo. Aunque la evidencia en la literatura médica es limitada, el uso de sustancias psicoactivas podría actuar como un factor desencadenante de crisis en pacientes con angioedema hereditario tipo 1. Este caso subraya la importancia de identificar posibles factores agravantes menos estudiados y sugiere la necesidad de una anamnesis dirigida al consumo de sustancias psicoactivas en pacientes con AEH. Esto podría explicarse por sus efectos sobre la vasodilatación, la liberación de mediadores inflamatorios y el aumento de la permeabilidad vascular, mecanismos que favorecen la acumulación de bradicinina. Dado el riesgo potencial, resulta fundamental considerar el consumo de drogas dentro de la evaluación integral de los factores precipitantes en estos pacientes.

Hereditary angioedema (HAE) is a rare disorder characterized by recurrent episodes of angioedema, most often due to a deficiency or dysfunction of C1 esterase inhibitor. This deficiency leads to an accumulation of bradykinin, a pro-inflammatory peptide that increases vascular permeability and causes localized swelling. Although some HAE flares occur spontaneously, known triggers include trauma, stress, and infection. Clinical manifestations typically involve swelling of the skin, gastrointestinal tract, and upper airway. SARS-CoV-2, the virus responsible for COVID-19, enters host cells via angiotensin-converting enzyme 2 (ACE2). Viral binding and subsequent ACE2 depletion impair bradykinin degradation, leading to increased bradykinin levels, a mechanism that mirrors the pathophysiology of HAE. This shared pathway may contribute to HAE exacerbations during COVID-19 infections. We report the case of a pediatric patient with known HAE who experienced a disease flare triggered by COVID-19. While bradykinin-driven swelling in adult HAE patients with COVID-19 has been documented, pediatric reports are exceedingly rare. To our knowledge, this is the first published case detailing the symptom progression and treatment timeline of a confirmed pediatric HAE patient following SARS-CoV-2 infection. This case aims to raise awareness of COVID-19 as a potential trigger for HAE flares in children and emphasizes the need for healthcare providers to educate families of pediatric HAE patients about flare management and preparedness in the context of COVID-19, especially given its continued global circulation.

Hereditary angioedema type 1 (HAE1) is a rare, genetically heterogeneous, and autosomal dominant disease. It is a highly variable, insidious, and potentially life-threatening condition, characterized by sudden local, often asymmetric, and episodic subcutaneous and submucosal swelling, caused by pathogenic molecular variants in the SERPING1 gene, which codes for C1-Inhibitor protein. This study performed the phenotypic and molecular characterization of a HAE1 cluster that includes the largest number of affected worldwide. A geographically HAE1 cluster was found in the northeast Colombian department of Boyaca, which accounts for four unrelated families, with 79 suspected to be affected members. Next-Generation Sequencing (NGS) was performed in 2 out of 4 families (Family 1 and Family 4), identifying the variants c.1420C>T and c.1238T>G, respectively. The latter corresponds to a novel mutation. For Families 2 and 3, the c.1417G>A variant was confirmed by Sanger sequencing. This variant had been previously reported to the patient prior to the beginning of this study. Using deep-learning methods, the structure of the C1-Inhibitor protein, p.Gln474* and p.Met413Arg was predicted, and we propose the molecular mechanism related to the etiology of the disease. Using Sanger sequencing, family segregation analysis was performed on 44 individuals belonging to the families analyzed. The identification of this cluster and its molecular analysis will allow the timely identification of new cases and the establishment of adequate treatment strategies. Our results establish the importance of performing population genetic studies in a multi-cluster region for genetic diseases.