RARE DISEASE
Hereditary angioedema type 1
Hereditary angioedema type 1
Hereditary angioedema type 1
Synonyms: HAE 1, HAE-I, Hereditary angioneurotic edema type 1
Synonyms: HAE 1, HAE-I, Hereditary angioneurotic edema type 1
Synonyms: HAE 1, HAE-I, Hereditary angioneurotic edema type 1
Drug discovery
1
drug
With orphan designation
Overview
Hereditary angioedema type 1 (HAE-1) is an autosomal dominant disorder caused by SERPING1 gene mutations, resulting in deficiency of functional C1 esterase inhibitor (C1-INH). This leads to dysregulated bradykinin production, causing recurrent, unpredictable swelling attacks involving subcutaneous tissues, visceral organs, and upper airways (risk of asphyxiation) [1][2][15].
Burden
Clinical: 42% experience weekly attacks pre-diagnosis; 69% undergo unnecessary procedures due to delayed diagnosis (avg. 10 years) [4][14]
Economic: High ER utilization (15,000–30,000 annual U.S. visits); productivity losses (~$5,750/year/patient) [9][14]
Humanistic: 56% report anxiety/depression; 63–89% have impaired work/school performance [4][7][9][14]
Therapies
On-demand: IV C1-INH concentrate (e.g., Berinert®), subcutaneous icatibant (bradykinin receptor antagonist), or ecallantide (kallikrein inhibitor) [3][8][13][17]
Short-term prophylaxis: Pre-procedure C1-INH infusion (e.g., Cinryze®) to prevent attack triggers [3][13]
Long-term prophylaxis: Subcutaneous C1-INH (Haegarda®), lanadelumab (monoclonal kallikrein antibody), or oral berotralstat (kallikrein inhibitor) [3][6][18]
Categories: rare allergic disease, rare genetic diseases, rare systemic and rheumatological diseases
Research Papers
515 drug discovery papers about Hereditary angioedema type 1, with 5 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
515 drug discovery papers about Hereditary angioedema type 1, with 5 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-24 | Evaluating deucrictibant for the treatment of hereditary angioedema.
Hereditary Angioedema (HAE) is a rare disease affecting approximately 1 in 50,000 people. It results in angioedema of the skin, abdominal tract and upper airway that results in disfiguration, abdominal pain and potential for asphyxia. Early therapies for HAE have significant drug burden due to intravenous administration (C1-inhibitor) or adverse events (androgens); however, newer therapies have reduced injection requirements, and some are oral. Over the past 6 years two oral therapies have been developed for HAE to include berotralstat for long term prophylaxis (LTP) and sebetralstat for on-demand therapy (ODT). Presently, deucrictibant, another oral HAE therapy, is under investigation and appears effective for LTP and ODT. This manuscript summarizes the development, pharmacokinetics, pharmacodynamics, and currently available clinical evidence regarding deucrictibant in HAE management. Deucrictibant is a promising therapeutic agent with a well-defined mechanism of action. Published and ongoing clinical studies demonstrate favorable safety, tolerability, and efficacy profiles for both LTP and ODT, offering a convenient oral alternative that may reduce treatment burden and improve patient quality of life.
2026-08-22 | Real-World Safety and Effectiveness of Icatibant in Patients With Hereditary Angioedema (HAE): Post-Marketing Surveillance in Japan.
Hereditary angioedema (HAE) is a rare, autosomal dominant, life-threatening disease characterized by recurrent attacks of swelling of the face, upper airway, gastrointestinal tract, limbs, and/or genitalia. Genetic mutations of the SERPING1 gene encoding the C1-inhibitor (C1-INH) plasma protein are associated with HAE-C1INH. HAE is also observed in patients with normal C1-INH (HAE-nC1INH). Icatibant is a selective bradykinin B2 receptor antagonist for treatment of acute attacks of HAE. Here we report safety and effectiveness data from a post-marketing, open-label, multicenter observational study of icatibant conducted in Japan (ClinicalTrials.gov ID: NCT04057131). Patients with HAE in Japan who initiated icatibant between November 2018 and June 2020 were enrolled; surveillance was completed in April 2023. In the Safety Analysis Set (n = 155), most patients were women (n = 116, 74.84%) and HAE types included HAE-C1INH-Type 1 (n = 83, 53.55%), HAE-C1INH-Type 2 (n = 9, 5.81%), unclassified HAE-C1INH (n = 16, 10.32%), and HAE-nC1INH (n = 22, 14.19%). Overall, 19 patients (12.26%) experienced adverse drug reactions (ADRs), most of which were mild in severity (n = 18, 11.61%). The most common ADRs were general disorders and administration site conditions (n = 18, 11.61%). No serious ADRs or ADRs of special interest other than hypersensitivity and injection site reaction were reported. In the Effectiveness Analysis Set (n = 100), 97 patients (97.00%) received 30 mg of icatibant. Among 417 HAE attacks, 234 were treated with icatibant alone and 48 with icatibant plus other. Among attacks treated with icatibant alone, median (interquartile range) time to first symptom relief was 60.0 (30.0-270.0) min, and median time to complete resolution of symptoms was 710.0 (148.5-1440.0) min. In conclusion, in this study of the real-world use of icatibant, no new safety concerns were reported. Icatibant was effective in providing early symptom relief for HAE attacks across a broad spectrum of patients, including patients with HAE-nC1INH, who were not included in previous clinical trials.
2026-08-15 | Berotralstat Tolerability and Effectiveness in Hereditary Angioedema: Berolife Study Results.
Berotralstat is a first-line once-daily oral prophylactic treatment for hereditary angioedema (HAE). Berolife was designed to evaluate the tolerability and effectiveness of berotralstat in real-world conditions. Berolife is an open-label, multicenter, observational study conducted in France from September 2021 to January 2024. The primary objective was to assess tolerability, and secondary objectives included characterization of the treated population and assessment of berotralstat effectiveness. HAE attack rate was assessed before and after initiation of berotralstat using the paired Wilcoxon rank-sum test. Altogether, 80 patients were enrolled in the study (75 with HAE-C1INH type 1 or 2 and 5 with HAE-nC1INH) and received at least one dose of berotralstat. At baseline, patients had a mean (standard deviation [SD]) age of 40.0 (17.5) years, and most (67.5%) had received prior long-term prophylaxis treatment. The mean (SD) duration of berotralstat treatment was 11.5 (8.5) months. Treatment-related adverse events (AEs) occurred in 45.0% of patients, with gastrointestinal disorders being the most common (diarrhea: 13.8%, abdominal pain: 12.5%, upper abdominal pain: 7.5%). Importantly, no treatment-related serious AEs were reported. A total of 61 patients were treated with berotralstat for ≥ 6 months and evaluated for effectiveness. At 6 months of treatment, a significant reduction in monthly HAE attack rates was observed (mean [SD]: 0.62 [0.66] vs. mean [SD]: 1.25 [1.10] at baseline; p = 0.001). Berotralstat was generally well tolerated with a tolerability profile consistent with prior clinical trials. Significant reductions in monthly HAE attack rates were observed, confirming its effectiveness in real-world settings.
2026-08-08 | Lanadelumab Use for Hereditary Angioedema Long-Term Prophylaxis Over the Last 7 Years: A Narrative Review of Clinical and Real-World Data.
Hereditary angioedema (HAE) is a rare genetic disease characterized by unpredictable, painful cutaneous and/or subcutaneous swelling attacks; laryngeal attacks can be fatal. For many patients, long-term prophylaxis (LTP) is critical for disease control and quality of life.Lanadelumab, a plasma kallikrein inhibitor, was approved for HAE LTP for adults and adolescents in 2018 and for children aged ≥ 2 years in 2023; it is currently one of the guideline-recommended, first-line LTP options. By integrating 7 years of cumulative clinical trial and real-world data, this narrative review summarizes lanadelumab long-term effectiveness and safety in adult, adolescent, and pediatric HAE populations. Outcomes in 41 peer-reviewed publications were evaluated, including 5 clinical trials involving 262 lanadelumab-treated patients and 28 real-world studies comprising ~ 700 patients. Across clinical trials, lanadelumab reduced attack rates by up to 100%, with an average of 24.9-27.3 patient-reported attack-free days per 28-day period. These findings were largely corroborated by real-world data, including 2 large observational studies with > 100 patients each. Patient-reported disease control and health-related quality of life improved consistently across both settings. The main treatment-related adverse events across studies were injection site reactions. Treatment persistence was generally high in clinical practice. Unmet needs remain for specific populations, including pregnant or lactating patients and those without access to guideline-recommended LTP. Future research should address real-world outcomes in pediatric patients, extended dosing intervals in well-controlled disease, transitions from other LTP therapies, and cost-effectiveness. Overall, sustained effectiveness, safety, and quality-of-life benefits of lanadelumab reinforce its role as a cornerstone of HAE management.
2026-08-06 | A plain language summary of oral berotralstat for preventive treatment of hereditary angioedema attacks in children: early safety and efficacy results of the ongoing APeX-P study
What is this summary about? This plain language summary describes the interim results (early findings) of an ongoing study called APeX-P, which was published in the Annals of Allergy, Asthma & Immunology journal in 2025. The study looked at berotralstat, an oral (taken by mouth) medication, as a treatment option for hereditary angioedema (HAE) in children. HAE is a rare genetic disease that causes episodes of swelling (attacks) in different parts of the body, which can be serious. Attacks in the tongue and throat can be life-threatening. Berotralstat is taken once a day. Before the APeX-P study, the medication was approved in several countries to help prevent HAE attacks in people aged 12 and older. Berotralstat is now approved for use in people aged 2 and older in the United States. The APeX-P study researchers looked at which doses of berotralstat are appropriate for children aged 2 to under age 12, how children tolerated the medication, and how well berotralstat helps to prevent HAE attacks. The study also assessed children’s experiences and burdens with HAE. What were the results? Most of the children participating in the APeX-P study started having symptoms of HAE before they were 6 years old. Before beginning the study, children experienced burden because of HAE attacks, including missing school and needing emergency medical care because of their symptoms. After taking berotralstat for 12 weeks, children had fewer HAE attacks. The lower rate of attacks continued for up to 48-weeks (about 1 year—the study was still ongoing). This meant that children had fewer days with HAE symptoms. During the first 12 weeks of treatment with berotralstat, 3 HAE attacks (across all children in the study) needed medical care in a doctor’s office, clinic, or hospital. This need for medical care was 86% less than the 22 attacks needing medical care in the 12 weeks before the children started taking the medication. Most children in the study experienced at least 1 side effect after taking berotralstat; only 2 side effects (mild nausea or ‘feeling queasy’ and moderate headache) in 2 children were considered to be caused by the medication. Side effects were mild to moderate except in 1 patient who had an accident and a broken arm that was not caused by the medication. The most common side effects included a common cold, upper respiratory infection (in the nose, throat, or sinuses), or headache. What do the results mean? In the APeX-P study, children taking berotralstat tolerated the treatment well. The interim results show that berotralstat prevented attacks from HAE in young children. How to say (download PDF and double click sound icon to play sound)… APeX-P: AY-peks-pee Berotralstat: bear-oh-TRAL-stat Bradykinin: bray-DEE-ki-nin Hereditary angioedema: huh-REH-duh-tree AN-jee-oh-eh-DEE-muh Kallikrein: kal-uh-KREE-in Prophylaxis: pro-fuh-LACK-sis Angioedema: Swelling in the tissue under the skin. Genetic disease: Diseases caused by changes in a person’s DNA that can develop spontaneously or be passed on from parents to children. Tolerated: To handle a medication without having side effects that are serious or bothersome, or that are manageable enough for patients to continue taking the treatment. This is an abstract of the Plain Language Summary of Publication article. View the full Plain Language Summary PDF of this article to read the full-text Link to original article here
proteins
2026-09-05 | Hereditary angioedema in women: Hormonal and reproductive influences on disease activity.
Background: Hereditary angioedema (HAE) is a rare, potentially life-threatening disorder characterized by recurrent edema of the extremities, abdomen, face, larynx, trunk, and genital region. It follows an autosomal dominant inheritance pattern and affects both sexes equally; however, attacks may occur more frequently and with greater severity in women due to hormonal factors. Aims: The aim of this study was to evaluate the impact of hormonal changes on HAE attacks in women and to determine how different reproductive stages and hormonal exposures affect attack frequency and course. Methods: In this retrospective descriptive cohort study, 36 postpubertal women with HAE were evaluated to assess the effects of reproductive factors, including menstruation, oral contraceptive use, pregnancy, delivery, lactation, and menopause, on attack frequency and disease activity. Results: Thirty patients had type I and six had type II HAE. The mean age at diagnosis was 23.5 years, with a mean diagnostic delay of 12.6 years. Menstruation triggered attacks in 52.8% of the patients. Among 26 patients with 94 pregnancies, 21.2% ended in spontaneous abortion, and 73.1% had at least one child diagnosed with HAE. During pregnancy, attack frequency increased in 30.6%, decreased in 27.7%, and was unchanged in 41.7%. Attacks occurred within 48 hours postpartum in six deliveries, and three patients reported increased attacks during lactation. After menopause, attacks increased in 25%, decreased in 33.3%, and were unchanged in 41.7%. Conclusion: Hormonal and reproductive life stages influence disease activity in women with HAE, although the direction and magnitude of these effects vary among individuals. The marked delay in diagnosis observed in this cohort suggests that many women experience pregnancies without disease-specific management. Earlier recognition of HAE and individualized treatment approaches may improve care during hormonally dynamic periods.
2026-06-01 | Concurrent hereditary angioedema type I and common variable immunodeficiency presenting as suspected antibiotic hypersensitivity: Case report and literature discussion.
Hereditary angioedema (HAE) and common variable immunodeficiency (CVID) are rare disorders with heterogeneous clinical presentations that pose significant diagnostic challenges. HAE is characterized by recurrent episodes of subcutaneous or submucosal edema affecting the skin, gastrointestinal tract, or airway, whereas CVID presents with variable immune dysfunction, recurrent infections, and impaired vaccine responses. The clinical manifestations of these conditions can mimic allergic reactions, drug hypersensitivity, mast cell disorders, autoimmune diseases, and other immunodeficiencies, making careful differential diagnosis essential. Here, we present an exceptionally rare case of a patient with concurrent HAE type I and CVID, initially evaluated for suspected antibiotic hypersensitivity, highlighting the complexity of diagnosis and therapeutic decision-making. Laboratory findings confirmed both conditions, showing low C1 inhibitor levels and activity, markedly reduced serum concentrations of immunoglobulin G (including subclasses G1, G2, and G4), immunoglobulin A, and immunoglobulin M, along with a poor specific antibody response to vaccines. Skin allergy and oral provocation tests were negative, effectively ruling out antibiotic hypersensitivity. The genetic analysis identified a heterozygous pathogenic SERPING1 variant, c.498C > A (p.Asn166Lys), previously reported in 1 Romanian and 1 Czech case, confirming the diagnosis of HAE. Human leukocyte antigen (HLA) genotyping revealed HLA-B∗35:01 and B∗44:01, with homozygosity for HLA-C∗04:01, alleles previously associated with increased susceptibility to CVID. Using this case as a framework, we review the literature on coexisting HAE and CVID, examining clinical presentations, diagnostic approaches, biomarker profiles, and reported HLA associations. The review highlights the critical importance of a comprehensive and personalized therapeutic approach, combining prophylactic and on-demand treatment for HAE with individualized immunoglobulin replacement for CVID. Integrating detailed clinical assessment with immunologic and genetic testing is essential for the management of rare, complex disorders, and further studies are needed to clarify potential immunogenetic links between HAE and CVID.
2026-01-23 | Functional physiological, psychological, and biochemical reactivity to socially evaluated cold pressor test in hereditary angioedema patients (FRoSEn).
Stressful physical or psychological events can trigger acute swelling attacks in patients with Hereditary Angioedema due to C1 Inhibitor deficiency (HAE-C1INH), although the stress-disease relationship remains unclear. The Socially Evaluated Cold Pressor Test (SECPT) reliably induces acute stress under controlled conditions. This study aimed to compare perceived stress, inflammatory markers, and cardiovascular responses to SECPT between HAE-C1INH patients and healthy controls (HC). Twenty HAE-C1INH patients (9 males, 44 ± 14 years) and age and sex matched HC underwent a 3-minute SECPT. Participants completed questionnaires assessing anxiety and depression (HADS), pain catastrophizing (PCS), and subjective stress (0-100 scale) before and after SECPT. Heart rate (HR) and arterial pressure (AP) were recorded. Blood samples for inflammatory cytokines (IL-6, IL-1ß, TNF-α) were collected at baseline, and 10 and 40 minutes after SECPT. Compared to HC, patients showed higher baseline HADS-A (7.3 ± 4.5 vs 4.7 ± 2.7), overall PCS (19.7 ± 12.6 vs 12.9 ± 8.7), and perceived stress during SECPT (60.6 ± 34.3 vs 34.6 ± 23.8). IL-6 levels were higher at baseline and 10 minutes post-test (2.63 ± 1.21 vs 1.84 ± 0.87; 2.78 ± 1.20 vs 1.91 ± 0.79 pg/ml), as were TNF-α levels across all phases (4.19 ± 1.38 vs 3.26 ± 1.55; 4.09 ± 1.39 vs 3.40 ± 1.48; 4.09 ± 1.28 vs 3.20 ± 1.57) while IL-1 ß remained unchanged. HR and AP variations were similar between groups. HAE-C1INH patients exhibited heightened perceived stress response to SECPT, and elevated baseline inflammation, despite comparable cardiovascular reactivity. These findings highlight a complex psychophysiological-inflammatory interplay in acute stress responses, suggesting the need to integrate psychological and biological frameworks in understanding HAE-C1INH triggers. NCT06414252.
2026-01-11 | Bradykinin reduces wound healing in human umbilical vein endothelial cells via downregulation of vascular endothelial growth factor A.
INTRODUCTION: Hereditary angioedema (HAE) is characterized by acute swelling attacks triggered by abnormally elevated levels of bradykinin. Despite persistently high bradykinin levels, patients experience only intermittent swelling episodes. Many HAE patients, however, report triggers such as trauma preceding angioedema attacks. This suggests the involvement of additional factors, such as mechanical damage to the endothelium. Bradykinin-mediated impairment of wound healing may contribute to swelling development—a concept known as the “second hit” hypothesis. Vascular endothelial growth factors (VEGF) and their receptors play a critical role in endothelial wound healing and have also been implicated in bradykinin-mediated angioedema. This study investigates the influence of bradykinin on endothelial wound healing, with a particular focus on VEGF. MATERIALS AND METHODS: Human umbilical vein endothelial cells were incubated with bradykinin and VEGF. Gene and protein expression were analyzed by real-time polymerase chain reaction, western blotting, and immunocytochemistry. Barrier function was assessed by measuring transendothelial electrical resistance, as well as apparent and water permeability. Proliferation rates were determined using resazurin assays and real-time cell analysis. Cell migration was assessed using invasion and migration assays, and the combined effects were evaluated using scratch assays. RESULTS: Bradykinin treatment led to reduced expression of the VEGFA isoform and its receptor VEGFR-2. VEGFA alone had no effect on bradykinin-induced barrier disruption. However, bradykinin significantly decreased endothelial proliferation and migration, resulting in impaired wound healing. This effect was counteracted by the addition of VEGFA. CONCLUSIONS: VEGFA and its receptor VEGFR-2 are key regulators of endothelial wound healing. Bradykinin impairs wound healing by reducing proliferation and migration, likely through downregulation of VEGFA and VEGFR-2. These findings support the hypothesis that bradykinin-mediated impairment of wound healing may contribute to the episodic nature of swelling attacks in patients with bradykinin-mediated angioedema, in line with the second hit hypothesis.
2026-01-01 | Cardiac and vascular autonomic control in patients with hereditary angioedema.
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. 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). 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 70° tilt (TILT). Heart rate and systolic BP (SBP) variability indices were derived. Variance (σ2 SBP) and low-frequency power (LFSBP) of SBP variability were used as markers of sympathetic vascular control. 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 σ2 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. 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. https://clinicaltrials.gov/study/NCT06408805?cond=Hereditary%20Angioedema&term=autonomic&rank=1.
antibodies
2026-09-18 | Isolated gastrointestinal hereditary angioedema associated with a pathogenic SERPING1 variant arising de novo: a case report.
Hereditary angioedema (HAE) is a rare genetic disorder typically characterized by cutaneous and submucosal edema. Cases presenting exclusively with gastrointestinal symptoms, devoid of concurrent or historical cutaneous or upper airway manifestations, are uncommon. This atypical presentation poses a considerable diagnostic challenge and often leads to a marked delay in diagnosis, particularly in patients without a family history. We report the case of a 28-year-old female with an over 6-year history of recurrent, self-limiting abdominal pain. During a severe attack, abdominal computed tomography angiography (CTA) revealed jejunal wall edema and ascites, accompanied by a dramatic surge in D-dimer (>20.00 mg/L FEU) and fibrin degradation products (FDP >120.00 mg/L), closely mimicking mesenteric ischemia. However, a retrospective review of medical history identified the persistent consumption of complement C4 (0.03-0.05 g/L). Subsequent testing showed a functional C1 esterase inhibitor (fC1-INH) level of <7.0% and a C1 esterase inhibitor (C1-INH) antigen level of 6.81 μg/mL, confirming type 1 HAE. Whole-exome sequencing (WES) identified the nonsense variant NM_000062.3:c.990C>A, p.(Tyr330Ter), in SERPING1. The variant was not detected in either biological parent, supporting a de novo origin. Under the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) framework, it was classified as pathogenic on the basis of PVS1 and PS2. An abdominal attack in May 2025 resolved rapidly after icatibant administration. Long-term prophylaxis (LTP) with lanadelumab was subsequently initiated following an individualized shared decision-making process. No breakthrough attacks or treatment related adverse events occurred from June 2025 through June 2026. This report highlights that HAE should be considered in patients with recurrent, unexplained, self-limiting abdominal pain, and C4 should be included in the initial evaluation. A negative family history does not exclude HAE.
2026-08-07 | Sustained Effectiveness of Lanadelumab in Preventing Hereditary Angioedema Attacks: The ENABLE Study.
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. 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. 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. 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.
2026-06-10 | Long-Term Integrated Safety and Efficacy of Garadacimab for Hereditary Angioedema Prophylaxis.
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% confidence interval) monthly attack rate was 0.2 (0.1, 0.2) with garadacimab (n = 164), corresponding to a 94.9% (93.1, 96.7) reduction from run-in (3.5 [3.2, 3.9]). These integrated data, representing the longest garadacimab exposure reported to date, confirm the favorable long-term safety profile of garadacimab (exposure ≤ 5.5 years), and durable efficacy with sustained protection against HAE attacks (exposure ≤ 3.2 years). ClinicalTrials.gov identifiers, NCT03712228, NCT04656418, NCT04739059.
2026-06-09 | Lanadelumab in Hereditary Angioedema: Extending Dose Intervals from Every 2 Weeks to Every 4 Weeks.
Both clinical trial and real-world data demonstrate the effectiveness of lanadelumab long-term prophylaxis (LTP) to prevent hereditary angioedema (HAE) attacks, which may be maintained after dose interval extension from every 2 weeks (Q2W) to every 4 weeks (Q4W) in patients with well-controlled disease (attack free for >6 months). This narrative review summarizes published data on lanadelumab treatment patterns collected from clinical trials and observational studies since US approval in 2018. Disease activity and HAE-related healthcare resource use at baseline and during the first 6 months of lanadelumab treatment may be useful indicators of patients with well-controlled disease who will be eligible for, and may derive benefit from, dose interval extension on lanadelumab. Patients who receive a dose interval extension could benefit from a reduction in treatment burden, but not all patients may be a good fit for interval extension. Although there are inherent limitations related to analyzing small sample sizes for subgroups of patients with a rare disease and for data derived from real-world studies, these data can inform physicians and patients about the characteristics and outcomes of patients who have successfully extended dosing intervals of lanadelumab LTP. This may in turn encourage regular monitoring to facilitate optimization of treatment and outcomes for each patient.
2026-03-21 | Advances in hereditary angioedema in the modern treatment era in China: a focus on diagnosis, treatment, and prognosis.
BACKGROUND: Hereditary angioedema (HAE) is a rare, potentially life-threatening genetic disorder that is caused by C1-inhibitor (C1INH) deficiency or dysfunction. This scoping review sought to map recent advances in the management of HAE among patients in China. MATERIALS AND METHODS: A comprehensive literature search was conducted using relevant keywords across the databases PubMed, Embase, the Cochrane Library, ClinicalTrial.gov, and Chinese databases such as the China National Knowledge Infrastructure and Wanfang. The search covered publications from database inception through September 2024. Data was extracted on patient characteristics, disease manifestations, diagnostic approaches, treatments, clinical outcomes, and quality of life (QoL). The selection of articles followed predefined inclusion criteria and was conducted in adherence to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) guidelines. RESULTS: A total of 92 articles were included in this scoping review. Across the literature, the diagnosis of HAE was primarily based on serum complement assessment, particularly measurements of C4 and C1INH levels, along with family history and clinical manifestations. Danazol was reported as the primary treatment in previous studies; however, more recent studies emphasized the increasing use of lanadelumab and icatibant. Icatibant was shown to provide rapid symptom relief during acute HAE attacks, whereas lanadelumab demonstrated effectiveness as a long-term prophylactic therapy by reducing the frequency of attacks. The reviewed studies indicated fewer HAE-related deaths reported in studies published after 2021 compared with previous studies (129 deaths reported up to 2021; five deaths reported between 2021 and September 2024). This reduction may be attributed to increased disease awareness, earlier diagnosis, and advances in therapeutic management. In parallel, several studies reported improvements in angioedema-related quality of life (QoL) scores among patients with HAE in China. CONCLUSION: Emerging therapies such as lanadelumab and icatibant are effective in reducing the frequency of attacks and providing rapid symptom relief in Chinese patients with HAE. Nevertheless, further research is warranted to optimize HAE management strategies and to address existing gaps in the evidence within the Chinese population.
oligonucleotides
2026-07-08 | Donidalorsen for the Treatment of Hereditary Angioedema: A Review of Clinical Studies.
Hereditary angioedema (HAE) is a rare disease characterized by recurrent attacks of severe tissue swelling caused by dysregulation of the kallikrein-kinin system. Donidalorsen is a triantennary N-acetyl galactosamine-conjugated antisense oligonucleotide designed to specifically and reversibly reduce plasma prekallikrein production by binding to plasma prekallikrein messenger RNA in the liver. This report reviews donidalorsen's mechanism of action and data on the pharmacodynamics, efficacy, patient-reported outcomes, and safety of donidalorsen from clinical trials in adolescent and adult participants. In a Phase 1 trial, subcutaneous (SC) administration of donidalorsen led to dose-dependent reductions in plasma prekallikrein concentrations. In a subsequent Phase 2, randomized, placebo-controlled study, donidalorsen 80 mg SC once every 4 weeks (Q4W) for 16 weeks resulted in a 90% mean reduction in monthly HAE attack rate vs placebo, which was sustained for up to 4 years in an open-label extension (OLE). In the Phase 3, randomized, placebo-controlled OASIS-HAE study, patients receiving donidalorsen 80 mg Q4W or once every 8 weeks (Q8W) experienced significant mean reductions in HAE attack rates vs placebo over Weeks 0 to 24 (Q4W: 81%; Q8W: 55%). Mean attack rates were reduced by 87% (Q4W) and 60% (Q8W) vs placebo over Weeks 4 to 24. Reductions in attack rate from OASIS-HAE baseline were sustained for up to 1 year in the OASISplus OLE (Q4W: 94%; Q8W: 95%). A notable study in the clinical program included a cohort of patients who switched from berotralstat, C1 inhibitor, or lanadelumab to donidalorsen for up to 1 year; mean attack rates were reduced by 68% vs baseline (on prior HAE prophylaxis). Donidalorsen treatment improved quality of life at all assessments. Across studies, donidalorsen had an acceptable safety and tolerability profile, with mostly mild to moderate adverse events reported. Overall, the clinical data are promising for donidalorsen as a long-term prophylactic medication for HAE.
2026-03-14 | Switching Long-Term Prophylaxis to Donidalorsen for Hereditary Angioedema: 1-Year OASISplus Results.
Donidalorsen is an antisense oligonucleotide designed to reduce plasma prekallikrein in patients with hereditary angioedema (HAE). The Switch cohort of the OASISplus study (NCT05392114) evaluated the long-term safety and efficacy of donidalorsen in patients who switched from a long-term prophylactic treatment (LTP) to donidalorsen with 1-year outcomes. This study enrolled patients with HAE aged ≥ 12 years previously on stable doses of an LTP (lanadelumab, berotralstat, C1 inhibitor). Patients directly switched from an LTP to donidalorsen 80 mg administered subcutaneously once every 4 weeks. Endpoints included incidence and severity of treatment-emergent adverse events (TEAEs; primary endpoint), monthly HAE attack rate, Angioedema Quality of Life (AE-QoL), and Angioedema Control Test (AECT) measured at baseline and Week 52. Sixty-five patients enrolled, and 54 (83.1%) completed 1 year. Eleven (16.9%) patients discontinued treatment during the first year, and one discontinued treatment after 1 year. Donidalorsen reduced HAE attack rates from baseline on the prior LTP by 67.6% over 52 weeks. Fifty-six of 64 (87.5%) dosed patients experienced a TEAE; most reported mild to moderate events. The most common treatment-related TEAEs were injection-site erythema (10.9%) and injection-site pruritus (10.9%). One patient had a serious adverse event that was not treatment-related. AE-QoL total score improved by 12.2 points (clinically meaningful ≥ 6 points) from baseline to Week 52, and 90.4% of patients had well-controlled disease (AECT ≥ 10) at Week 52. In patients who switched from another LTP, donidalorsen was well tolerated and improved long-term HAE attack rates, quality of life, and disease control.
2026-03-10 | Donidalorsen for hereditary angioedema: Long-term results from a 4-year, phase 2, open-label extension study.
Hereditary angioedema (HAE) is a rare disorder caused by kallikrein-kinin system dysregulation. Donidalorsen is a prekallikrein-directed antisense oligonucleotide that can rebalance this system by reducing prekallikrein production and is indicated for prophylaxis to prevent HAE attacks in patients 12 years of age and older. To report results from a 4-year, phase 2, open-label extension study of donidalorsen (NCT04307381). The study on-treatment period included fixed (weeks 0-12) and flexible (weeks 16-208) treatment periods. Patients received donidalorsen 80 mg subcutaneously every 4 weeks (Q4W) in the fixed treatment period and could receive 80 mg every 8 weeks (Q8W) in the flexible treatment period if attack free for greater than or equal to 12 weeks or 100 mg Q4W if disease was not adequately controlled. End points are summarized through the end of the study (week 208). Of 17 patients with HAE-C1INH-type 1 or HAE-C1INH-type 2, 13 (76%) completed 4 years of treatment (median exposure: 3.99 years). Eight patients changed to donidalorsen Q8W; 5 stayed on Q8W to study completion. One patient received 100 mg Q4W. Mean monthly HAE attack rates decreased by 97% overall from baseline to the on-treatment period, with 97% (Q4W) and 83% (Q8W) decreases to the flexible treatment period. The median longest attack-free interval was 990 days. No serious treatment-emergent adverse events (TEAEs) occurred. One patient (6%) (100 mg Q4W) discontinued due to a TEAE (injection-site discoloration). Seven patients (41%) reported treatment-related TEAEs; the only treatment-related TEAEs reported in more than 1 patient were injection-site reactions. In this 4-year study, donidalorsen led to sustained reductions in monthly HAE attack rate with an acceptable safety profile. ClinicalTrials.gov Identifier: NCT04307381 (https://www. gov/study/NCT04307381).
2026-03-02 | Donidalorsen for Long-Term Prophylaxis of Hereditary Angioedema Attacks: Results from the OASISplus Open-Label Extension Cohort at Year 1.
Donidalorsen, a prekallikrein-directed antisense oligonucleotide indicated for prophylaxis of hereditary angioedema (HAE) attacks in patients aged ≥12 years, demonstrated efficacy and acceptable safety in the phase 3, placebo-controlled OASIS-HAE trial (NCT05139810). Here, we report 1-year results from the corresponding open-label extension (OLE) cohort of the OASISplus study (NCT05392114). OASISplus included patients who rolled over from OASIS-HAE. Patients who received donidalorsen 80 mg or placebo subcutaneously every 4 weeks (Q4W) in OASIS-HAE received donidalorsen Q4W in OASISplus. Patients who received donidalorsen 80 mg or placebo every 8 weeks (Q8W) in OASIS-HAE received donidalorsen Q8W or Q4W, if not attack-free in the final 8 weeks of OASIS-HAE. The primary endpoint was safety (ie, incidence of treatment-emergent adverse events [TEAEs]). Secondary endpoints included the monthly rate of HAE attacks and Angioedema Quality of Life (AE-QoL). The OLE cohort included 83 patients (Q4W, n=69 [83%]; Q8W, n=14 [17%]). Of these, 75 (90.4%) completed Year 1, and 6 patients receiving donidalorsen Q8W in OASIS-HAE switched to the Q4W dosing group in the OLE. Median donidalorsen exposure was 392.3 days. From Weeks 0 to 52, reductions in mean HAE attack rate from OASIS-HAE baseline were 94% (Q4W) and 95% (Q8W), and patients reported clinically meaningful improvements in mean AE-QoL total score at Week 52 (Q4W, 28.1 points; Q8W, 26.7 points). Twenty-two (27%) patients reported treatment-related TEAEs; none were serious, and injection-site reactions were the most frequently reported. Donidalorsen demonstrated sustained reductions in HAE attack rate, improvements in QoL, and an acceptable safety profile after 1 year of treatment.
2026-02-02 | Population Pharmacokinetic/Pharmacodynamic Modeling of Donidalorsen, an Antisense Oligonucleotide in Development for Prophylaxis of Hereditary Angioedema.
Hereditary angioedema (HAE) is a rare disorder linked to kallikrein-kinin system dysregulation, which leads to uncontrolled activation of plasma prekallikrein. Donidalorsen is an antisense oligonucleotide designed to selectively degrade prekallikrein messenger RNA and thereby reduce prekallikrein production. We aimed to develop population pharmacokinetic and pharmacokinetic/pharmacodynamic models of donidalorsen and evaluate the impact of potential intrinsic/extrinsic covariates on exposure and prekallikrein response. Plasma donidalorsen and prekallikrein data were obtained from phase 1 to 3 studies in healthy volunteers (NCT03263507, 721744-CS9) and adult and adolescent patients with HAE (NCT04030598, NCT05139810). The evaluated doses were 20, 40, 60, and 80 mg every 4 weeks (Q4W) and 80 mg every 8 weeks (Q8W), administered subcutaneously over 13-21 weeks. Donidalorsen pharmacokinetics were well described by a linear 2-compartment model with first-order absorption. The population terminal elimination half-life was 31.4 days. Prekallikrein was well described by an indirect response model with inhibition of prekallikrein production by donidalorsen. Covariate analysis identified body weight as the main factor affecting pharmacokinetic exposure; however, this effect was not considered clinically significant. The developed population pharmacokinetic/pharmacodynamic model well characterized the donidalorsen exposure-prekallikrein response relationship. Modeling analyses support that no dose adjustment is needed with respect to intrinsic/extrinsic factors in adults and adolescents with HAE. The nearly identical simulated pharmacokinetic or prekallikrein time courses for Q4W versus monthly dosing and for Q8W versus every-2-month dosing regimens support switching to more convenient regimens for patients.
other
2026-07-27 | Lonvoguran ziclumeran: a CRISPR-CAS9-based gene therapy for the treatment of hereditary angioedema.
Hereditary angioedema (HAE) is a rare genetic disorder characterized by recurrent swelling caused by dysregulation of the kallikrein-kinin pathway. Although current therapies effectively reduce attack frequency, treatment remains lifelong. Lonvoguran ziclumeran (Lonvo-z; NTLA-2002) is the first systemically administered in vivo CRISPR/Cas9 gene-editing therapy designed to provide durable suppression of plasma kallikrein through permanent disruption of the KLKB1 gene. This review summarizes the pathophysiology and current management of HAE, the development of Lonvo-z, its lipid nanoparticle delivery platform, and the technical advances enabling in vivo genome editing. Preclinical studies and clinical evidence, including early-phase trials and the Phase 3 HAELO study, are reviewed with emphasis on efficacy, safety and clinical implications. Lonvo-z represents a major milestone in precision medicine and the clinical application of systemic genome editing. A single administration has produced sustained reductions in plasma kallikrein levels and HAE attack frequency. Although long-term follow-up is ongoing, current evidence supports its potential as the first one-time disease-modifying treatment for HAE and a landmark advance in CRISPR-based therapeutics.
2026-07-07 | Living-Donor Kidney Transplantation Between Mother and Son With Clinically Confirmed Hereditary Angioedema.
Hereditary angioedema (HAE) is a rare autosomal dominant disorder resulting from SERPING1-related C1-inhibitor deficiency. Surgical stress and airway manipulation may precipitate life-threatening attacks. Experience with kidney transplantation in patients with HAE remains extremely limited. We describe a 19-year-old male with end-stage kidney disease secondary to congenital obstructive uropathy and nephrolithiasis, who underwent successful living-donor kidney transplantation from his mother, also diagnosed with HAE type I. Because danazol is unavailable in Argentina, both donor and recipient received compounded stanozolol 2 mg daily, starting 5 days preoperatively and continuing for 5 days postoperatively. Fresh frozen plasma (FFP, 10 mL/kg) was administered before extubation to raise C1-inhibitor levels, and icatibant was kept on standby for rescue. Neither donor nor recipient experienced perioperative angioedema. Both had uneventful recoveries, with the recipient maintaining stable graft function over 10 months of follow-up (latest serum creatinine 1.4 mg/dL). This report demonstrates that living-donor kidney transplantation between two individuals affected by HAE can be performed safely with individualized prophylaxis and multidisciplinary coordination.
2026-01-01 | A Case of Hereditary Angioedema Managed with Fresh Frozen Plasma
Abstract Hereditary angioedema (HAE) is a rare autosomal dominant disorder due to deficiency or dysfunction of the complement 1 esterase inhibitor (C1-INH) and leading to bradykinin-mediated angioedema. It commonly affects the skin, gastrointestinal tract, and upper airway and may be life-threatening. Conventional therapies such as corticosteroids, antihistamines, and epinephrine are usually ineffective. [1,2] We report a case of HAE type I with recurrent exacerbations and progressive laryngeal edema causing respiratory distress, unresponsive to standard therapy. The patient was electively intubated for airway protection. Due to nonavailability of C1-INH concentrate and kallikrein inhibitors in India, fresh frozen plasma (FFP) was administered. The patient showed marked clinical improvement and was successfully extubated within 48 h. Steroids were tapered, and the patient was discharged in stable condition. This case highlights the importance of early diagnosis and the role of FFP as an effective alternative therapy in resource-limited settings.
2025-11-14 | Long-Term Attenuation of Vascular Hyperpermeability in a Hereditary Angioedema Mouse Model by Adenine Base Editing.
Hereditary angioedema (HAE) is a rare and potentially life-threatening disorder caused by dysregulated kallikrein-kinin signaling and bradykinin-induced vascular hyperpermeability. Current therapies targeting this pathway are effective but require lifelong administration, underscoring the need for durable and potentially curative interventions. Adenine base editors (ABEs), engineered from CRISPR/Cas systems, enable precise single-nucleotide modifications with minimal genomic disruption, offering a promising strategy for long-term gene silencing. NG-ABE8e was delivered via AAV8 or lipid nanoparticles (LNP) to disrupt the exon 2 splice donor site of Klkb1 in Serping1+/- mice. Editing outcomes were quantified by high-throughput sequencing; serum kallikrein levels were measured by ELISA; and vascular permeability was evaluated using Evans blue dye extravasation, fluorescent tracer leakage, and VE-cadherin immunostaining. Safety evaluations included off-target analysis, histopathology, serum biochemistry, activated partial thromboplastin time (aPTT), and systemic hemodynamic stability. AAV8-NG-ABE8e induced > 60% A•T-to-G•C conversion at the target site, promoting exon 2 skipping and reducing Klkb1 mRNA and serum kallikrein levels by > 85%, an effect sustained for at least 1 year. AAV8-NG-ABE8e also reversed bradykinin-driven vascular hyperpermeability and attenuated inflammatory gene signatures. Prolongation of aPTT was observed only when circulating kallikrein levels declined below 2 μg/mL. Similarly, LNP-mediated delivery of NG-ABE8e mRNA resulted in > 90% reductions in Klkb1 expression and serum kallikrein levels. No evidence of significant long-term toxicity was detected. These findings demonstrate that, in a murine model, NG-ABE8e-mediated disruption of Klkb1 enables durable suppression of serum kallikrein and vascular stabilization, suggesting its potential as a promising single-intervention strategy for the treatment of HAE.
2025-11-06 | CRISPR-Cas9 gene editing for hereditary angioedema: current treatments and emerging therapies
Hereditary angioedema (HAE) is a rare autosomal dominant disorder marked by episodic, non-urticarial swelling due to C1 esterase inhibitor (C1-INH) deficiency or dysfunction, leading to excessive bradykinin-mediated vascular permeability. While current treatments focus on symptomatic control using C1-INH replacement or kallikrein inhibitors, they require frequent administration and do not address the underlying genetic defect. CRISPR-Cas9 gene-editing technologies, particularly the investigational therapy NTLA-2002, offer a transformative approach by targeting the KLKB1 gene to durably reduce plasma kallikrein levels. This narrative review summarizes the pathophysiology and conventional treatments of HAE, and highlights emerging clinical evidence supporting the safety and efficacy of NTLA-2002. Preliminary trials demonstrate substantial reductions in HAE attack frequency and plasma kallikrein, with minimal adverse events. However, concerns about long-term safety, off-target effects, ethical implications, and accessibility remain. CRISPR-based therapeutics such as NTLA-2002 represent a paradigm shift in the management of HAE and underscore the broader potential of in vivo gene editing for genetic disorders.
small molecules
2026-08-24 | Evaluating deucrictibant for the treatment of hereditary angioedema.
Hereditary Angioedema (HAE) is a rare disease affecting approximately 1 in 50,000 people. It results in angioedema of the skin, abdominal tract and upper airway that results in disfiguration, abdominal pain and potential for asphyxia. Early therapies for HAE have significant drug burden due to intravenous administration (C1-inhibitor) or adverse events (androgens); however, newer therapies have reduced injection requirements, and some are oral. Over the past 6 years two oral therapies have been developed for HAE to include berotralstat for long term prophylaxis (LTP) and sebetralstat for on-demand therapy (ODT). Presently, deucrictibant, another oral HAE therapy, is under investigation and appears effective for LTP and ODT. This manuscript summarizes the development, pharmacokinetics, pharmacodynamics, and currently available clinical evidence regarding deucrictibant in HAE management. Deucrictibant is a promising therapeutic agent with a well-defined mechanism of action. Published and ongoing clinical studies demonstrate favorable safety, tolerability, and efficacy profiles for both LTP and ODT, offering a convenient oral alternative that may reduce treatment burden and improve patient quality of life.
2026-08-22 | Real-World Safety and Effectiveness of Icatibant in Patients With Hereditary Angioedema (HAE): Post-Marketing Surveillance in Japan.
Hereditary angioedema (HAE) is a rare, autosomal dominant, life-threatening disease characterized by recurrent attacks of swelling of the face, upper airway, gastrointestinal tract, limbs, and/or genitalia. Genetic mutations of the SERPING1 gene encoding the C1-inhibitor (C1-INH) plasma protein are associated with HAE-C1INH. HAE is also observed in patients with normal C1-INH (HAE-nC1INH). Icatibant is a selective bradykinin B2 receptor antagonist for treatment of acute attacks of HAE. Here we report safety and effectiveness data from a post-marketing, open-label, multicenter observational study of icatibant conducted in Japan (ClinicalTrials.gov ID: NCT04057131). Patients with HAE in Japan who initiated icatibant between November 2018 and June 2020 were enrolled; surveillance was completed in April 2023. In the Safety Analysis Set (n = 155), most patients were women (n = 116, 74.84%) and HAE types included HAE-C1INH-Type 1 (n = 83, 53.55%), HAE-C1INH-Type 2 (n = 9, 5.81%), unclassified HAE-C1INH (n = 16, 10.32%), and HAE-nC1INH (n = 22, 14.19%). Overall, 19 patients (12.26%) experienced adverse drug reactions (ADRs), most of which were mild in severity (n = 18, 11.61%). The most common ADRs were general disorders and administration site conditions (n = 18, 11.61%). No serious ADRs or ADRs of special interest other than hypersensitivity and injection site reaction were reported. In the Effectiveness Analysis Set (n = 100), 97 patients (97.00%) received 30 mg of icatibant. Among 417 HAE attacks, 234 were treated with icatibant alone and 48 with icatibant plus other. Among attacks treated with icatibant alone, median (interquartile range) time to first symptom relief was 60.0 (30.0-270.0) min, and median time to complete resolution of symptoms was 710.0 (148.5-1440.0) min. In conclusion, in this study of the real-world use of icatibant, no new safety concerns were reported. Icatibant was effective in providing early symptom relief for HAE attacks across a broad spectrum of patients, including patients with HAE-nC1INH, who were not included in previous clinical trials.
2026-08-15 | Berotralstat Tolerability and Effectiveness in Hereditary Angioedema: Berolife Study Results.
Berotralstat is a first-line once-daily oral prophylactic treatment for hereditary angioedema (HAE). Berolife was designed to evaluate the tolerability and effectiveness of berotralstat in real-world conditions. Berolife is an open-label, multicenter, observational study conducted in France from September 2021 to January 2024. The primary objective was to assess tolerability, and secondary objectives included characterization of the treated population and assessment of berotralstat effectiveness. HAE attack rate was assessed before and after initiation of berotralstat using the paired Wilcoxon rank-sum test. Altogether, 80 patients were enrolled in the study (75 with HAE-C1INH type 1 or 2 and 5 with HAE-nC1INH) and received at least one dose of berotralstat. At baseline, patients had a mean (standard deviation [SD]) age of 40.0 (17.5) years, and most (67.5%) had received prior long-term prophylaxis treatment. The mean (SD) duration of berotralstat treatment was 11.5 (8.5) months. Treatment-related adverse events (AEs) occurred in 45.0% of patients, with gastrointestinal disorders being the most common (diarrhea: 13.8%, abdominal pain: 12.5%, upper abdominal pain: 7.5%). Importantly, no treatment-related serious AEs were reported. A total of 61 patients were treated with berotralstat for ≥ 6 months and evaluated for effectiveness. At 6 months of treatment, a significant reduction in monthly HAE attack rates was observed (mean [SD]: 0.62 [0.66] vs. mean [SD]: 1.25 [1.10] at baseline; p = 0.001). Berotralstat was generally well tolerated with a tolerability profile consistent with prior clinical trials. Significant reductions in monthly HAE attack rates were observed, confirming its effectiveness in real-world settings.
2026-08-08 | Lanadelumab Use for Hereditary Angioedema Long-Term Prophylaxis Over the Last 7 Years: A Narrative Review of Clinical and Real-World Data.
Hereditary angioedema (HAE) is a rare genetic disease characterized by unpredictable, painful cutaneous and/or subcutaneous swelling attacks; laryngeal attacks can be fatal. For many patients, long-term prophylaxis (LTP) is critical for disease control and quality of life.Lanadelumab, a plasma kallikrein inhibitor, was approved for HAE LTP for adults and adolescents in 2018 and for children aged ≥ 2 years in 2023; it is currently one of the guideline-recommended, first-line LTP options. By integrating 7 years of cumulative clinical trial and real-world data, this narrative review summarizes lanadelumab long-term effectiveness and safety in adult, adolescent, and pediatric HAE populations. Outcomes in 41 peer-reviewed publications were evaluated, including 5 clinical trials involving 262 lanadelumab-treated patients and 28 real-world studies comprising ~ 700 patients. Across clinical trials, lanadelumab reduced attack rates by up to 100%, with an average of 24.9-27.3 patient-reported attack-free days per 28-day period. These findings were largely corroborated by real-world data, including 2 large observational studies with > 100 patients each. Patient-reported disease control and health-related quality of life improved consistently across both settings. The main treatment-related adverse events across studies were injection site reactions. Treatment persistence was generally high in clinical practice. Unmet needs remain for specific populations, including pregnant or lactating patients and those without access to guideline-recommended LTP. Future research should address real-world outcomes in pediatric patients, extended dosing intervals in well-controlled disease, transitions from other LTP therapies, and cost-effectiveness. Overall, sustained effectiveness, safety, and quality-of-life benefits of lanadelumab reinforce its role as a cornerstone of HAE management.
2026-08-06 | A plain language summary of oral berotralstat for preventive treatment of hereditary angioedema attacks in children: early safety and efficacy results of the ongoing APeX-P study
What is this summary about? This plain language summary describes the interim results (early findings) of an ongoing study called APeX-P, which was published in the Annals of Allergy, Asthma & Immunology journal in 2025. The study looked at berotralstat, an oral (taken by mouth) medication, as a treatment option for hereditary angioedema (HAE) in children. HAE is a rare genetic disease that causes episodes of swelling (attacks) in different parts of the body, which can be serious. Attacks in the tongue and throat can be life-threatening. Berotralstat is taken once a day. Before the APeX-P study, the medication was approved in several countries to help prevent HAE attacks in people aged 12 and older. Berotralstat is now approved for use in people aged 2 and older in the United States. The APeX-P study researchers looked at which doses of berotralstat are appropriate for children aged 2 to under age 12, how children tolerated the medication, and how well berotralstat helps to prevent HAE attacks. The study also assessed children’s experiences and burdens with HAE. What were the results? Most of the children participating in the APeX-P study started having symptoms of HAE before they were 6 years old. Before beginning the study, children experienced burden because of HAE attacks, including missing school and needing emergency medical care because of their symptoms. After taking berotralstat for 12 weeks, children had fewer HAE attacks. The lower rate of attacks continued for up to 48-weeks (about 1 year—the study was still ongoing). This meant that children had fewer days with HAE symptoms. During the first 12 weeks of treatment with berotralstat, 3 HAE attacks (across all children in the study) needed medical care in a doctor’s office, clinic, or hospital. This need for medical care was 86% less than the 22 attacks needing medical care in the 12 weeks before the children started taking the medication. Most children in the study experienced at least 1 side effect after taking berotralstat; only 2 side effects (mild nausea or ‘feeling queasy’ and moderate headache) in 2 children were considered to be caused by the medication. Side effects were mild to moderate except in 1 patient who had an accident and a broken arm that was not caused by the medication. The most common side effects included a common cold, upper respiratory infection (in the nose, throat, or sinuses), or headache. What do the results mean? In the APeX-P study, children taking berotralstat tolerated the treatment well. The interim results show that berotralstat prevented attacks from HAE in young children. How to say (download PDF and double click sound icon to play sound)… APeX-P: AY-peks-pee Berotralstat: bear-oh-TRAL-stat Bradykinin: bray-DEE-ki-nin Hereditary angioedema: huh-REH-duh-tree AN-jee-oh-eh-DEE-muh Kallikrein: kal-uh-KREE-in Prophylaxis: pro-fuh-LACK-sis Angioedema: Swelling in the tissue under the skin. Genetic disease: Diseases caused by changes in a person’s DNA that can develop spontaneously or be passed on from parents to children. Tolerated: To handle a medication without having side effects that are serious or bothersome, or that are manageable enough for patients to continue taking the treatment. This is an abstract of the Plain Language Summary of Publication article. View the full Plain Language Summary PDF of this article to read the full-text Link to original article here
proteins
2026-09-05 | Hereditary angioedema in women: Hormonal and reproductive influences on disease activity.
Background: Hereditary angioedema (HAE) is a rare, potentially life-threatening disorder characterized by recurrent edema of the extremities, abdomen, face, larynx, trunk, and genital region. It follows an autosomal dominant inheritance pattern and affects both sexes equally; however, attacks may occur more frequently and with greater severity in women due to hormonal factors. Aims: The aim of this study was to evaluate the impact of hormonal changes on HAE attacks in women and to determine how different reproductive stages and hormonal exposures affect attack frequency and course. Methods: In this retrospective descriptive cohort study, 36 postpubertal women with HAE were evaluated to assess the effects of reproductive factors, including menstruation, oral contraceptive use, pregnancy, delivery, lactation, and menopause, on attack frequency and disease activity. Results: Thirty patients had type I and six had type II HAE. The mean age at diagnosis was 23.5 years, with a mean diagnostic delay of 12.6 years. Menstruation triggered attacks in 52.8% of the patients. Among 26 patients with 94 pregnancies, 21.2% ended in spontaneous abortion, and 73.1% had at least one child diagnosed with HAE. During pregnancy, attack frequency increased in 30.6%, decreased in 27.7%, and was unchanged in 41.7%. Attacks occurred within 48 hours postpartum in six deliveries, and three patients reported increased attacks during lactation. After menopause, attacks increased in 25%, decreased in 33.3%, and were unchanged in 41.7%. Conclusion: Hormonal and reproductive life stages influence disease activity in women with HAE, although the direction and magnitude of these effects vary among individuals. The marked delay in diagnosis observed in this cohort suggests that many women experience pregnancies without disease-specific management. Earlier recognition of HAE and individualized treatment approaches may improve care during hormonally dynamic periods.
2026-06-01 | Concurrent hereditary angioedema type I and common variable immunodeficiency presenting as suspected antibiotic hypersensitivity: Case report and literature discussion.
Hereditary angioedema (HAE) and common variable immunodeficiency (CVID) are rare disorders with heterogeneous clinical presentations that pose significant diagnostic challenges. HAE is characterized by recurrent episodes of subcutaneous or submucosal edema affecting the skin, gastrointestinal tract, or airway, whereas CVID presents with variable immune dysfunction, recurrent infections, and impaired vaccine responses. The clinical manifestations of these conditions can mimic allergic reactions, drug hypersensitivity, mast cell disorders, autoimmune diseases, and other immunodeficiencies, making careful differential diagnosis essential. Here, we present an exceptionally rare case of a patient with concurrent HAE type I and CVID, initially evaluated for suspected antibiotic hypersensitivity, highlighting the complexity of diagnosis and therapeutic decision-making. Laboratory findings confirmed both conditions, showing low C1 inhibitor levels and activity, markedly reduced serum concentrations of immunoglobulin G (including subclasses G1, G2, and G4), immunoglobulin A, and immunoglobulin M, along with a poor specific antibody response to vaccines. Skin allergy and oral provocation tests were negative, effectively ruling out antibiotic hypersensitivity. The genetic analysis identified a heterozygous pathogenic SERPING1 variant, c.498C > A (p.Asn166Lys), previously reported in 1 Romanian and 1 Czech case, confirming the diagnosis of HAE. Human leukocyte antigen (HLA) genotyping revealed HLA-B∗35:01 and B∗44:01, with homozygosity for HLA-C∗04:01, alleles previously associated with increased susceptibility to CVID. Using this case as a framework, we review the literature on coexisting HAE and CVID, examining clinical presentations, diagnostic approaches, biomarker profiles, and reported HLA associations. The review highlights the critical importance of a comprehensive and personalized therapeutic approach, combining prophylactic and on-demand treatment for HAE with individualized immunoglobulin replacement for CVID. Integrating detailed clinical assessment with immunologic and genetic testing is essential for the management of rare, complex disorders, and further studies are needed to clarify potential immunogenetic links between HAE and CVID.
2026-01-23 | Functional physiological, psychological, and biochemical reactivity to socially evaluated cold pressor test in hereditary angioedema patients (FRoSEn).
Stressful physical or psychological events can trigger acute swelling attacks in patients with Hereditary Angioedema due to C1 Inhibitor deficiency (HAE-C1INH), although the stress-disease relationship remains unclear. The Socially Evaluated Cold Pressor Test (SECPT) reliably induces acute stress under controlled conditions. This study aimed to compare perceived stress, inflammatory markers, and cardiovascular responses to SECPT between HAE-C1INH patients and healthy controls (HC). Twenty HAE-C1INH patients (9 males, 44 ± 14 years) and age and sex matched HC underwent a 3-minute SECPT. Participants completed questionnaires assessing anxiety and depression (HADS), pain catastrophizing (PCS), and subjective stress (0-100 scale) before and after SECPT. Heart rate (HR) and arterial pressure (AP) were recorded. Blood samples for inflammatory cytokines (IL-6, IL-1ß, TNF-α) were collected at baseline, and 10 and 40 minutes after SECPT. Compared to HC, patients showed higher baseline HADS-A (7.3 ± 4.5 vs 4.7 ± 2.7), overall PCS (19.7 ± 12.6 vs 12.9 ± 8.7), and perceived stress during SECPT (60.6 ± 34.3 vs 34.6 ± 23.8). IL-6 levels were higher at baseline and 10 minutes post-test (2.63 ± 1.21 vs 1.84 ± 0.87; 2.78 ± 1.20 vs 1.91 ± 0.79 pg/ml), as were TNF-α levels across all phases (4.19 ± 1.38 vs 3.26 ± 1.55; 4.09 ± 1.39 vs 3.40 ± 1.48; 4.09 ± 1.28 vs 3.20 ± 1.57) while IL-1 ß remained unchanged. HR and AP variations were similar between groups. HAE-C1INH patients exhibited heightened perceived stress response to SECPT, and elevated baseline inflammation, despite comparable cardiovascular reactivity. These findings highlight a complex psychophysiological-inflammatory interplay in acute stress responses, suggesting the need to integrate psychological and biological frameworks in understanding HAE-C1INH triggers. NCT06414252.
2026-01-11 | Bradykinin reduces wound healing in human umbilical vein endothelial cells via downregulation of vascular endothelial growth factor A.
INTRODUCTION: Hereditary angioedema (HAE) is characterized by acute swelling attacks triggered by abnormally elevated levels of bradykinin. Despite persistently high bradykinin levels, patients experience only intermittent swelling episodes. Many HAE patients, however, report triggers such as trauma preceding angioedema attacks. This suggests the involvement of additional factors, such as mechanical damage to the endothelium. Bradykinin-mediated impairment of wound healing may contribute to swelling development—a concept known as the “second hit” hypothesis. Vascular endothelial growth factors (VEGF) and their receptors play a critical role in endothelial wound healing and have also been implicated in bradykinin-mediated angioedema. This study investigates the influence of bradykinin on endothelial wound healing, with a particular focus on VEGF. MATERIALS AND METHODS: Human umbilical vein endothelial cells were incubated with bradykinin and VEGF. Gene and protein expression were analyzed by real-time polymerase chain reaction, western blotting, and immunocytochemistry. Barrier function was assessed by measuring transendothelial electrical resistance, as well as apparent and water permeability. Proliferation rates were determined using resazurin assays and real-time cell analysis. Cell migration was assessed using invasion and migration assays, and the combined effects were evaluated using scratch assays. RESULTS: Bradykinin treatment led to reduced expression of the VEGFA isoform and its receptor VEGFR-2. VEGFA alone had no effect on bradykinin-induced barrier disruption. However, bradykinin significantly decreased endothelial proliferation and migration, resulting in impaired wound healing. This effect was counteracted by the addition of VEGFA. CONCLUSIONS: VEGFA and its receptor VEGFR-2 are key regulators of endothelial wound healing. Bradykinin impairs wound healing by reducing proliferation and migration, likely through downregulation of VEGFA and VEGFR-2. These findings support the hypothesis that bradykinin-mediated impairment of wound healing may contribute to the episodic nature of swelling attacks in patients with bradykinin-mediated angioedema, in line with the second hit hypothesis.
2026-01-01 | Cardiac and vascular autonomic control in patients with hereditary angioedema.
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. 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). 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 70° tilt (TILT). Heart rate and systolic BP (SBP) variability indices were derived. Variance (σ2 SBP) and low-frequency power (LFSBP) of SBP variability were used as markers of sympathetic vascular control. 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 σ2 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. 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. https://clinicaltrials.gov/study/NCT06408805?cond=Hereditary%20Angioedema&term=autonomic&rank=1.
antibodies
2026-09-18 | Isolated gastrointestinal hereditary angioedema associated with a pathogenic SERPING1 variant arising de novo: a case report.
Hereditary angioedema (HAE) is a rare genetic disorder typically characterized by cutaneous and submucosal edema. Cases presenting exclusively with gastrointestinal symptoms, devoid of concurrent or historical cutaneous or upper airway manifestations, are uncommon. This atypical presentation poses a considerable diagnostic challenge and often leads to a marked delay in diagnosis, particularly in patients without a family history. We report the case of a 28-year-old female with an over 6-year history of recurrent, self-limiting abdominal pain. During a severe attack, abdominal computed tomography angiography (CTA) revealed jejunal wall edema and ascites, accompanied by a dramatic surge in D-dimer (>20.00 mg/L FEU) and fibrin degradation products (FDP >120.00 mg/L), closely mimicking mesenteric ischemia. However, a retrospective review of medical history identified the persistent consumption of complement C4 (0.03-0.05 g/L). Subsequent testing showed a functional C1 esterase inhibitor (fC1-INH) level of <7.0% and a C1 esterase inhibitor (C1-INH) antigen level of 6.81 μg/mL, confirming type 1 HAE. Whole-exome sequencing (WES) identified the nonsense variant NM_000062.3:c.990C>A, p.(Tyr330Ter), in SERPING1. The variant was not detected in either biological parent, supporting a de novo origin. Under the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) framework, it was classified as pathogenic on the basis of PVS1 and PS2. An abdominal attack in May 2025 resolved rapidly after icatibant administration. Long-term prophylaxis (LTP) with lanadelumab was subsequently initiated following an individualized shared decision-making process. No breakthrough attacks or treatment related adverse events occurred from June 2025 through June 2026. This report highlights that HAE should be considered in patients with recurrent, unexplained, self-limiting abdominal pain, and C4 should be included in the initial evaluation. A negative family history does not exclude HAE.
2026-08-07 | Sustained Effectiveness of Lanadelumab in Preventing Hereditary Angioedema Attacks: The ENABLE Study.
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. 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. 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. 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.
2026-06-10 | Long-Term Integrated Safety and Efficacy of Garadacimab for Hereditary Angioedema Prophylaxis.
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% confidence interval) monthly attack rate was 0.2 (0.1, 0.2) with garadacimab (n = 164), corresponding to a 94.9% (93.1, 96.7) reduction from run-in (3.5 [3.2, 3.9]). These integrated data, representing the longest garadacimab exposure reported to date, confirm the favorable long-term safety profile of garadacimab (exposure ≤ 5.5 years), and durable efficacy with sustained protection against HAE attacks (exposure ≤ 3.2 years). ClinicalTrials.gov identifiers, NCT03712228, NCT04656418, NCT04739059.
2026-06-09 | Lanadelumab in Hereditary Angioedema: Extending Dose Intervals from Every 2 Weeks to Every 4 Weeks.
Both clinical trial and real-world data demonstrate the effectiveness of lanadelumab long-term prophylaxis (LTP) to prevent hereditary angioedema (HAE) attacks, which may be maintained after dose interval extension from every 2 weeks (Q2W) to every 4 weeks (Q4W) in patients with well-controlled disease (attack free for >6 months). This narrative review summarizes published data on lanadelumab treatment patterns collected from clinical trials and observational studies since US approval in 2018. Disease activity and HAE-related healthcare resource use at baseline and during the first 6 months of lanadelumab treatment may be useful indicators of patients with well-controlled disease who will be eligible for, and may derive benefit from, dose interval extension on lanadelumab. Patients who receive a dose interval extension could benefit from a reduction in treatment burden, but not all patients may be a good fit for interval extension. Although there are inherent limitations related to analyzing small sample sizes for subgroups of patients with a rare disease and for data derived from real-world studies, these data can inform physicians and patients about the characteristics and outcomes of patients who have successfully extended dosing intervals of lanadelumab LTP. This may in turn encourage regular monitoring to facilitate optimization of treatment and outcomes for each patient.
2026-03-21 | Advances in hereditary angioedema in the modern treatment era in China: a focus on diagnosis, treatment, and prognosis.
BACKGROUND: Hereditary angioedema (HAE) is a rare, potentially life-threatening genetic disorder that is caused by C1-inhibitor (C1INH) deficiency or dysfunction. This scoping review sought to map recent advances in the management of HAE among patients in China. MATERIALS AND METHODS: A comprehensive literature search was conducted using relevant keywords across the databases PubMed, Embase, the Cochrane Library, ClinicalTrial.gov, and Chinese databases such as the China National Knowledge Infrastructure and Wanfang. The search covered publications from database inception through September 2024. Data was extracted on patient characteristics, disease manifestations, diagnostic approaches, treatments, clinical outcomes, and quality of life (QoL). The selection of articles followed predefined inclusion criteria and was conducted in adherence to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) guidelines. RESULTS: A total of 92 articles were included in this scoping review. Across the literature, the diagnosis of HAE was primarily based on serum complement assessment, particularly measurements of C4 and C1INH levels, along with family history and clinical manifestations. Danazol was reported as the primary treatment in previous studies; however, more recent studies emphasized the increasing use of lanadelumab and icatibant. Icatibant was shown to provide rapid symptom relief during acute HAE attacks, whereas lanadelumab demonstrated effectiveness as a long-term prophylactic therapy by reducing the frequency of attacks. The reviewed studies indicated fewer HAE-related deaths reported in studies published after 2021 compared with previous studies (129 deaths reported up to 2021; five deaths reported between 2021 and September 2024). This reduction may be attributed to increased disease awareness, earlier diagnosis, and advances in therapeutic management. In parallel, several studies reported improvements in angioedema-related quality of life (QoL) scores among patients with HAE in China. CONCLUSION: Emerging therapies such as lanadelumab and icatibant are effective in reducing the frequency of attacks and providing rapid symptom relief in Chinese patients with HAE. Nevertheless, further research is warranted to optimize HAE management strategies and to address existing gaps in the evidence within the Chinese population.
oligonucleotides
2026-07-08 | Donidalorsen for the Treatment of Hereditary Angioedema: A Review of Clinical Studies.
Hereditary angioedema (HAE) is a rare disease characterized by recurrent attacks of severe tissue swelling caused by dysregulation of the kallikrein-kinin system. Donidalorsen is a triantennary N-acetyl galactosamine-conjugated antisense oligonucleotide designed to specifically and reversibly reduce plasma prekallikrein production by binding to plasma prekallikrein messenger RNA in the liver. This report reviews donidalorsen's mechanism of action and data on the pharmacodynamics, efficacy, patient-reported outcomes, and safety of donidalorsen from clinical trials in adolescent and adult participants. In a Phase 1 trial, subcutaneous (SC) administration of donidalorsen led to dose-dependent reductions in plasma prekallikrein concentrations. In a subsequent Phase 2, randomized, placebo-controlled study, donidalorsen 80 mg SC once every 4 weeks (Q4W) for 16 weeks resulted in a 90% mean reduction in monthly HAE attack rate vs placebo, which was sustained for up to 4 years in an open-label extension (OLE). In the Phase 3, randomized, placebo-controlled OASIS-HAE study, patients receiving donidalorsen 80 mg Q4W or once every 8 weeks (Q8W) experienced significant mean reductions in HAE attack rates vs placebo over Weeks 0 to 24 (Q4W: 81%; Q8W: 55%). Mean attack rates were reduced by 87% (Q4W) and 60% (Q8W) vs placebo over Weeks 4 to 24. Reductions in attack rate from OASIS-HAE baseline were sustained for up to 1 year in the OASISplus OLE (Q4W: 94%; Q8W: 95%). A notable study in the clinical program included a cohort of patients who switched from berotralstat, C1 inhibitor, or lanadelumab to donidalorsen for up to 1 year; mean attack rates were reduced by 68% vs baseline (on prior HAE prophylaxis). Donidalorsen treatment improved quality of life at all assessments. Across studies, donidalorsen had an acceptable safety and tolerability profile, with mostly mild to moderate adverse events reported. Overall, the clinical data are promising for donidalorsen as a long-term prophylactic medication for HAE.
2026-03-14 | Switching Long-Term Prophylaxis to Donidalorsen for Hereditary Angioedema: 1-Year OASISplus Results.
Donidalorsen is an antisense oligonucleotide designed to reduce plasma prekallikrein in patients with hereditary angioedema (HAE). The Switch cohort of the OASISplus study (NCT05392114) evaluated the long-term safety and efficacy of donidalorsen in patients who switched from a long-term prophylactic treatment (LTP) to donidalorsen with 1-year outcomes. This study enrolled patients with HAE aged ≥ 12 years previously on stable doses of an LTP (lanadelumab, berotralstat, C1 inhibitor). Patients directly switched from an LTP to donidalorsen 80 mg administered subcutaneously once every 4 weeks. Endpoints included incidence and severity of treatment-emergent adverse events (TEAEs; primary endpoint), monthly HAE attack rate, Angioedema Quality of Life (AE-QoL), and Angioedema Control Test (AECT) measured at baseline and Week 52. Sixty-five patients enrolled, and 54 (83.1%) completed 1 year. Eleven (16.9%) patients discontinued treatment during the first year, and one discontinued treatment after 1 year. Donidalorsen reduced HAE attack rates from baseline on the prior LTP by 67.6% over 52 weeks. Fifty-six of 64 (87.5%) dosed patients experienced a TEAE; most reported mild to moderate events. The most common treatment-related TEAEs were injection-site erythema (10.9%) and injection-site pruritus (10.9%). One patient had a serious adverse event that was not treatment-related. AE-QoL total score improved by 12.2 points (clinically meaningful ≥ 6 points) from baseline to Week 52, and 90.4% of patients had well-controlled disease (AECT ≥ 10) at Week 52. In patients who switched from another LTP, donidalorsen was well tolerated and improved long-term HAE attack rates, quality of life, and disease control.
2026-03-10 | Donidalorsen for hereditary angioedema: Long-term results from a 4-year, phase 2, open-label extension study.
Hereditary angioedema (HAE) is a rare disorder caused by kallikrein-kinin system dysregulation. Donidalorsen is a prekallikrein-directed antisense oligonucleotide that can rebalance this system by reducing prekallikrein production and is indicated for prophylaxis to prevent HAE attacks in patients 12 years of age and older. To report results from a 4-year, phase 2, open-label extension study of donidalorsen (NCT04307381). The study on-treatment period included fixed (weeks 0-12) and flexible (weeks 16-208) treatment periods. Patients received donidalorsen 80 mg subcutaneously every 4 weeks (Q4W) in the fixed treatment period and could receive 80 mg every 8 weeks (Q8W) in the flexible treatment period if attack free for greater than or equal to 12 weeks or 100 mg Q4W if disease was not adequately controlled. End points are summarized through the end of the study (week 208). Of 17 patients with HAE-C1INH-type 1 or HAE-C1INH-type 2, 13 (76%) completed 4 years of treatment (median exposure: 3.99 years). Eight patients changed to donidalorsen Q8W; 5 stayed on Q8W to study completion. One patient received 100 mg Q4W. Mean monthly HAE attack rates decreased by 97% overall from baseline to the on-treatment period, with 97% (Q4W) and 83% (Q8W) decreases to the flexible treatment period. The median longest attack-free interval was 990 days. No serious treatment-emergent adverse events (TEAEs) occurred. One patient (6%) (100 mg Q4W) discontinued due to a TEAE (injection-site discoloration). Seven patients (41%) reported treatment-related TEAEs; the only treatment-related TEAEs reported in more than 1 patient were injection-site reactions. In this 4-year study, donidalorsen led to sustained reductions in monthly HAE attack rate with an acceptable safety profile. ClinicalTrials.gov Identifier: NCT04307381 (https://www. gov/study/NCT04307381).
2026-03-02 | Donidalorsen for Long-Term Prophylaxis of Hereditary Angioedema Attacks: Results from the OASISplus Open-Label Extension Cohort at Year 1.
Donidalorsen, a prekallikrein-directed antisense oligonucleotide indicated for prophylaxis of hereditary angioedema (HAE) attacks in patients aged ≥12 years, demonstrated efficacy and acceptable safety in the phase 3, placebo-controlled OASIS-HAE trial (NCT05139810). Here, we report 1-year results from the corresponding open-label extension (OLE) cohort of the OASISplus study (NCT05392114). OASISplus included patients who rolled over from OASIS-HAE. Patients who received donidalorsen 80 mg or placebo subcutaneously every 4 weeks (Q4W) in OASIS-HAE received donidalorsen Q4W in OASISplus. Patients who received donidalorsen 80 mg or placebo every 8 weeks (Q8W) in OASIS-HAE received donidalorsen Q8W or Q4W, if not attack-free in the final 8 weeks of OASIS-HAE. The primary endpoint was safety (ie, incidence of treatment-emergent adverse events [TEAEs]). Secondary endpoints included the monthly rate of HAE attacks and Angioedema Quality of Life (AE-QoL). The OLE cohort included 83 patients (Q4W, n=69 [83%]; Q8W, n=14 [17%]). Of these, 75 (90.4%) completed Year 1, and 6 patients receiving donidalorsen Q8W in OASIS-HAE switched to the Q4W dosing group in the OLE. Median donidalorsen exposure was 392.3 days. From Weeks 0 to 52, reductions in mean HAE attack rate from OASIS-HAE baseline were 94% (Q4W) and 95% (Q8W), and patients reported clinically meaningful improvements in mean AE-QoL total score at Week 52 (Q4W, 28.1 points; Q8W, 26.7 points). Twenty-two (27%) patients reported treatment-related TEAEs; none were serious, and injection-site reactions were the most frequently reported. Donidalorsen demonstrated sustained reductions in HAE attack rate, improvements in QoL, and an acceptable safety profile after 1 year of treatment.
2026-02-02 | Population Pharmacokinetic/Pharmacodynamic Modeling of Donidalorsen, an Antisense Oligonucleotide in Development for Prophylaxis of Hereditary Angioedema.
Hereditary angioedema (HAE) is a rare disorder linked to kallikrein-kinin system dysregulation, which leads to uncontrolled activation of plasma prekallikrein. Donidalorsen is an antisense oligonucleotide designed to selectively degrade prekallikrein messenger RNA and thereby reduce prekallikrein production. We aimed to develop population pharmacokinetic and pharmacokinetic/pharmacodynamic models of donidalorsen and evaluate the impact of potential intrinsic/extrinsic covariates on exposure and prekallikrein response. Plasma donidalorsen and prekallikrein data were obtained from phase 1 to 3 studies in healthy volunteers (NCT03263507, 721744-CS9) and adult and adolescent patients with HAE (NCT04030598, NCT05139810). The evaluated doses were 20, 40, 60, and 80 mg every 4 weeks (Q4W) and 80 mg every 8 weeks (Q8W), administered subcutaneously over 13-21 weeks. Donidalorsen pharmacokinetics were well described by a linear 2-compartment model with first-order absorption. The population terminal elimination half-life was 31.4 days. Prekallikrein was well described by an indirect response model with inhibition of prekallikrein production by donidalorsen. Covariate analysis identified body weight as the main factor affecting pharmacokinetic exposure; however, this effect was not considered clinically significant. The developed population pharmacokinetic/pharmacodynamic model well characterized the donidalorsen exposure-prekallikrein response relationship. Modeling analyses support that no dose adjustment is needed with respect to intrinsic/extrinsic factors in adults and adolescents with HAE. The nearly identical simulated pharmacokinetic or prekallikrein time courses for Q4W versus monthly dosing and for Q8W versus every-2-month dosing regimens support switching to more convenient regimens for patients.
other
2026-07-27 | Lonvoguran ziclumeran: a CRISPR-CAS9-based gene therapy for the treatment of hereditary angioedema.
Hereditary angioedema (HAE) is a rare genetic disorder characterized by recurrent swelling caused by dysregulation of the kallikrein-kinin pathway. Although current therapies effectively reduce attack frequency, treatment remains lifelong. Lonvoguran ziclumeran (Lonvo-z; NTLA-2002) is the first systemically administered in vivo CRISPR/Cas9 gene-editing therapy designed to provide durable suppression of plasma kallikrein through permanent disruption of the KLKB1 gene. This review summarizes the pathophysiology and current management of HAE, the development of Lonvo-z, its lipid nanoparticle delivery platform, and the technical advances enabling in vivo genome editing. Preclinical studies and clinical evidence, including early-phase trials and the Phase 3 HAELO study, are reviewed with emphasis on efficacy, safety and clinical implications. Lonvo-z represents a major milestone in precision medicine and the clinical application of systemic genome editing. A single administration has produced sustained reductions in plasma kallikrein levels and HAE attack frequency. Although long-term follow-up is ongoing, current evidence supports its potential as the first one-time disease-modifying treatment for HAE and a landmark advance in CRISPR-based therapeutics.
2026-07-07 | Living-Donor Kidney Transplantation Between Mother and Son With Clinically Confirmed Hereditary Angioedema.
Hereditary angioedema (HAE) is a rare autosomal dominant disorder resulting from SERPING1-related C1-inhibitor deficiency. Surgical stress and airway manipulation may precipitate life-threatening attacks. Experience with kidney transplantation in patients with HAE remains extremely limited. We describe a 19-year-old male with end-stage kidney disease secondary to congenital obstructive uropathy and nephrolithiasis, who underwent successful living-donor kidney transplantation from his mother, also diagnosed with HAE type I. Because danazol is unavailable in Argentina, both donor and recipient received compounded stanozolol 2 mg daily, starting 5 days preoperatively and continuing for 5 days postoperatively. Fresh frozen plasma (FFP, 10 mL/kg) was administered before extubation to raise C1-inhibitor levels, and icatibant was kept on standby for rescue. Neither donor nor recipient experienced perioperative angioedema. Both had uneventful recoveries, with the recipient maintaining stable graft function over 10 months of follow-up (latest serum creatinine 1.4 mg/dL). This report demonstrates that living-donor kidney transplantation between two individuals affected by HAE can be performed safely with individualized prophylaxis and multidisciplinary coordination.
2026-01-01 | A Case of Hereditary Angioedema Managed with Fresh Frozen Plasma
Abstract Hereditary angioedema (HAE) is a rare autosomal dominant disorder due to deficiency or dysfunction of the complement 1 esterase inhibitor (C1-INH) and leading to bradykinin-mediated angioedema. It commonly affects the skin, gastrointestinal tract, and upper airway and may be life-threatening. Conventional therapies such as corticosteroids, antihistamines, and epinephrine are usually ineffective. [1,2] We report a case of HAE type I with recurrent exacerbations and progressive laryngeal edema causing respiratory distress, unresponsive to standard therapy. The patient was electively intubated for airway protection. Due to nonavailability of C1-INH concentrate and kallikrein inhibitors in India, fresh frozen plasma (FFP) was administered. The patient showed marked clinical improvement and was successfully extubated within 48 h. Steroids were tapered, and the patient was discharged in stable condition. This case highlights the importance of early diagnosis and the role of FFP as an effective alternative therapy in resource-limited settings.
2025-11-14 | Long-Term Attenuation of Vascular Hyperpermeability in a Hereditary Angioedema Mouse Model by Adenine Base Editing.
Hereditary angioedema (HAE) is a rare and potentially life-threatening disorder caused by dysregulated kallikrein-kinin signaling and bradykinin-induced vascular hyperpermeability. Current therapies targeting this pathway are effective but require lifelong administration, underscoring the need for durable and potentially curative interventions. Adenine base editors (ABEs), engineered from CRISPR/Cas systems, enable precise single-nucleotide modifications with minimal genomic disruption, offering a promising strategy for long-term gene silencing. NG-ABE8e was delivered via AAV8 or lipid nanoparticles (LNP) to disrupt the exon 2 splice donor site of Klkb1 in Serping1+/- mice. Editing outcomes were quantified by high-throughput sequencing; serum kallikrein levels were measured by ELISA; and vascular permeability was evaluated using Evans blue dye extravasation, fluorescent tracer leakage, and VE-cadherin immunostaining. Safety evaluations included off-target analysis, histopathology, serum biochemistry, activated partial thromboplastin time (aPTT), and systemic hemodynamic stability. AAV8-NG-ABE8e induced > 60% A•T-to-G•C conversion at the target site, promoting exon 2 skipping and reducing Klkb1 mRNA and serum kallikrein levels by > 85%, an effect sustained for at least 1 year. AAV8-NG-ABE8e also reversed bradykinin-driven vascular hyperpermeability and attenuated inflammatory gene signatures. Prolongation of aPTT was observed only when circulating kallikrein levels declined below 2 μg/mL. Similarly, LNP-mediated delivery of NG-ABE8e mRNA resulted in > 90% reductions in Klkb1 expression and serum kallikrein levels. No evidence of significant long-term toxicity was detected. These findings demonstrate that, in a murine model, NG-ABE8e-mediated disruption of Klkb1 enables durable suppression of serum kallikrein and vascular stabilization, suggesting its potential as a promising single-intervention strategy for the treatment of HAE.
2025-11-06 | CRISPR-Cas9 gene editing for hereditary angioedema: current treatments and emerging therapies
Hereditary angioedema (HAE) is a rare autosomal dominant disorder marked by episodic, non-urticarial swelling due to C1 esterase inhibitor (C1-INH) deficiency or dysfunction, leading to excessive bradykinin-mediated vascular permeability. While current treatments focus on symptomatic control using C1-INH replacement or kallikrein inhibitors, they require frequent administration and do not address the underlying genetic defect. CRISPR-Cas9 gene-editing technologies, particularly the investigational therapy NTLA-2002, offer a transformative approach by targeting the KLKB1 gene to durably reduce plasma kallikrein levels. This narrative review summarizes the pathophysiology and conventional treatments of HAE, and highlights emerging clinical evidence supporting the safety and efficacy of NTLA-2002. Preliminary trials demonstrate substantial reductions in HAE attack frequency and plasma kallikrein, with minimal adverse events. However, concerns about long-term safety, off-target effects, ethical implications, and accessibility remain. CRISPR-based therapeutics such as NTLA-2002 represent a paradigm shift in the management of HAE and underscore the broader potential of in vivo gene editing for genetic disorders.
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Drug Discovery Landscape
1 orphan drug designation for Hereditary angioedema type 1.
1 orphan drug designation for Hereditary angioedema type 1.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
C1-inhibitor | proteins | FDA | Baxter Healthcare Corp. |
“Terminated” – programs with discontinued clinical trials, or with no updates reported for 5 years after completion or 12 years after the last trial started.
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