RARE DISEASE
Hereditary angioedema with C1Inh deficiency
Hereditary angioedema with C1Inh deficiency
Hereditary angioedema with C1Inh deficiency
Synonyms: HAE with C1 inhibitor deficiency, HAE with C1Inh deficiency, Hereditary angioneurotic edema with C1 inhibitor deficiency, Hereditary angioneurotic edema with C1Inh deficiency
Synonyms: HAE with C1 inhibitor deficiency, HAE with C1Inh deficiency, Hereditary angioneurotic edema with C1 inhibitor deficiency, Hereditary angioneurotic edema with C1Inh deficiency
Synonyms: HAE with C1 inhibitor deficiency, HAE with C1Inh deficiency, Hereditary angioneurotic edema with C1 inhibitor deficiency, Hereditary angioneurotic edema with C1Inh deficiency
Drug discovery
7
drugs
With orphan designations
Overview
Hereditary angioedema with C1 inhibitor deficiency (C1-INH-HAE) is a rare autosomal dominant disorder caused by SERPING1 mutations, leading to quantitative (type I) or qualitative (type II) C1-INH deficiency. This results in unregulated bradykinin production, causing recurrent subcutaneous/submucosal edema involving the skin, gastrointestinal tract, and upper airways. Life-threatening laryngeal edema occurs in 30–50% of untreated cases. Diagnosis requires serum C4 and functional C1-INH testing. Management includes acute therapies (C1-INH concentrates, icatibant) and long-term prophylaxis (C1-INH, kallikrein inhibitors, androgens) [1][2][10][12].
Burden
Mortality: Up to 30% lifetime risk of fatal laryngeal edema without prompt treatment [5][15].
Morbidity: 30% undergo unnecessary abdominal surgeries due to misdiagnosis; 70% report anxiety/depression [2][4][9].
Economic impact: Frequent ED visits, absenteeism, and reduced productivity (50% experience work/school impairment) [4][9][14].
Therapies
Acute attacks: C1-INH replacement (IV/SC), bradykinin B2 receptor antagonists (icatibant), and recombinant kallikrein inhibitors (ecallantide) [5][6][8][13].
Prophylaxis: Long-term C1-INH therapy, subcutaneous kallikrein inhibitors (lanadelumab), oral plasma kallikrein inhibitors (berotralstat), and attenuated androgens (danazol) [3][5][8][13].
Emerging therapies: Antisense oligonucleotides targeting prekallikrein and monoclonal antibodies against factor XIIa [9][13].
Categories: rare allergic disease, rare genetic diseases, rare systemic and rheumatological diseases
Research Papers
1,138 drug discovery papers about Hereditary angioedema with C1Inh deficiency, with 6 first-in-class and 13 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,138 drug discovery papers about Hereditary angioedema with C1Inh deficiency, with 6 first-in-class and 13 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
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.
2026-08-24 | 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.
2026-08-11 | Hereditary Angioedema Presenting as Recurrent Abdominal Pain: A Diagnostic Challenge
Background: This case report highlights the importance of prompt recognition of hereditary angioedema (HAE) in patients with recurrent abdominal attacks that may mimic surgical emergencies and lead to unnecessary interventions. Case Presentation: A 29-year-old man presented with severe recurrent abdominal pain associated with loose stools. Each episode lasted 3-5 days and resolved spontaneously. Further enquiry revealed a 16-year history of recurrent angioedema involving the face, lips, oral cavity, dorsum of both hands, and large joints of the lower limbs, with multiple episodes each year. The long-standing symptoms and diagnostic delay raised strong clinical suspicion of C1 esterase inhibitor (C1-INH) deficiency. Contrast-enhanced computed tomography of the abdomen and subsequent colonoscopy were performed during an attack. Laboratory evaluation showed low serum C4, low quantitative C1-INH levels, and markedly reduced C1-INH functional activity, findings consistent with Type 1 HAE. The patient was subsequently started on tranexamic acid. At follow-up, he was clinically improved, with complete resolution of symptoms and no recurrence of attacks. Conclusion: This case highlights the importance of recognising abdominal attacks in patients with C1-INH deficiency. Such attacks can be debilitating, may mimic surgical emergencies, and may contribute to prolonged diagnostic delay. Careful recognition of the recurrent pattern of abdominal symptoms together with non-pruritic, non-pitting angioedema and appropriate biochemical testing can support timely diagnosis and help avoid unnecessary interventions.
2026-08-04 | [Current and future therapies for bradykinin-mediated angioedema].
Bradykinin-mediated angioedema, particularly hereditary angioedema due to C1 esterase inhibitor deficiency or dysfunction (HAE-C1INH), is caused by dysregulation of the kallikrein-kinin system with excessive bradykinin generation and subsequent increased vascular permeability. Modern HAE management is based on three major therapeutic strategies: on-demand treatment, short-term prophylaxis (STP), and long-term prophylaxis (LTP). On-demand treatment options include plasma-derived and recombinant C1 inhibitor (C1INH) concentrates, the bradykinin B2 receptor antagonist icatibant, and, more recently, the first orally available plasma kallikrein inhibitor, sebetralstat. Short-term prophylaxis prior to invasive medical procedures is performed as replacement therapy by intravenous administration of C1INH concentrates. The goal of long-term prophylaxis is complete disease control with reduction of attack frequency and/or severity and improvement of quality of life. LTP therapies include subcutaneous and intravenous C1INH preparations, the oral kallikrein inhibitor berotralstat, the anti-kallikrein monoclonal antibody lanadelumab, the factor XIIa inhibitor garadacimab, and the antisense oligonucleotide donidalorsen. Currently under development are the oral bradykinin B2 receptor antagonist deucrictibant, which is intended for both on-demand treatment and long-term prophylaxis in different formulations, long-acting antibodies, such as navenibart, and CRISPR/Cas9-based gene-editing therapies, such as NTLA-2002 with potential functional curative properties. In particular, orally available and long-acting therapies are expected to improve adherence, self-management, and quality of life in affected patients.
2026-07-25 | Hereditary Angioedema: On-demand Treatment and Long-term Prophylaxis - A Global Reality.
Hereditary Angioedema (HAE) is a rare disorder of recurrent swellings of the subcutaneous and/or mucosal tissues due to defects in the contact system regulation of bradykinin production. The swellings can be disfiguring, cause debilitating abdominal pain, or be fatal with laryngeal obstruction. Over the last decade there has been immense successes in management of HAE owing to development of drugs targeting the contact system. This review focuses on management of HAE due to C1-INH deficiency/dysfunction including a global perspective which is under-represented in the literature. HAE with normal C1-INH is outside the scope of this article. The review provides summaries of clinical trials that has led to licensing of new HAE medications and discusses access to these modern drugs from a global perspective.
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.
2026-04-23 | Hemophilia and hereditary angioedema: parallel therapeutic advances in genetic diseases of serine protease pathways.
Hemophilia and hereditary angioedema (HAE) are rare monogenic disorders characterized by the dysregulation of serine protease-based biological pathways, that is, blood coagulation and the kallikrein-kinin system. Although clinical manifestations differ profoundly (bleeding vs angioedema), both diseases have recently undergone parallel therapeutic revolutions, shaped by advances in molecular biology and biotechnology. Early management in the 1970s relied for both diseases on the episodic administration of plasma-derived products, subsequently replaced by recombinant products that improved safety and feasibility of prophylaxis regimens. In the last 20 years, the development of nonreplacement products, such as emicizumab and rebalancing agents in hemophilia and kallikrein/bradykinin pathway inhibitors in HAE, shifted clinical practice from the episodic management of clinical events to their prevention. More recently, gene and RNA-based therapies are further transforming both diseases toward curative attempts: in hemophilia, adeno-associated virus vector-mediated gene therapy and lentiviral stem-cell approaches; in HAE, antisense oligonucleotide-mediated kallikrein suppression. Emerging genome-editing approaches and biomarker- and genotype-driven strategies are poised to further improve and personalize treatment. The therapeutic trajectories of rare diseases such as hemophilia and HAE illustrate how mechanistic insights enable the transition from the episodic management of acute events to long-term disease control, offering prospects for curative interventions.
2026-03-19 | Characterization of a unique pathogenic variant in the SERPING1 gene of a patient with hereditary angioedema type I.
Hereditary angioedema (HAE) is a rare genetic disease characterized by sudden onset of edema involving various organs. Among the three subtypes of the disease, HAE types I and II are caused by heterozygous variants in SERPING1 gene encoding C1 inhibitor (C1INH). The pathogenicity of each variant, however, has not fully been revealed. To assess the mechanism how a SERPING1 gene-variant identified in a patient with HAE type I caused the disease. Genetic analysis was conducted for a Japanese patient with HAE type I. The consequences resulting from the SERPING1 gene-variant were analyzed at mRNA levels. Overexpression studies in cultured cells were performed to analyze behavior of the mutant C1INH proteins. Effect of a small interfering RNA specific to the mutant SERPING1-mRNA on expression of wild-type C1INH was also tested. We identified a recurrent heterozygous variant c.820 A>G (p.Ile274Val) in the patient's SERPING1 gene. While we did not find any abnormalities in C1INH with the p.Ile274Val-variant, we found that the variant c.820 A>G caused an aberrant splicing event leading to a frameshift and a premature termination codon. This truncated protein clearly showed a dominant-negative effect against the wild-type C1INH. Finally, we showed that knock-down of the mutant SERPING1-mRNA recovered expression of the wild-type C1INH. A unique pathogenic mechanism for the SERPING1 gene-variant c.820 A>G has been disclosed. Furthermore, our findings have raised the possibility that RNA interference could be a new therapeutic tool for the disease.
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).
proteins
2026-09-26 | Family Tree Mapping of Genetic and Phenotypic Codes of Hereditary Angioedema.
Background and Objectives: Hereditary angioedema due to C1 inhibitor deficiency (HAE-C1INH) is a rare autosomal dominant disorder caused by mutations in the SERPING1 gene and is characterized by considerable clinical variability among affected individuals. Although genotype-phenotype correlations have been reported, data from populations with high consanguinity rates remain limited. Therefore, this study aimed to construct pedigrees of HAE-C1INH families harboring SERPING1 mutations and to investigate whether mutation type is associated with phenotypic characteristics, particularly age at disease onset and C1 inhibitor functional activity. Materials and Methods: Eleven HAE-C1INH probands and their families were followed up at the Allergy and Immunology Department of Internal Medicine, Ege University Faculty of Medicine. Of the 295 family members identified through pedigree construction, 109 had symptoms compatible with HAE-C1INH, and 53 of these symptomatic individuals had both a confirmed SERPING1 genetic result and an available C1-INH functional measurement. Pedigrees were created using the Progeny Pedigree Drawing Software (Progeny Genetics LLC, Delray Beach, FL, USA). Demographic data, disease characteristics, C1-INH function levels, and SERPING1 mutation types were obtained from patient files. Results: A total of 295 individuals (151 males and 144 females) from 11 HAE-C1INH families were identified through pedigree construction. The analytical cohort comprised 53 symptomatic individuals, of whom 7 (13.2%) were homozygous for the variant. Among heterozygous patients (n = 46), 27 (58.7%) had missense mutations, 7 (15.2%) had nonsense mutations, 7 (15.2%) had large deletions, and 5 (10.9%) had frameshift deletion mutations. Patients carrying missense mutations had significantly higher median C1-INH functional activity (28.5%) than those with other mutation types (14.1%) (p = 0.026), and the median age of disease onset was significantly later in the missense group (20 years) than in the non-missense group (8 years) (p < 0.001). Annual HAE attack frequency was also lower in the missense group (median, 12 vs. 48 attacks per year; p = 0.009). Conclusions: Exploratory individual-level analyses showed higher residual C1-INH functional activity and later symptom onset among individuals carrying missense SERPING1 variants than among those carrying pooled non-missense loss-of-function variants. However, familial clustering and the small number of independent families limit the strength and generalizability of these findings.
2026-09-25 | Prevalence and impact of sleep disorders in patients with hereditary angioedema: A multicenter cross-sectional study in Latin America.
Hereditary angioedema (HAE) is a rare disease characterized by recurrent swelling episodes that may affect sleep and quality of life. Because data on sleep disorders in Latin American patients with HAE are limited, we assessed their prevalence and clinical correlates using structured sleep and HAE patient-reported outcome measures. To assess the prevalence/impact of sleep disorders in HAE patients using validated tools. This cross-sectional, multicenter online survey included adult patients (> = 18 years) with clinician-confirmed HAE from 13 reference centers in five Latin American countries. Data were collected between August and December 2023. Sleep was assessed using the Global Sleep Assessment Questionnaire (GSAQ), SATED scale, and STOP-Bang; HAE was assessed using the Hereditary Angioedema Activity Score (HAE-AS), Angioedema Control Test (AECT), and Angioedema Quality of Life questionnaire (AE-QoL). Logistic regression models were adjusted for age, sex, and BMI. The final analytic sample included 139 participants. Most patients had HAE-C1INH type 1 (64.0%) and were female (68.4%). Only 6.5% had good sleep health, and the mean SATED score was 5.46 (1.87). Insomnia was reported by 54.0% of participants, and 34.5% had STOP-Bang moderate-to-high OSA risk. In age-, sex-, and BMI-adjusted models, severe HAE activity was associated with higher odds of insomnia (OR = 2.62, 95% CI: 1.28-5.35, P = 0.008), RLS/PLMD (OR = 5.85, 95% CI: 1.59-21.62, P = 0.008), and STOP-Bang moderate-to-high OSA risk (OR = 2.37, 95% CI: 1.01-5.55, P = 0.047). Higher AE-QoL fatigue/mood and fears/shame scores were associated with several sleep outcomes. AECT control status did not show a consistent independent association after simultaneous adjustment. In this exploratory cross-sectional study, HAE activity and quality-of-life impairment were associated with several sleep outcomes. Targeted sleep screening may be useful in HAE care pathways if these associations are confirmed in prospective studies.
2026-04-27 | Berotralstat and Health-Related Quality of Life in Hereditary Angioedema: Pooled Analysis of the APeX-2 and APeX-J Trials.
In the phase 3 APeX-2 and APeX-J trials, improvements in health-related quality of life (HRQoL) were reported for berotralstat, the only oral, once-daily, long-term prophylaxis for hereditary angioedema (HAE). We conducted a post hoc trial analysis to evaluate the impact of berotralstat on HRQoL versus placebo through 24 weeks, and the long-term effects of treatment up to 96 weeks, using pooled APeX-2 and APeX-J patient data. Patients receiving berotralstat 150 mg or placebo using the Angioedema QoL (AE-QoL) questionnaire; total and domain scores were analysed. Changes from baseline through Week 24 were compared using mixed models for repeated measures (MMRM) to estimate least squares mean differences (LSMDs) with 95% confidence intervals (CI) and nominal p-values. After Week 24, in the absence of a placebo comparator, long-term changes from baseline were evaluated using within-subject effect sizes (Cohen's d) through Week 96 in patients receiving berotralstat. Clinical meaningful improvements in AE-QoL total and domain scores were assessed by minimal clinically important difference (6-point reduction in AE-QoL total score) and distributional criterion methods, respectively. The manufacturer of berotralstat (BioCryst Pharmaceuticals) funded this study. Overall, 47 and 45 patients received berotralstat and placebo, respectively. At Week 24, berotralstat showed significantly greater improvement in AE-QoL total (LSMD: -7.4; 95% CI: -14.3, -0.6; p < 0.05), functioning domain (LSMD: -10.9; 95% CI: -19.6, -2.3; p = 0.013) and fears/shame domain (LSMD: -8.7; 95% CI: -17.2, -0.2; p = 0.046) scores compared with placebo. Among patients receiving berotralstat, consistent sustained improvements were observed across all AE-QoL domains up to Week 96. Analyses of meaningful improvement in total score and domains showed an increase over time in the proportion of patients achieving meaningful change. Berotralstat significantly improved HRQoL versus placebo through 24 weeks and showed long-term beneficial effects through 96 weeks.
2026-02-10 | Novel SERPING1 Genetic Variant in Two Family Members with Hereditary Angioedema.
Hereditary angioedema is a rare, autosomal dominant, genetic disorder characterized by recurrent episodes of angioedema. Over 800 SERPING1 gene variants have been reported, and their clinical profiles and causal genetic variants are highly heterogeneous. We report two cases of hereditary angioedema (HAE) in a Portuguese family: a 27-year-old male, under lanadelumab, and his 57-year-old father, kept on on-demand treatment. Genetic testing was performed following international guidelines. The Hereditary Angioedema Database Annotation highlighted a heterozygous insertion at exon 3 (c.336_337insC). This variant predicts a frameshift of the transcript, with the introduction of a premature STOP codon in C1-INH protein (p.Ser113LeufsTer20). We report the identification of a novel pathogenic SERPING1 variant in a family with HAE type 1, assisted by the Hereditary Angioedema Database Annotation variant prioritization tool. Our results may contribute to the identification of additional families with the same variant and can further enhance the knowledge about this condition.
2026-02-05 | Recent advances in factor XII(a) inhibitors: an updated patent landscape (2020-present).
Factor XII (FXII) is a liver-derived plasma zymogen that autoactivates on anionic surfaces to FXIIa, which drives the contact blood coagulation pathway, kallikrein-kinin signaling, fibrinolysis, and classical complement. Although congenital FXII(a) deficiency is largely asymptomatic, dysregulated activity is linked to thrombosis, hereditary angioedema (HAE), and neuroinflammation, making FXII(a) an attractive therapeutic target. This review provides a brief overview of FXII/FXIIa structure and function to highlight its suitability as a therapeutic target. It then summarizes patents published between 2020 and 2025 (patent search using Espacenet, Google Patents, and SciFinder) covering FXII(a)-targeting agents across diverse modalities, including small molecules, proteins and peptides, monoclonal antibodies, oligonucleotides, and siRNAs. Patent analysis indicates that most FXII(a) inhibitors remain in early preclinical development, though a growing subset has shown in vivo efficacy in models of thrombosis, HAE, sepsis, and neuroinflammation. The breadth and pace of 2020-2025 filings, together with accumulating translational data, should accelerate progression from patents to clinical candidates, particularly for contact-activation indications (e.g. device-related thrombosis). Resolving full-length FXII/α-FXIIa structures would further enable allosteric inhibitors design.
antibodies
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.
2026-08-05 | Diagnostic delay, SERPING1 allelic heterogeneity, and real-world lanadelumab prophylaxis in Chinese patients with hereditary angioedema due to C1 inhibitor deficiency
Background Hereditary angioedema due to C1 inhibitor deficiency (HAE-C1INH) is a rare and potentially life-threatening bradykinin-mediated disorder most commonly associated with pathogenic variants in SERPING1 . Data from Chinese patients remain limited, particularly regarding diagnostic delay, SERPING1 allelic heterogeneity, and real-world use of lanadelumab prophylaxis. Methods In this single-center retrospective observational study, we reviewed 10 consecutive unrelated index patients with confirmed HAE-C1INH managed at Henan Provincial People’s Hospital from January 2022 to May 2026. Clinical data, complement results, and SERPING1 Sanger sequencing findings were analyzed. Variants were classified according to ACMG/AMP criteria. Seven patients received lanadelumab long-term prophylaxis. Annualized attack rates and Angioedema Control Test scores before and during prophylaxis were compared using the Wilcoxon signed-rank test. Results The cohort included 6 females and 4 males, with a mean age of 32.8 ± 9.9 years. Nine patients had HAE-C1INH type 1 and one had type 2. The mean age at symptom onset was 21.7 ± 11.1 years, and the mean diagnostic delay was 9.4 ± 7.0 years. All patients had recurrent peripheral edema, 7 had abdominal attacks, and 6 had facial and/or laryngeal involvement. One patient required emergency tracheotomy. Serum C4 was reduced during attacks in all patients, and C1q levels were normal. Ten distinct heterozygous SERPING1 variants were identified, including 3 frameshift variants, 6 missense variants, and 1 in-frame deletion. Among the 7 patients receiving lanadelumab, the median annualized attack rate decreased from 11 (IQR, 7–23) to 0 (IQR, 0–1) attacks/year, and the median AECT score increased from 3 (IQR, 2–4) to 13 (IQR, 13–13). No serious adverse events were recorded. Conclusions This single-center retrospective study showed substantial diagnostic delay, marked SERPING1 allelic heterogeneity, and favorable real-world outcomes with lanadelumab prophylaxis in Chinese patients with HAE-C1INH. Earlier complement testing and access to appropriate genetic testing may shorten diagnostic delay. Larger prospective studies are needed to define individualized long-term prophylaxis strategies in Chinese patients.
2026-07-01 | Exploratory analysis of genetic variation, clinical activity score, and lanadelumab response in two families with hereditary angioedema due to C1-inhibitor esterase deficiency
Abstract Background : Hereditary angioedema due to C1-inhibitor esterase (C1INH) deficiency is caused by mutations in the SERPING1 gene. The same mutation can cause variable disease severity, highlighting the role of genetic and clinical factors in disease expression. The aim of this study was to evaluate these factors alongside the effectiveness of lanadelumab in two families. Case presentation : Here, we conducted a comparative analysis of affected members from two families including clinical activity scores, C1INH activity levels at diagnosis and genetic mutations. In lanadelumab treated patients, efficacy was evaluated three and 12 months post-initiation, and the two groups were compared. In family 1, eight affected individuals were identified across five generations. A deletion in exon 4 was detected in three of the six living patients. The clinical activity score was ≥5 in all and the C1INH activity level ≤ 40 % in five of them. In the three sisters receiving lanadelumab, the uncontrolled disease became a controlled one. In family 2, 16 affected individuals were identified across four generations, with eight patients followed at our center. A missense mutation in exon 8 was detected in five patients. Un undetectable C1INH activity level and clinical activity scores ≥5 was identified in five patient. In two from the three patients treated with lanadelumab a markedly reduction in attacks frequency weas obtained (from 9 to 2 in both of them) and one patient became symptom-free. Conclusions : The relationship between specific genetic mutations, clinical severity score, and response to prophylactic treatment remains inconclusive.
2026-06-30 | Effectiveness and Safety of Lanadelumab in the Treatment of Patients with Hereditary Angioedema in Routine Clinical Practice in the Russian Federation.
Background: Hereditary angioedema (HAE) caused by C1 inhibitor deficiency is a rare condition marked by recurrent swelling of the skin and mucous membranes. This study evaluated the effectiveness and safety of lanadelumab in routine clinical practice in Russia (IISR-2021-200085). Methods: A prospective cohort of 30 individuals with HAE was observed. Most patients were women (87%), with a mean age of 34 years; Seventeen percent of participants were adolescents. Prior to initiating lanadelumab, 16 patients (53%) had been receiving long-term prophylaxis, which was discontinued once lanadelumab was started. Treatment outcomes were assessed by comparing attack frequency, medication use for acute events, disease control scores, and quality of life before and after lanadelumab therapy. Results: Before treatment, patients reported an average of 8.6 attacks per month. After 6 months of lanadelumab treatment, the mean attack frequency was reduced to 0.5 per month (p < 0.001). Use of acute therapies decreased from 4.73 to 0.43 doses per month (p < 0.001). Disease control improved substantially, and quality-of-life scores improved from 58.2 to 25.3 points (p < 0.001). No significant lanadelumab-related adverse events were observed. Conclusion: In routine clinical practice, lanadelumab proved highly effective in reducing attack rates, enhancing disease control, and improving quality of life in patients with hereditary angioedema. The therapy was well tolerated, with no serious safety concerns identified. These findings reinforce lanadelumab as a reliable long-term prophylactic option for hereditary angioedema management.
2026-06-22 | Hereditary angioedema attack trends among patients maintained on lanadelumab long-term prophylaxis.
Longitudinal studies using real-world data are needed to assess the effectiveness of long-term prophylaxis (LTP) for hereditary angioedema (HAE) during successive years of treatment. This United States-based retrospective analysis assessed the longitudinal effectiveness of lanadelumab LTP on attack rate reduction year on year in lanadelumab-treated patients with HAE. Data were from the Consortium of Independent Immunology Clinic's HAE Patient Registry, a dataset managed by Trio Health. Patients who were treated with lanadelumab between August 2018 and December 2023 and who remained on treatment for at least 6 months were included. Data were collected during routine clinic visits, with the time between clinic visits defined as "follow-up intervals" for outcome assessment. Given data were ascertained from real-world clinical practices, visits did not occur at uniform fixed intervals. Patients were followed for up to 4 visits after lanadelumab initiation. The analysis included 141 patients with HAE due to C1 inhibitor deficiency or dysfunction. The mean ± SD duration on lanadelumab was over 3.5 years (1305 days ± 567). Mean length of follow-up intervals 1 to 4 were 376, 267, 286, and 283 days, respectively. Lanadelumab discontinuation rates were low (range 1.3%-3.1%) across the 4 intervals. The mean ± SD monthly attack rates ranged from 0.21 ± 0.43 (interval 1) to 0.16 ± 0.38 (interval 4) (P = .399 vs interval 1). The percentage of attack-free patients increased from 40% during interval 1 to 53% during interval 4. Patients on lanadelumab for at least 6 months had low discontinuation rates. Attack rates were low, and the proportion of attack-free patients increased across intervals, indicating attack-free status was achievable in the later years on treatment.
other
2026-07-28 | Status of Current Clinical Trials on Therapy for Hereditary Angioedema 2309515
Abstract Introduction Hereditary angioedema (HAE) is a rare autosomal dominant deficiency or dysfunction of C1 esterase inhibitor, resulting in dysregulated kallikrein—bradykinin signaling and potentially life-threatening angioedema. While existing C1-INH products and kallikrein inhibitors have improved disease control, new clinical trials aim to further reduce treatment burden and achieve durable prophylaxis through novel therapeutic strategies. Methods Active and recruiting HAE clinical trials were identified through the trial registry on clinicaltrials.gov. Results A total of twenty-two trials were identified, eleven of which are recruiting as of December 2025, and eleven others that are active but no longer recruiting. The sole drug in phase 4 is CSL312 (Garadacimab), a fully human IgG4 monoclonal antibody targeting activated factor XIIa. Drugs in phase 3 include: NTLA-2002, a single-dose intravenous gene therapy targeting inactivation of the KLKB1 gene; Navenibart, an IgG1 monoclonal antibody inhibiting activated kallikrein; OCTA-C1-INH, a virus-inactivated, nanofiltrated, highly purified concentrate of C1-INH derived from pooled human plasma; ADX-324, an siRNA therapy to reduce hepatic production of prekallikrein (PKK); Donidalorsen, an antisense oligonucleotide targeted against hepatic PKK mRNA; Sebetralstat and berotralstat, both plasma kallikrein inhibitors that reduce production of bradykinin; and deucrictibant, a competitive bradykinin B2 receptor antagonist. Drugs in phase 2 are: BW-20805, another siRNA therapy targeting human hepatic PKK mRNA; and BMN 331, an AAV5-based gene therapy that introduces the SERPING1 gene which encodes wild-type human C1INH protein. Conclusion Advances in gene therapy, biologics, RNA interference therapeutics, and improved replacement strategies hold promise for transforming both rescue and prophylactic management for HAE. Ongoing evaluation of safety, durability of response, and real-world applicability will be critical in defining the future standard of care for HAE. Funding Source n/a Topic Categories Translational and Interventional Immunology (TI)
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.
2026-06-21 | Modeling Hereditary Angioedema With Personalized EPSC-Derived Hepatocytes: A CRISPR-Validated Platform for Mutation-Specific Mechanisms and Therapeutic Innovation.
Hereditary angioedema (HAE) with C1 esterase inhibitor (C1INH) deficiency is caused by pathogenic SERPING1 mutations that disrupt production of the plasma protease inhibitor C1INH. However, the molecular mechanisms and consequences of patient-specific mutations remain poorly understood due to the lack of physiologically relevant human models. Here, we established a personalized, isogenic, stem-cell-derived hepatocyte platform to investigate the underlying mutation-specific mechanisms of HAE. Specifically, peripheral blood mononuclear cell (PBMC)-expanded erythroblasts from four representative HAE-C1INH-Type1 patients containing distinct point, insertion, deletion, or large fragment SERPING1 mutations were reprogrammed into expanded potential stem cells (EPSCs) and further differentiated into hepatocyte-like cells (HLCs). These HLCs exhibited appropriate transcriptional transitions, mature hepatic features, and C1INH secretion comparable to that observed in human plasma. All patient-derived HLCs demonstrated impaired C1INH secretion with mutation-specific differences in both SERPING1 transcription and intracellular accumulation. Moreover, to verify that the mutations directly drive the phenotype, we performed CRISPR/Cas9-mediated genome repair, which restored SERPING1 mRNA expression and C1INH secretion. Conversely, identical patient mutations installed into healthy EPSCs showed the same transcriptional and secretory defects, confirming sufficiency. Collectively, we have established a robust human hepatocyte model that accurately recapitulates key hepatocyte-specific aspects of HAE pathophysiology and provides a scalable foundation for investigation of future precision therapies.
2026-01-01 | Coexistence of Hereditary Angioedema and Homozygous Factor V Leiden Mutation in a 31-Year-Old Patient: A Rare Clinical Overlap.
Abstract Background:Hereditary angioedema (HAE) is a rare autosomal dominant disorder which is caused by deficiency or dysfunction of C1-esterase inhibitor (C1-INH). This leads to dysregulation of the kallikrein–bradykinin pathway which is responsible for recurrent episodes of non-pruritic angioedema seen in these cases. The condition typically manifests as episodic swelling of the skin, gastrointestinal tract or involvement of airway. It is frequently misdiagnosed as allergic angioedema due to overlapping clinical features. Factor V Leiden mutation the most common inherited thrombophilia is caused by a point mutation in the F5 gene that produces resistance to activated protein C and increases the risk of venous thromboembolism. Although both disorders involve dysregulationof plasma protease cascades reports describing their coexistence are exceedingly rare. This case highlights the diagnostic and therapeutic challenges associated with the simultaneous presence of HAE and homozygous Factor V Leiden mutation.Case Report:A 31-year-old woman presented with recurrent episodes of facial and right upper limb edema. This was accompanied by burning sensation, body aches and abdominal cramps. Episodes occurred one to two times per week and resolved spontaneously within two to six hours. The patient, diagnosed case of homozygous Factor V Leiden mutation, had a prior history of recurrent venous thromboembolism including deep venous thrombosis and pulmonary embolism. Physical examination during attacks revealed non-pitting and non-pruritic edema. There was minimal response to antihistamines and bronchodilators. Serum tryptase was normal and autoimmune markers were negative. In addition C1- INH levels were reduced with normal C1q.Complement C4 levels were decreased. These changesconfirmed the diagnosis of hereditary angioedema secondary to C1-INH deficiency. Initial treatment with fresh frozen plasma was started which was subsequently discontinued due to worsening pulmonary arterial hypertension. Therapeutic plasmapheresis was performed which caused marked symptomatic improvement.Conclusion:This is a rare case in whom there was coexistence of hereditary angioedema due to C1-INH deficiency and homozygous Factor V Leiden mutation. This represents a rare clinical overlap involving dysregulation of complement, kallikrein–kinin and coagulation pathways. Recognition of bradykininmediated angioedema in patients with recurrent swelling unresponsive to antihistamines is essential for appropriate management as these patients are less likely to respond to antihistamines, corticosteroids, or epinephrine Keywords: C1-Esterase Inhibitor Deficiency, Factor V Leiden Mutation, Hereditary Angioedema, Plasmapheresis, Venous Thromboembolism
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.
small molecules
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.
2026-08-24 | 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.
2026-08-11 | Hereditary Angioedema Presenting as Recurrent Abdominal Pain: A Diagnostic Challenge
Background: This case report highlights the importance of prompt recognition of hereditary angioedema (HAE) in patients with recurrent abdominal attacks that may mimic surgical emergencies and lead to unnecessary interventions. Case Presentation: A 29-year-old man presented with severe recurrent abdominal pain associated with loose stools. Each episode lasted 3-5 days and resolved spontaneously. Further enquiry revealed a 16-year history of recurrent angioedema involving the face, lips, oral cavity, dorsum of both hands, and large joints of the lower limbs, with multiple episodes each year. The long-standing symptoms and diagnostic delay raised strong clinical suspicion of C1 esterase inhibitor (C1-INH) deficiency. Contrast-enhanced computed tomography of the abdomen and subsequent colonoscopy were performed during an attack. Laboratory evaluation showed low serum C4, low quantitative C1-INH levels, and markedly reduced C1-INH functional activity, findings consistent with Type 1 HAE. The patient was subsequently started on tranexamic acid. At follow-up, he was clinically improved, with complete resolution of symptoms and no recurrence of attacks. Conclusion: This case highlights the importance of recognising abdominal attacks in patients with C1-INH deficiency. Such attacks can be debilitating, may mimic surgical emergencies, and may contribute to prolonged diagnostic delay. Careful recognition of the recurrent pattern of abdominal symptoms together with non-pruritic, non-pitting angioedema and appropriate biochemical testing can support timely diagnosis and help avoid unnecessary interventions.
2026-08-04 | [Current and future therapies for bradykinin-mediated angioedema].
Bradykinin-mediated angioedema, particularly hereditary angioedema due to C1 esterase inhibitor deficiency or dysfunction (HAE-C1INH), is caused by dysregulation of the kallikrein-kinin system with excessive bradykinin generation and subsequent increased vascular permeability. Modern HAE management is based on three major therapeutic strategies: on-demand treatment, short-term prophylaxis (STP), and long-term prophylaxis (LTP). On-demand treatment options include plasma-derived and recombinant C1 inhibitor (C1INH) concentrates, the bradykinin B2 receptor antagonist icatibant, and, more recently, the first orally available plasma kallikrein inhibitor, sebetralstat. Short-term prophylaxis prior to invasive medical procedures is performed as replacement therapy by intravenous administration of C1INH concentrates. The goal of long-term prophylaxis is complete disease control with reduction of attack frequency and/or severity and improvement of quality of life. LTP therapies include subcutaneous and intravenous C1INH preparations, the oral kallikrein inhibitor berotralstat, the anti-kallikrein monoclonal antibody lanadelumab, the factor XIIa inhibitor garadacimab, and the antisense oligonucleotide donidalorsen. Currently under development are the oral bradykinin B2 receptor antagonist deucrictibant, which is intended for both on-demand treatment and long-term prophylaxis in different formulations, long-acting antibodies, such as navenibart, and CRISPR/Cas9-based gene-editing therapies, such as NTLA-2002 with potential functional curative properties. In particular, orally available and long-acting therapies are expected to improve adherence, self-management, and quality of life in affected patients.
2026-07-25 | Hereditary Angioedema: On-demand Treatment and Long-term Prophylaxis - A Global Reality.
Hereditary Angioedema (HAE) is a rare disorder of recurrent swellings of the subcutaneous and/or mucosal tissues due to defects in the contact system regulation of bradykinin production. The swellings can be disfiguring, cause debilitating abdominal pain, or be fatal with laryngeal obstruction. Over the last decade there has been immense successes in management of HAE owing to development of drugs targeting the contact system. This review focuses on management of HAE due to C1-INH deficiency/dysfunction including a global perspective which is under-represented in the literature. HAE with normal C1-INH is outside the scope of this article. The review provides summaries of clinical trials that has led to licensing of new HAE medications and discusses access to these modern drugs from a global perspective.
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.
2026-04-23 | Hemophilia and hereditary angioedema: parallel therapeutic advances in genetic diseases of serine protease pathways.
Hemophilia and hereditary angioedema (HAE) are rare monogenic disorders characterized by the dysregulation of serine protease-based biological pathways, that is, blood coagulation and the kallikrein-kinin system. Although clinical manifestations differ profoundly (bleeding vs angioedema), both diseases have recently undergone parallel therapeutic revolutions, shaped by advances in molecular biology and biotechnology. Early management in the 1970s relied for both diseases on the episodic administration of plasma-derived products, subsequently replaced by recombinant products that improved safety and feasibility of prophylaxis regimens. In the last 20 years, the development of nonreplacement products, such as emicizumab and rebalancing agents in hemophilia and kallikrein/bradykinin pathway inhibitors in HAE, shifted clinical practice from the episodic management of clinical events to their prevention. More recently, gene and RNA-based therapies are further transforming both diseases toward curative attempts: in hemophilia, adeno-associated virus vector-mediated gene therapy and lentiviral stem-cell approaches; in HAE, antisense oligonucleotide-mediated kallikrein suppression. Emerging genome-editing approaches and biomarker- and genotype-driven strategies are poised to further improve and personalize treatment. The therapeutic trajectories of rare diseases such as hemophilia and HAE illustrate how mechanistic insights enable the transition from the episodic management of acute events to long-term disease control, offering prospects for curative interventions.
2026-03-19 | Characterization of a unique pathogenic variant in the SERPING1 gene of a patient with hereditary angioedema type I.
Hereditary angioedema (HAE) is a rare genetic disease characterized by sudden onset of edema involving various organs. Among the three subtypes of the disease, HAE types I and II are caused by heterozygous variants in SERPING1 gene encoding C1 inhibitor (C1INH). The pathogenicity of each variant, however, has not fully been revealed. To assess the mechanism how a SERPING1 gene-variant identified in a patient with HAE type I caused the disease. Genetic analysis was conducted for a Japanese patient with HAE type I. The consequences resulting from the SERPING1 gene-variant were analyzed at mRNA levels. Overexpression studies in cultured cells were performed to analyze behavior of the mutant C1INH proteins. Effect of a small interfering RNA specific to the mutant SERPING1-mRNA on expression of wild-type C1INH was also tested. We identified a recurrent heterozygous variant c.820 A>G (p.Ile274Val) in the patient's SERPING1 gene. While we did not find any abnormalities in C1INH with the p.Ile274Val-variant, we found that the variant c.820 A>G caused an aberrant splicing event leading to a frameshift and a premature termination codon. This truncated protein clearly showed a dominant-negative effect against the wild-type C1INH. Finally, we showed that knock-down of the mutant SERPING1-mRNA recovered expression of the wild-type C1INH. A unique pathogenic mechanism for the SERPING1 gene-variant c.820 A>G has been disclosed. Furthermore, our findings have raised the possibility that RNA interference could be a new therapeutic tool for the disease.
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).
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2026-09-26 | Family Tree Mapping of Genetic and Phenotypic Codes of Hereditary Angioedema.
Background and Objectives: Hereditary angioedema due to C1 inhibitor deficiency (HAE-C1INH) is a rare autosomal dominant disorder caused by mutations in the SERPING1 gene and is characterized by considerable clinical variability among affected individuals. Although genotype-phenotype correlations have been reported, data from populations with high consanguinity rates remain limited. Therefore, this study aimed to construct pedigrees of HAE-C1INH families harboring SERPING1 mutations and to investigate whether mutation type is associated with phenotypic characteristics, particularly age at disease onset and C1 inhibitor functional activity. Materials and Methods: Eleven HAE-C1INH probands and their families were followed up at the Allergy and Immunology Department of Internal Medicine, Ege University Faculty of Medicine. Of the 295 family members identified through pedigree construction, 109 had symptoms compatible with HAE-C1INH, and 53 of these symptomatic individuals had both a confirmed SERPING1 genetic result and an available C1-INH functional measurement. Pedigrees were created using the Progeny Pedigree Drawing Software (Progeny Genetics LLC, Delray Beach, FL, USA). Demographic data, disease characteristics, C1-INH function levels, and SERPING1 mutation types were obtained from patient files. Results: A total of 295 individuals (151 males and 144 females) from 11 HAE-C1INH families were identified through pedigree construction. The analytical cohort comprised 53 symptomatic individuals, of whom 7 (13.2%) were homozygous for the variant. Among heterozygous patients (n = 46), 27 (58.7%) had missense mutations, 7 (15.2%) had nonsense mutations, 7 (15.2%) had large deletions, and 5 (10.9%) had frameshift deletion mutations. Patients carrying missense mutations had significantly higher median C1-INH functional activity (28.5%) than those with other mutation types (14.1%) (p = 0.026), and the median age of disease onset was significantly later in the missense group (20 years) than in the non-missense group (8 years) (p < 0.001). Annual HAE attack frequency was also lower in the missense group (median, 12 vs. 48 attacks per year; p = 0.009). Conclusions: Exploratory individual-level analyses showed higher residual C1-INH functional activity and later symptom onset among individuals carrying missense SERPING1 variants than among those carrying pooled non-missense loss-of-function variants. However, familial clustering and the small number of independent families limit the strength and generalizability of these findings.
2026-09-25 | Prevalence and impact of sleep disorders in patients with hereditary angioedema: A multicenter cross-sectional study in Latin America.
Hereditary angioedema (HAE) is a rare disease characterized by recurrent swelling episodes that may affect sleep and quality of life. Because data on sleep disorders in Latin American patients with HAE are limited, we assessed their prevalence and clinical correlates using structured sleep and HAE patient-reported outcome measures. To assess the prevalence/impact of sleep disorders in HAE patients using validated tools. This cross-sectional, multicenter online survey included adult patients (> = 18 years) with clinician-confirmed HAE from 13 reference centers in five Latin American countries. Data were collected between August and December 2023. Sleep was assessed using the Global Sleep Assessment Questionnaire (GSAQ), SATED scale, and STOP-Bang; HAE was assessed using the Hereditary Angioedema Activity Score (HAE-AS), Angioedema Control Test (AECT), and Angioedema Quality of Life questionnaire (AE-QoL). Logistic regression models were adjusted for age, sex, and BMI. The final analytic sample included 139 participants. Most patients had HAE-C1INH type 1 (64.0%) and were female (68.4%). Only 6.5% had good sleep health, and the mean SATED score was 5.46 (1.87). Insomnia was reported by 54.0% of participants, and 34.5% had STOP-Bang moderate-to-high OSA risk. In age-, sex-, and BMI-adjusted models, severe HAE activity was associated with higher odds of insomnia (OR = 2.62, 95% CI: 1.28-5.35, P = 0.008), RLS/PLMD (OR = 5.85, 95% CI: 1.59-21.62, P = 0.008), and STOP-Bang moderate-to-high OSA risk (OR = 2.37, 95% CI: 1.01-5.55, P = 0.047). Higher AE-QoL fatigue/mood and fears/shame scores were associated with several sleep outcomes. AECT control status did not show a consistent independent association after simultaneous adjustment. In this exploratory cross-sectional study, HAE activity and quality-of-life impairment were associated with several sleep outcomes. Targeted sleep screening may be useful in HAE care pathways if these associations are confirmed in prospective studies.
2026-04-27 | Berotralstat and Health-Related Quality of Life in Hereditary Angioedema: Pooled Analysis of the APeX-2 and APeX-J Trials.
In the phase 3 APeX-2 and APeX-J trials, improvements in health-related quality of life (HRQoL) were reported for berotralstat, the only oral, once-daily, long-term prophylaxis for hereditary angioedema (HAE). We conducted a post hoc trial analysis to evaluate the impact of berotralstat on HRQoL versus placebo through 24 weeks, and the long-term effects of treatment up to 96 weeks, using pooled APeX-2 and APeX-J patient data. Patients receiving berotralstat 150 mg or placebo using the Angioedema QoL (AE-QoL) questionnaire; total and domain scores were analysed. Changes from baseline through Week 24 were compared using mixed models for repeated measures (MMRM) to estimate least squares mean differences (LSMDs) with 95% confidence intervals (CI) and nominal p-values. After Week 24, in the absence of a placebo comparator, long-term changes from baseline were evaluated using within-subject effect sizes (Cohen's d) through Week 96 in patients receiving berotralstat. Clinical meaningful improvements in AE-QoL total and domain scores were assessed by minimal clinically important difference (6-point reduction in AE-QoL total score) and distributional criterion methods, respectively. The manufacturer of berotralstat (BioCryst Pharmaceuticals) funded this study. Overall, 47 and 45 patients received berotralstat and placebo, respectively. At Week 24, berotralstat showed significantly greater improvement in AE-QoL total (LSMD: -7.4; 95% CI: -14.3, -0.6; p < 0.05), functioning domain (LSMD: -10.9; 95% CI: -19.6, -2.3; p = 0.013) and fears/shame domain (LSMD: -8.7; 95% CI: -17.2, -0.2; p = 0.046) scores compared with placebo. Among patients receiving berotralstat, consistent sustained improvements were observed across all AE-QoL domains up to Week 96. Analyses of meaningful improvement in total score and domains showed an increase over time in the proportion of patients achieving meaningful change. Berotralstat significantly improved HRQoL versus placebo through 24 weeks and showed long-term beneficial effects through 96 weeks.
2026-02-10 | Novel SERPING1 Genetic Variant in Two Family Members with Hereditary Angioedema.
Hereditary angioedema is a rare, autosomal dominant, genetic disorder characterized by recurrent episodes of angioedema. Over 800 SERPING1 gene variants have been reported, and their clinical profiles and causal genetic variants are highly heterogeneous. We report two cases of hereditary angioedema (HAE) in a Portuguese family: a 27-year-old male, under lanadelumab, and his 57-year-old father, kept on on-demand treatment. Genetic testing was performed following international guidelines. The Hereditary Angioedema Database Annotation highlighted a heterozygous insertion at exon 3 (c.336_337insC). This variant predicts a frameshift of the transcript, with the introduction of a premature STOP codon in C1-INH protein (p.Ser113LeufsTer20). We report the identification of a novel pathogenic SERPING1 variant in a family with HAE type 1, assisted by the Hereditary Angioedema Database Annotation variant prioritization tool. Our results may contribute to the identification of additional families with the same variant and can further enhance the knowledge about this condition.
2026-02-05 | Recent advances in factor XII(a) inhibitors: an updated patent landscape (2020-present).
Factor XII (FXII) is a liver-derived plasma zymogen that autoactivates on anionic surfaces to FXIIa, which drives the contact blood coagulation pathway, kallikrein-kinin signaling, fibrinolysis, and classical complement. Although congenital FXII(a) deficiency is largely asymptomatic, dysregulated activity is linked to thrombosis, hereditary angioedema (HAE), and neuroinflammation, making FXII(a) an attractive therapeutic target. This review provides a brief overview of FXII/FXIIa structure and function to highlight its suitability as a therapeutic target. It then summarizes patents published between 2020 and 2025 (patent search using Espacenet, Google Patents, and SciFinder) covering FXII(a)-targeting agents across diverse modalities, including small molecules, proteins and peptides, monoclonal antibodies, oligonucleotides, and siRNAs. Patent analysis indicates that most FXII(a) inhibitors remain in early preclinical development, though a growing subset has shown in vivo efficacy in models of thrombosis, HAE, sepsis, and neuroinflammation. The breadth and pace of 2020-2025 filings, together with accumulating translational data, should accelerate progression from patents to clinical candidates, particularly for contact-activation indications (e.g. device-related thrombosis). Resolving full-length FXII/α-FXIIa structures would further enable allosteric inhibitors design.
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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.
2026-08-05 | Diagnostic delay, SERPING1 allelic heterogeneity, and real-world lanadelumab prophylaxis in Chinese patients with hereditary angioedema due to C1 inhibitor deficiency
Background Hereditary angioedema due to C1 inhibitor deficiency (HAE-C1INH) is a rare and potentially life-threatening bradykinin-mediated disorder most commonly associated with pathogenic variants in SERPING1 . Data from Chinese patients remain limited, particularly regarding diagnostic delay, SERPING1 allelic heterogeneity, and real-world use of lanadelumab prophylaxis. Methods In this single-center retrospective observational study, we reviewed 10 consecutive unrelated index patients with confirmed HAE-C1INH managed at Henan Provincial People’s Hospital from January 2022 to May 2026. Clinical data, complement results, and SERPING1 Sanger sequencing findings were analyzed. Variants were classified according to ACMG/AMP criteria. Seven patients received lanadelumab long-term prophylaxis. Annualized attack rates and Angioedema Control Test scores before and during prophylaxis were compared using the Wilcoxon signed-rank test. Results The cohort included 6 females and 4 males, with a mean age of 32.8 ± 9.9 years. Nine patients had HAE-C1INH type 1 and one had type 2. The mean age at symptom onset was 21.7 ± 11.1 years, and the mean diagnostic delay was 9.4 ± 7.0 years. All patients had recurrent peripheral edema, 7 had abdominal attacks, and 6 had facial and/or laryngeal involvement. One patient required emergency tracheotomy. Serum C4 was reduced during attacks in all patients, and C1q levels were normal. Ten distinct heterozygous SERPING1 variants were identified, including 3 frameshift variants, 6 missense variants, and 1 in-frame deletion. Among the 7 patients receiving lanadelumab, the median annualized attack rate decreased from 11 (IQR, 7–23) to 0 (IQR, 0–1) attacks/year, and the median AECT score increased from 3 (IQR, 2–4) to 13 (IQR, 13–13). No serious adverse events were recorded. Conclusions This single-center retrospective study showed substantial diagnostic delay, marked SERPING1 allelic heterogeneity, and favorable real-world outcomes with lanadelumab prophylaxis in Chinese patients with HAE-C1INH. Earlier complement testing and access to appropriate genetic testing may shorten diagnostic delay. Larger prospective studies are needed to define individualized long-term prophylaxis strategies in Chinese patients.
2026-07-01 | Exploratory analysis of genetic variation, clinical activity score, and lanadelumab response in two families with hereditary angioedema due to C1-inhibitor esterase deficiency
Abstract Background : Hereditary angioedema due to C1-inhibitor esterase (C1INH) deficiency is caused by mutations in the SERPING1 gene. The same mutation can cause variable disease severity, highlighting the role of genetic and clinical factors in disease expression. The aim of this study was to evaluate these factors alongside the effectiveness of lanadelumab in two families. Case presentation : Here, we conducted a comparative analysis of affected members from two families including clinical activity scores, C1INH activity levels at diagnosis and genetic mutations. In lanadelumab treated patients, efficacy was evaluated three and 12 months post-initiation, and the two groups were compared. In family 1, eight affected individuals were identified across five generations. A deletion in exon 4 was detected in three of the six living patients. The clinical activity score was ≥5 in all and the C1INH activity level ≤ 40 % in five of them. In the three sisters receiving lanadelumab, the uncontrolled disease became a controlled one. In family 2, 16 affected individuals were identified across four generations, with eight patients followed at our center. A missense mutation in exon 8 was detected in five patients. Un undetectable C1INH activity level and clinical activity scores ≥5 was identified in five patient. In two from the three patients treated with lanadelumab a markedly reduction in attacks frequency weas obtained (from 9 to 2 in both of them) and one patient became symptom-free. Conclusions : The relationship between specific genetic mutations, clinical severity score, and response to prophylactic treatment remains inconclusive.
2026-06-30 | Effectiveness and Safety of Lanadelumab in the Treatment of Patients with Hereditary Angioedema in Routine Clinical Practice in the Russian Federation.
Background: Hereditary angioedema (HAE) caused by C1 inhibitor deficiency is a rare condition marked by recurrent swelling of the skin and mucous membranes. This study evaluated the effectiveness and safety of lanadelumab in routine clinical practice in Russia (IISR-2021-200085). Methods: A prospective cohort of 30 individuals with HAE was observed. Most patients were women (87%), with a mean age of 34 years; Seventeen percent of participants were adolescents. Prior to initiating lanadelumab, 16 patients (53%) had been receiving long-term prophylaxis, which was discontinued once lanadelumab was started. Treatment outcomes were assessed by comparing attack frequency, medication use for acute events, disease control scores, and quality of life before and after lanadelumab therapy. Results: Before treatment, patients reported an average of 8.6 attacks per month. After 6 months of lanadelumab treatment, the mean attack frequency was reduced to 0.5 per month (p < 0.001). Use of acute therapies decreased from 4.73 to 0.43 doses per month (p < 0.001). Disease control improved substantially, and quality-of-life scores improved from 58.2 to 25.3 points (p < 0.001). No significant lanadelumab-related adverse events were observed. Conclusion: In routine clinical practice, lanadelumab proved highly effective in reducing attack rates, enhancing disease control, and improving quality of life in patients with hereditary angioedema. The therapy was well tolerated, with no serious safety concerns identified. These findings reinforce lanadelumab as a reliable long-term prophylactic option for hereditary angioedema management.
2026-06-22 | Hereditary angioedema attack trends among patients maintained on lanadelumab long-term prophylaxis.
Longitudinal studies using real-world data are needed to assess the effectiveness of long-term prophylaxis (LTP) for hereditary angioedema (HAE) during successive years of treatment. This United States-based retrospective analysis assessed the longitudinal effectiveness of lanadelumab LTP on attack rate reduction year on year in lanadelumab-treated patients with HAE. Data were from the Consortium of Independent Immunology Clinic's HAE Patient Registry, a dataset managed by Trio Health. Patients who were treated with lanadelumab between August 2018 and December 2023 and who remained on treatment for at least 6 months were included. Data were collected during routine clinic visits, with the time between clinic visits defined as "follow-up intervals" for outcome assessment. Given data were ascertained from real-world clinical practices, visits did not occur at uniform fixed intervals. Patients were followed for up to 4 visits after lanadelumab initiation. The analysis included 141 patients with HAE due to C1 inhibitor deficiency or dysfunction. The mean ± SD duration on lanadelumab was over 3.5 years (1305 days ± 567). Mean length of follow-up intervals 1 to 4 were 376, 267, 286, and 283 days, respectively. Lanadelumab discontinuation rates were low (range 1.3%-3.1%) across the 4 intervals. The mean ± SD monthly attack rates ranged from 0.21 ± 0.43 (interval 1) to 0.16 ± 0.38 (interval 4) (P = .399 vs interval 1). The percentage of attack-free patients increased from 40% during interval 1 to 53% during interval 4. Patients on lanadelumab for at least 6 months had low discontinuation rates. Attack rates were low, and the proportion of attack-free patients increased across intervals, indicating attack-free status was achievable in the later years on treatment.
other
2026-07-28 | Status of Current Clinical Trials on Therapy for Hereditary Angioedema 2309515
Abstract Introduction Hereditary angioedema (HAE) is a rare autosomal dominant deficiency or dysfunction of C1 esterase inhibitor, resulting in dysregulated kallikrein—bradykinin signaling and potentially life-threatening angioedema. While existing C1-INH products and kallikrein inhibitors have improved disease control, new clinical trials aim to further reduce treatment burden and achieve durable prophylaxis through novel therapeutic strategies. Methods Active and recruiting HAE clinical trials were identified through the trial registry on clinicaltrials.gov. Results A total of twenty-two trials were identified, eleven of which are recruiting as of December 2025, and eleven others that are active but no longer recruiting. The sole drug in phase 4 is CSL312 (Garadacimab), a fully human IgG4 monoclonal antibody targeting activated factor XIIa. Drugs in phase 3 include: NTLA-2002, a single-dose intravenous gene therapy targeting inactivation of the KLKB1 gene; Navenibart, an IgG1 monoclonal antibody inhibiting activated kallikrein; OCTA-C1-INH, a virus-inactivated, nanofiltrated, highly purified concentrate of C1-INH derived from pooled human plasma; ADX-324, an siRNA therapy to reduce hepatic production of prekallikrein (PKK); Donidalorsen, an antisense oligonucleotide targeted against hepatic PKK mRNA; Sebetralstat and berotralstat, both plasma kallikrein inhibitors that reduce production of bradykinin; and deucrictibant, a competitive bradykinin B2 receptor antagonist. Drugs in phase 2 are: BW-20805, another siRNA therapy targeting human hepatic PKK mRNA; and BMN 331, an AAV5-based gene therapy that introduces the SERPING1 gene which encodes wild-type human C1INH protein. Conclusion Advances in gene therapy, biologics, RNA interference therapeutics, and improved replacement strategies hold promise for transforming both rescue and prophylactic management for HAE. Ongoing evaluation of safety, durability of response, and real-world applicability will be critical in defining the future standard of care for HAE. Funding Source n/a Topic Categories Translational and Interventional Immunology (TI)
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.
2026-06-21 | Modeling Hereditary Angioedema With Personalized EPSC-Derived Hepatocytes: A CRISPR-Validated Platform for Mutation-Specific Mechanisms and Therapeutic Innovation.
Hereditary angioedema (HAE) with C1 esterase inhibitor (C1INH) deficiency is caused by pathogenic SERPING1 mutations that disrupt production of the plasma protease inhibitor C1INH. However, the molecular mechanisms and consequences of patient-specific mutations remain poorly understood due to the lack of physiologically relevant human models. Here, we established a personalized, isogenic, stem-cell-derived hepatocyte platform to investigate the underlying mutation-specific mechanisms of HAE. Specifically, peripheral blood mononuclear cell (PBMC)-expanded erythroblasts from four representative HAE-C1INH-Type1 patients containing distinct point, insertion, deletion, or large fragment SERPING1 mutations were reprogrammed into expanded potential stem cells (EPSCs) and further differentiated into hepatocyte-like cells (HLCs). These HLCs exhibited appropriate transcriptional transitions, mature hepatic features, and C1INH secretion comparable to that observed in human plasma. All patient-derived HLCs demonstrated impaired C1INH secretion with mutation-specific differences in both SERPING1 transcription and intracellular accumulation. Moreover, to verify that the mutations directly drive the phenotype, we performed CRISPR/Cas9-mediated genome repair, which restored SERPING1 mRNA expression and C1INH secretion. Conversely, identical patient mutations installed into healthy EPSCs showed the same transcriptional and secretory defects, confirming sufficiency. Collectively, we have established a robust human hepatocyte model that accurately recapitulates key hepatocyte-specific aspects of HAE pathophysiology and provides a scalable foundation for investigation of future precision therapies.
2026-01-01 | Coexistence of Hereditary Angioedema and Homozygous Factor V Leiden Mutation in a 31-Year-Old Patient: A Rare Clinical Overlap.
Abstract Background:Hereditary angioedema (HAE) is a rare autosomal dominant disorder which is caused by deficiency or dysfunction of C1-esterase inhibitor (C1-INH). This leads to dysregulation of the kallikrein–bradykinin pathway which is responsible for recurrent episodes of non-pruritic angioedema seen in these cases. The condition typically manifests as episodic swelling of the skin, gastrointestinal tract or involvement of airway. It is frequently misdiagnosed as allergic angioedema due to overlapping clinical features. Factor V Leiden mutation the most common inherited thrombophilia is caused by a point mutation in the F5 gene that produces resistance to activated protein C and increases the risk of venous thromboembolism. Although both disorders involve dysregulationof plasma protease cascades reports describing their coexistence are exceedingly rare. This case highlights the diagnostic and therapeutic challenges associated with the simultaneous presence of HAE and homozygous Factor V Leiden mutation.Case Report:A 31-year-old woman presented with recurrent episodes of facial and right upper limb edema. This was accompanied by burning sensation, body aches and abdominal cramps. Episodes occurred one to two times per week and resolved spontaneously within two to six hours. The patient, diagnosed case of homozygous Factor V Leiden mutation, had a prior history of recurrent venous thromboembolism including deep venous thrombosis and pulmonary embolism. Physical examination during attacks revealed non-pitting and non-pruritic edema. There was minimal response to antihistamines and bronchodilators. Serum tryptase was normal and autoimmune markers were negative. In addition C1- INH levels were reduced with normal C1q.Complement C4 levels were decreased. These changesconfirmed the diagnosis of hereditary angioedema secondary to C1-INH deficiency. Initial treatment with fresh frozen plasma was started which was subsequently discontinued due to worsening pulmonary arterial hypertension. Therapeutic plasmapheresis was performed which caused marked symptomatic improvement.Conclusion:This is a rare case in whom there was coexistence of hereditary angioedema due to C1-INH deficiency and homozygous Factor V Leiden mutation. This represents a rare clinical overlap involving dysregulation of complement, kallikrein–kinin and coagulation pathways. Recognition of bradykininmediated angioedema in patients with recurrent swelling unresponsive to antihistamines is essential for appropriate management as these patients are less likely to respond to antihistamines, corticosteroids, or epinephrine Keywords: C1-Esterase Inhibitor Deficiency, Factor V Leiden Mutation, Hereditary Angioedema, Plasmapheresis, Venous Thromboembolism
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.
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Drug Discovery Landscape
7 orphan drug designations for Hereditary angioedema with C1Inh deficiency, including 3 approved therapies.
7 orphan drug designations for Hereditary angioedema with C1Inh deficiency, including 3 approved therapies.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Adeno-Associated Viral Vector encoding C1 Esterase Inhibitor | gene therapies | FDA | — | Adverum Biotechnologies, Inc. |
berotralstat [Orladeyo] | small molecules | FDA | Approved | BioCryst Pharmaceuticals, Inc. |
berotralstat [ORLADEYO™] | small molecules | FDA | Approved | BioCryst Pharmaceuticals, Inc. |
Conestat alfa [Ruconest] | proteins | EMA | Pharming Group N.V. | |
recombinant human C1-esterase inhibitor | proteins | FDA | Pharming Group N.V. | |
C1-esterase inhibitor (recombinant) [RUCONEST] | proteins | FDA | Approved | Pharming Group N.V. |
C1 esterase inhibitor (human) | proteins | FDA | Alpha Therapeutic Corporation |
“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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