RARE DISEASE
Hereditary angioedema with normal C1Inh not related to F12 or PLG variant
Hereditary angioedema with normal C1Inh not related to F12 or PLG variant
Hereditary angioedema with normal C1Inh not related to F12 or PLG variant
Drug discovery
0
drugs
With orphan designations
Overview
Hereditary angioedema with normal C1 inhibitor (HAE-nC1INH) unrelated to F12 or PLG variants is a rare bradykinin-mediated disorder characterized by recurrent swelling episodes without urticaria or pruritus. It is autosomal dominant, with normal C1-INH levels/function and unknown genetic drivers in most cases [4][8][17]. Diagnosis requires excluding C1-INH deficiency, medication-induced angioedema, and mast cell-mediated causes [4][6].
Burden
Severe morbidity: 42% report weekly attacks, often involving laryngeal (66%) or abdominal (89%) swelling [7][12].
High healthcare utilization: Delayed diagnosis (≥10 years), frequent ED visits, and unnecessary interventions (69% of cases) [7][11].
Quality-of-life impact: Functional limitations in 78% of patients, with anxiety/depression exacerbating disease cycles [7][11].
Therapies
Acute attacks: Bradykinin B2 receptor antagonists (icatibant) or C1-INH replacement (off-label use) [2][14].
Prophylaxis: Subcutaneous C1-INH (Haegarda®) or antifibrinolytics (tranexamic acid), though evidence is limited [6][14][17].
No targeted therapies exist; management mirrors HAE-C1-INH strategies with variable efficacy [4][10].
Categories: rare allergic disease, rare genetic diseases, rare systemic and rheumatological diseases
Research Papers
76 drug discovery papers about Hereditary angioedema with normal C1Inh not related to F12 or PLG variant, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
76 drug discovery papers about Hereditary angioedema with normal C1Inh not related to F12 or PLG variant, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-22 | Real-World Safety and Effectiveness of Icatibant in Patients With Hereditary Angioedema (HAE): Post-Marketing Surveillance in Japan.
Hereditary angioedema (HAE) is a rare, autosomal dominant, life-threatening disease characterized by recurrent attacks of swelling of the face, upper airway, gastrointestinal tract, limbs, and/or genitalia. Genetic mutations of the SERPING1 gene encoding the C1-inhibitor (C1-INH) plasma protein are associated with HAE-C1INH. HAE is also observed in patients with normal C1-INH (HAE-nC1INH). Icatibant is a selective bradykinin B2 receptor antagonist for treatment of acute attacks of HAE. Here we report safety and effectiveness data from a post-marketing, open-label, multicenter observational study of icatibant conducted in Japan (ClinicalTrials.gov ID: NCT04057131). Patients with HAE in Japan who initiated icatibant between November 2018 and June 2020 were enrolled; surveillance was completed in April 2023. In the Safety Analysis Set (n = 155), most patients were women (n = 116, 74.84%) and HAE types included HAE-C1INH-Type 1 (n = 83, 53.55%), HAE-C1INH-Type 2 (n = 9, 5.81%), unclassified HAE-C1INH (n = 16, 10.32%), and HAE-nC1INH (n = 22, 14.19%). Overall, 19 patients (12.26%) experienced adverse drug reactions (ADRs), most of which were mild in severity (n = 18, 11.61%). The most common ADRs were general disorders and administration site conditions (n = 18, 11.61%). No serious ADRs or ADRs of special interest other than hypersensitivity and injection site reaction were reported. In the Effectiveness Analysis Set (n = 100), 97 patients (97.00%) received 30 mg of icatibant. Among 417 HAE attacks, 234 were treated with icatibant alone and 48 with icatibant plus other. Among attacks treated with icatibant alone, median (interquartile range) time to first symptom relief was 60.0 (30.0-270.0) min, and median time to complete resolution of symptoms was 710.0 (148.5-1440.0) min. In conclusion, in this study of the real-world use of icatibant, no new safety concerns were reported. Icatibant was effective in providing early symptom relief for HAE attacks across a broad spectrum of patients, including patients with HAE-nC1INH, who were not included in previous clinical trials.
2026-08-20 | Diagnostic delay, SERPING1 allelic heterogeneity, and real-world lanadelumab prophylaxis in Chinese patients with hereditary angioedema due to C1 inhibitor deficiency.
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. 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. 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. 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.
2026-06-26 | Clinical experience with berotralstat in patients with hereditary angioedema: an Italian case series from the ITACA cohort.
Background. Recent advancements in hereditary angioedema (HAE) management have focused mainly on long-term prophylaxis (LTP), aiming to achieve total disease control and normalize patients' lives. The latest international guidelines recommend as first-line options for LTP plasma-derived C1-INH, lanadelumab, and berotralstat. Berotralstat is a highly selective inhibitor of plasma kallikrein and the first licensed oral therapy for HAE, to be taken once daily. Given the limited clinical experience with berotralstat in Italy, members of the Italian Network for Hereditary and Acquired Angioedema (ITACA) here present and discuss some representative clinical cases treated with berotralstat in their institutions to provide practical guidance for the use of this medication. Methods. Three main topics were identified, (I) the switch from injectable medications to new oral therapies, with a focus on shared decision-making, (II) the switch from androgens to berotralstat, and (III) the management of comorbid patients, with a focus on polypharmacy. Results. The Italian experience to date indicates that (I) the decision on LTP should be always shared with patients and, given the importance for patients of administration route, berotralstat should always be considered and proposed; (II) an overlap period between androgens and berotralstat, with progressive tapering of androgens, is the more appropriate strategy when planning this shift; (III) potential drug-drug interactions must be evaluated in patients on multiple medications, with berotralstat showing a good safety profile in this perspective. Conclusions. Patient engagement, awareness of androgen risks, transition strategies and drug-interaction evaluation are essential to guide individualized LTP choices.
2026-06-22 | Ex vivo bradykinin as a functional biomarker for angioedema with normal C1-inhibitor.
Bradykinin-mediated angioedema (AE-BK) remains diagnostically challenging particularly in patients with normal C1-inhibitor, where diagnosis primarily relies on clinical criteria. Routine laboratory tests can identify complement deficiency in hereditary angioedema due to C1-inhibitor deficiency (HAE-C1INH) but not directly assess kallikrein-kinin system dysregulation underlying these conditions. We sought to investigate potential associations between BK generation following ex vivo cold activation and clinical phenotypes of AE-BK, with or without C1-inhibitor deficiency. Functional total BK generation ex vivo was quantified using a validated LC-MS/MS assay in cold-activated EDTA blood samples from 181 individuals: 46 with HAE-C1INH, 68 with recurrent angioedema and normal C1-inhibitor clinically suspected to be AE-BK, and 67 controls. A subset of patients in both angioedema groups was receiving long-term prophylaxis with plasma kallikrein inhibitors. Elevated total BK following ex vivo activation was observed in most patients not on long-term prophylaxis (90.3% of HAE-C1INH; 57.4% of suspected AE-BK). Serial measurements demonstrated marked BK increases during acute angioedema episodes and stable levels during remission. Total BK levels correlated with plasma kallikrein activity and were reduced toward the reference range in patients receiving long-term prophylaxis with plasma kallikrein inhibitor therapy in both AE-BK subtypes. The measurement of ex vivo BK generation by LC-MS/MS is associated with clinical features of AE-BK and with pharmacologic inhibition of kallikrein-kinin system. These observations suggest that this assay may have a role in pathophysiology-based patient stratification and treatment monitoring for AE-BK, though further prospective multicenter studies are warranted to clarify its diagnostic performance and clinical utility.
2026-02-22 | Management of pregnancy, delivery and breast-feeding in hereditary angioedema: an analysis of 15 pregnancies with conventional treatment approaches and a case of Lanadelumab use.
BACKGROUND: The course of hereditary angioedema (HAE) during pregnancy varies greatly. Limited treatment options complicate the management of HAE in this period. This study aimed to examine the clinical progression of HAE throughout the perinatal period in relation to management strategies. Additionally, we reported the first documented case of Lanadelumab (Takhzyro) therapy during pregnancy in a patient with HAE. RESULTS: We performed an observational study at the University Hospital Zurich (a tertiary treatment center), in which we included 7 HAE female HAE patients. We analyzed 15 pregnancies of these women. The average maternal age at delivery was 33 years (range: 21–41), and the average gestational age was 40 + 3/7 weeks. Fourteen deliveries were spontaneous, with one requiring vacuum extraction. There were no miscarriages during the study period. Maternal C1-INH levels averaged 0.09 g/l (range: 0.04–0.16), and functional activity averaged 28% (range: 17–42%). Of the 15 newborns, 8 were HAE-positive. Their mean birth weight was 3170 g (±546), compared to 3618 g (±225) in HAE-negative children. No significant complications or adverse outcomes were observed in either group. Attack frequency during pregnancy increased in 4 cases, decreased in 7, and remained unchanged in 4. Most women (60%) received plasma-derived C1-inhibitor (Berinert) for acute management; 27% used it prophylactically during pregnancy. One patient received combination therapy with Lanadelumab/Takhzyro® and Berinert®, showing good tolerability and effectiveness. The pregnancy proceeded without complications and the child was born healthy at term with normal birth weight. CONCLUSIONS: The variable evolution of HAE symptoms during pregnancy highlights the need for flexible and personalized treatment plans. Plasma-derived C1-inhibitor remains the recommended treatment during pregnancy due to its favorable therapeutic and safety profile. The first documented use of Lanadelumab during pregnancy was well tolerated and linked to positive outcomes for both mother and newborn. Although these findings are promising, further research is necessary to confirm the safety and effectiveness of Lanadelumab in this setting.
proteins
2025-12-17 | Treatment of Hereditary Angioedema With Plasma-Derived C1 Inhibitor: A Review.
Hereditary angioedema (HAE) is clinically characterized by recurrent episodes of localized edema. HAE typically occurs due to a deficiency of functional C1 inhibitor (C1INH, HAE-C1INH); in addition, several types of HAE with normal quantity and activity of C1INH (HAE-nC1INH) have recently been classified, which occur due to different gene mutations. C1INH plays an integral role in the kallikrein-kinin system, where a deficiency of functional C1INH results in overproduction of bradykinin leading to subcutaneous and submucosal edema. Plasma-derived C1INH (pdC1INH) replacement therapy for hereditary angioedema has been in use clinically for over 40 years and has been developed for both intravenous and subcutaneous administrations. In this review, we provide an in-depth overview of the efficacy and safety of pdC1INH in clinical trials and real-world studies, and guideline recommendations for pdC1INH replacement therapy as a first-line treatment for on-demand therapy, short-term prophylaxis, and long-term prophylaxis in patients with HAE-C1INH Type 1 and 2, including special patient populations.
2025-11-05 | C1 esterase inhibitor (C1-INH) response as a supportive diagnostic criterion for patients with suspected hereditary angioedema with normal C1-INH.
Diagnosis of hereditary angioedema (HAE) with normal C1INH level (HAE-nl-C1INH) is based on several criteria, including either an associated genetic variant identified or family history of recurrent angioedema plus lack of high-dose antihistamine response. A rapid, durable response to bradykinin-targeted medication is considered supportive, and this study aimed to evaluate the use of recombinant human C1 esterase inhibitor (rhC1-INH) in this regard. A retrospective medical records review was conducted for angioedema/HAE codes. Thirty-one patients with HAE-nl-C1INH were identified (female, 87.1%; mean age, 46.2 years; range, 16-74 years). All patients had experienced recurrent angioedema, with documentation of antihistamine and/or mast cell-targeted therapy ineffectiveness and normal/near-normal laboratory data. Genetic testing (n = 9) found no known pathogenic variants of HAE. Diagnosis of HAE-nl-C1INH was confirmed in the 31 patients via a favorable response after intravenous rhC1-INH (weight-based; maximum, 4200 U) during an angioedema attack. Only 30.0% (9/30) of patients with documented information had been aware of a family history of recurrent angioedema/HAE. In conclusion, reliance on a family history of recurrent angioedema as a diagnostic criterion may delay accurate diagnosis and access to effective treatment. These results support that responsiveness to C1-INH replacement therapy may also be a useful supportive diagnostic criterion for HAE-nl-C1INH.
2024-02-15 | Hereditary Angioedema With a Normal Complement Level.
Hereditary angioedema (HAE) is an uncommon autosomal dominant disorder, characterized by episodes of oropharyngeal, gastrointestinal, and subcutaneous tissue swelling, often accompanied by discomfort. HAE is primarily associated with mutations in the SERPING1 gene, resulting in insufficient levels or impaired function of C1 esterase inhibitor (C1-INH), an important regulatory protein of the complement system. While types 1 and 2 HAE are well-established entities caused by quantitative and qualitative defects in C1-INH, respectively, the emergence of type 3 HAE, also known as estrogen-dependent HAE, has expanded our understanding of this complex disorder. In this case, a 2-year-old girl with Down syndrome visited the ER after experiencing lip and tongue swelling following the ingestion of ground pepper. Her laboratory results showed that her complement levels were within normal limits despite clinical symptoms. This situation leads to the specific variant of hereditary angioedema called hereditary angioedema with a normal C1 esterase inhibitor (HAE-NI-C1-INH). Although there are currently no approved treatments, positive responses have been seen to her use of C1-INH concentrate and tranexamic acid to alleviate both immediate and delayed symptoms.
2023-12-12 | Patient outcomes associated with subcutaneous C1INH prophylaxis for hereditary angioedema: a retrospective analysis.
Real-world data on subcutaneous C1INH (C1INH[SC]) usage and patient-level impacts on hereditary angioedema (HAE)-related outcomes and quality of life (QoL) are both lacking and challenging to generate using conventional study methodologies. Using a hybrid study design involving patient interviews supplemented by retrospective medical chart data review, we conducted a real-world assessment of the impact of C1INH(SC) prophylaxis on HAE attack patterns, QoL, and on-demand medication use. The study was conducted at seven US sites and included 36 adults with HAE who had been treated with C1INH(SC) long-term prophylaxis following ≥ 12 months of on-demand management only. Patients underwent 30-min interviews, facilitated and analyzed by a trained qualitative research specialist. Medical records were reviewed for 12 months before (pre-index) and after (post-index) initiation of C1INH(SC). Using interview data with descriptive terms converted to numerical values, we compared pre- versus post-index attack frequency, severity, and rescue medication usage. Mean (SD) annualized attack frequency per patient decreased 82.0%, from 38.8 (38.8) attacks/year pre-index to 7.0 (15.3) attacks/year (P < 0.001); the median number of attacks decreased by 97.0% (30 pre-index to 1 post-index). For 20 patients, the annualized attack rate after starting C1INH(SC) prophylaxis was ≤ 1 attack/year; 12 of these patients reported 0 attacks. Mean (SD) attack severity (scale: 0 = none/mild to 4 = very severe) decreased from 2.3 (0.7) pre-index to 0.9 (0.9) post-index (P < 0.001). Mean/median rescue medication use decreased by 77.2%/96.3%. Improved QoL was narratively described for many domains. These real-world findings indicate that long-term prophylaxis with C1INH(SC) markedly improves important factors that contribute to the goal of achieving total disease control and normalization of patients' lives, including fewer and less severe attacks, less rescue medication usage, and improved QoL.
2023-11-30 | Plasma-derived C1 esterase inhibitor pharmacokinetics and safety in patients with hereditary angioedema.
Over 40 years of use demonstrates that complement 1 esterase inhibitor (C1-INH) concentrate is effective and well tolerated for acute edema attacks and prophylaxis in patients with hereditary angioedema. OCTA-C1-INH is a new stable, virus-inactivated, nanofiltrated concentrate of C1-INH derived from human plasma. We investigated the pharmacokinetics and safety profile of new C1-INH in people with hereditary angioedema during an attack-free period. In this prospective, multicenter, open-label, single-arm study, adults with hereditary angioedema type I/II received a single intravenous dose of 20 IU/kg C1-INH. Blood samples were taken ≤30 minutes before infusion, and 0, 0.25, 1, 2, 6, 12, 24, 48, 72, 120, 144, and 168 hours after infusion. The primary end point was assessing the pharmacokinetic parameters of C1-INH measured by C1-INH activity. Safety end points were also examined. Twenty patients received a single dose of 20 IU/kg new C1-INH with a mean (standard deviation) total dose of 1457.3 (356.51) IU. Mean (standard deviation) area under the curve normalized by dose was 51.6 (17.9) h∙IU/mL/IU, maximum blood concentration was 1.14 (0.989) IU/mL, incremental recovery was 0.0466 (0.051) (IU∙kg)/(IU∙mL), half-life was 0.598 (0.716) hours, and time to maximum concentration was 0.598 (0.716) hours. No thromboembolic events were recorded. No treatment-emergent adverse events were rated as severe/serious. PK parameters of new C1-INH were in line with those reported for other C1-INH concentrates. New C1-INH demonstrated a favorable safety profile in patients with C1-INH deficiency. Further studies are warranted to determine the effectiveness and longer-term safety of new C1-INH.
oligonucleotides
2021-12-07 | Leveraging Genetics for Hereditary Angioedema: A Road Map to Precision Medicine.
Biochemical studies performed during the last decades resulted in the development of various innovative medicinal products for hereditary angioedema (HAE). These therapeutic agents target the production or the function of bradykinin-the main mediator of HAE due to C1-inhibitor (C1-INH) deficiency. However, despite these remarkable achievements, current knowledge cannot provide convincing explanations for the clinical variability of the disease. As a consequence, treatment indications apply for drugs available for C1-INH deficiency. The advent of high-throughput next-generation sequencing technologies may assist in covering the missing part of our understanding of HAE pathogenesis. During the last 3 years alone, several new entities were added to the already described genotypes. The recent discovery of four novel target genes expands our understanding of other causes which may explain recurrent angioedema in individuals and families with normal C1-INH activity. Furthermore, new genetic technologies allowed the recognition of deep intronic variants associated with the disease, and elegant functional studies characterized new variants for the C1-INH gene. Thus, evidence has been provided regarding pathogenetic aspects remaining obscure for many years, such as the defective intracellular transport of mutant C1-INH, and environmental effect on the disease expression. Therefore, it seems that the stage for Precision Medicine era in HAE management is ready. Disease endotypes are expected to be uncovered and specified targets for therapeutic intervention will be detected, promising a more effective, individualized management of the disease.
2020-09-11 | Study of angiopoietin and plasminogen genes in hereditary angioedema.
To investigate the presence of the Angiopoietin 1 (ANGPT1) and Plasminogen (PLG) mutations in patients with Hereditary Angioedema (HAE) and normal C1 esterase inhibitor (C1-INH) levels, who do not harbor the F12 gene mutation. Patients clinically diagnosed with HAE but without C1-INH deficiency or dysfunction and F12 gene mutation were evaluated. DNA extraction, quantification, and dilution were performed at a concentration of 100 ng/µL, followed by a DNA amplification (PCR) for molecular evaluation of exon 2 of the ANGPT1 gene and exon 9 of the PLG gene for identification of mutations c.807G>T / p.A119S and c.988A>G / p.K330E, respectively. The PCR product was evaluated in 1% agarose gel electrophoresis. Sequencing was performed using the Sanger method. The electropherograms were analyzed using the FASTA® program. DNA samples from 15 women were sequenced. Their ages ranged from 10 to 60 years and the normal C1 esterase and C4 inhibitor serum levels ranged from 22 to 39 mg/dL and from 10 to 40 mg/dL, respectively. No mutations were detected in the analyzed exons of ANGPT1 and PLG. However, a single-nucleotide polymorphism (SNP) was detected in two homozygotic and five heterozygotic patients. Further studies are needed to evaluate these SNPs and scrutinize their potential for use as molecular markers of HAE and as novel therapeutic targets.
1999-01-07 | Regulation of C1 inhibitor synthesis.
The primary biologic roles of C1 inhibitor (C1-INH) are the regulation of activation of the classical complement pathway and of the contact system of kinin formation. Heterozygosity for deficiency or dysfunction of C1-INH results in hereditary angioedema (HAE). This deficiency results in loss of homeostasis with unregulated complement and contact system activation. Due to the consequent C1-INH consumption, plasma levels of C1-INH in patients with HAE are decreased below 50% of normal. In addition, diminished synthesis contributes to the lowered levels in some patients. The hepatocyte is the primary source of C1-INH, although a number of other cell types, including peripheral blood monocytes, microglial cells, fibroblasts, endothelial cells, the placenta, and megakaryocytes also synthesize and secrete the protein both in vivo and in vitro. Interferon-gamma and alpha (IFN), colony stimulating factor-1, interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) all induce C1-INH synthesis in a variety of cell types. The IFN-response elements in the 5'-flanking region and in the first intron have been partially characterized, as have several of the promoter elements that direct basal transcription of the gene. However, although androgen therapy, in vivo, results in an increase in C1-INH plasma levels, a direct effect of androgens on C1-INH synthesis has not been convincingly demonstrated. Although the C1-INH gene contains a potential glucocorticoid/androgen response element, this element does not appear to respond to androgen. Continued analysis of the transcriptional regulation of the C1-INH gene may lead to new approaches to therapy of HAE.
antibodies
2026-03-08 | Open-label phase 1b/2 trial of navenibart, a long-acting plasma kallikrein inhibitor for hereditary angioedema.
Hereditary angioedema (HAE), characterized by unpredictable, painful, recurrent swelling events (HAE attacks), poses a significant health care burden. This phase 1b/2 trial (ALPHA-STAR) assessed the safety, efficacy, pharmacokinetics, pharmacodynamics, and immunogenicity of navenibart, a novel long-acting monoclonal antibody targeting plasma kallikrein. This global, dose-ranging, proof-of-concept trial assigned adults with HAE due to C1 inhibitor deficiency (HAE-C1INH) sequentially to 3 cohorts: 450 mg as a single dose on day 1 (cohort 1); 600 mg on day 1 and 300 mg on day 84 (cohort 2); or 600 mg on days 1 and 28 (cohort 3). Study assessments lasted up to 9 months (6 months after final dose). Primary end points included safety, secondary end points included clinical outcomes, and exploratory end points included quality of life. Twenty-nine participants received navenibart and completed the trial. There were no severe or serious treatment-emergent adverse events, and no treatment-emergent adverse events led to discontinuation. The most common treatment-emergent adverse events were headache, nasopharyngitis, and urinary tract infection. Rapid reductions in HAE attack rates (including moderate and severe attacks) versus baseline were observed in all cohorts. Overall, the mean (standard deviation) time-normalized monthly attack rate was reduced from 2.23 (1.46) at baseline to 0.31 (0.48) after treatment with navenibart. The overall mean (median) reduction in time-normalized monthly attack rate was 86.3% (95.4%) compared with baseline. Participants had improved Angioedema Quality of Life total scores, with a mean decrease ranging 21.0 to 30.3 points. Navenibart was well tolerated and substantially reduced HAE attacks, providing support for every-3-month and every-6-month administration of navenibart to prevent HAE attacks.
2026-01-14 | Patient-reported disease burden and health care utilization of HAE-nl-C1INH: insights from a real-world survey.
Hereditary angioedema (HAE), a rare genetic disorder, is classified into 3 types: Type 1 (low C1 esterase inhibitor [C1-INH]), Type 2 (dysfunctional C1-INH), and HAE-nl-C1INH (normal C1-INH levels). This study aimed to compare characteristics among individuals with HAE Type 1/2 and HAE-nl-C1INH. A cross-sectional online survey was conducted (June 2020-September 2021) among adults with HAE to capture various patient-specific data and health care utilization. Statistical analyses included Fisher exact test, t test, and odds ratios (OR) with 95% confidence intervals (CI). Eighty-nine participants were included (HAE Type 1/2, n = 44; HAE-nl-C1INH, n = 45). No significant differences in demographics, treatment characteristics, and HAE triggers were observed between groups. Participants with HAE-nl-C1INH were less likely to be diagnosed before 18 years of age (4% vs. 32%; OR, 0.10; 95% CI, 0.02-0.50) and had higher odds of experiencing frequent HAE attacks (47% vs. 14%; OR, 5.5; 95% CI, 2.0-15.7) than those with HAE Type 1/2. Participants with HAE-nl-C1INH also had increased odds of orofacial-laryngeal swelling (31% vs. 16%; OR, 2.3; 95% CI, 1.1-4.7), more frequent doctor visits (> 1 visit/month: 31% vs. 11%; OR, 3.5; 95% CI, 1.1-10.8), and more concomitant conditions (93% vs. 77%; OR, 3.8; 95% CI, 1.6-9.2). The total health-related quality of life score was significantly worse in participants with HAE-nl-C1INH (53.6 vs. 38.2; p = 0.0001). Participants with HAE-nl-C1INH experience a significantly greater disease burden than those with HAE Type 1/2, emphasizing the need for improved diagnosis, targeted treatment strategies, and a deeper understanding of the prevalence and pathophysiology of HAE-nl-C1INH.
2025-12-03 | Management of hereditary angioedema with normal C1Inh: a series of 163 French patients.
The diagnosis of hereditary angioedema with a normal C1Inh was genetic. The two most frequent pathogenic variants are found in the FXII and PLG genes. Their management is similar to that of HAE patients with C1Inh deficiency but without evidence-based medicine. The French Reference Centre for Angioedema (CREAK) Our center identified all patients with HAE with a normal C1Inh to evaluate their therapeutic management. This was a national retrospective study conducted in our center the CREAK network. A total of 287 patients were identified with an F12 pathogenic variant (133 families), 38 with PLG (12 families) and one patient with KNG1. Among these patients, 111 patients with HAE-FXII and 19 patients with HAE-PLG were symptomatic. More women than men were symptomatic (86.3% vs. 30.8%, respectively) (p < 0,0001). The mean age at first attack was 24 ± 12 years. 49% of patients with HAE-FXII were estrogen dependent (vs. 0% HAE-PLG, p < 0,01). 91% of patients with HAE-PLG needed to receive at least one attack of icatibant with 100% efficacy. 67% of patients with HAE-FXII were treated at least once: 56% with icatibant and 54% with C1Inh concentrate (during pregnancy). 12,6% of patients with HAE-FXII and 47,4% of patients with HAE-PLG required long-term prophylactic treatment: 66,7% of patients HAE-PLG who were taking tranexamic acid were attack-free (vs. 37,5 3% of HAE-FXII patients). 100% of patients with HAE-FXII treated with lanadelumab were completely asymptomatic (vs. 25% of patients with HAE-PLG). HAE patients with a normal C1inh have specific clinical features, including a later age at first attack than HAE patients with a normal C1inh, high sensitivity to estrogens of HAE-FXII and the location of the HAE-PLG on the tongue. The treatments used for HAE patients with C1Inh deficiency appear to be effective and safe. Low-dose progestin-only pills are good contraceptive options.
2025-09-06 | Insights From the First 820 Patients From the Brazilian Multicenter Registry of Hereditary Angioedema: The Key Role of Genetic Testing and Targeted Therapies.
Hereditary angioedema (HAE) is a rare autosomal dominant disorder with a prevalence of 1:50,000 individuals. Delayed diagnosis and deaths from asphyxia still occur. To identify knowledge and management gaps regarding clinical, genetic, and therapeutic aspects of HAE in Brazil, aiming to improve patient care and outcomes. A Brazilian multicenter HAE registry was established, with patients' data included by treating physicians using the REDCap (Research Electronic Data Capture) platform. Of the 820 patients with HAE enrolled, 68.8% were female. Most (72.4%) experienced HAE due to C1 inhibitor deficiency (HAE-C1INH), whereas 19.4% had HAE with normal C1INH caused by variants in the F12 gene (HAE-FXII). Onset of symptoms occurred earlier in HAE-C1INH as compared with HAE-FXII (mean 11.2 years vs 19.4 years, respectively), and time for diagnosis was shorter in patients younger than 18 years, as compared with those 18 years and older (mean 1.8 years vs 14.5 years, respectively). Regarding treatment, 52.8% received first-line on-demand therapies (icatibant or plasma-derived C1INH [pdC1INH]). Only 4.8% used first-line options for long-term prophylaxis (LTP), such as lanadelumab or subcutaneous/intravenous pdC1INH. Attenuated androgens were used for LTP in 52% of patients, with adverse effects reported for 34.8%. Brazilian patients with HAE share common aspects with global patients, including predominance in women, and HAE-C1INH as the most common subtype. Available genetic testing allowed for identification of a notable proportion of HAE-FXII (19.4% of the patients). Despite recent advances, access to first-line therapies for LTP of HAE attacks remains limited.
2025-08-26 | Expanding the Genetic and Clinical Spectrum of Hereditary Angioedema with Normal C1 Inhibitor: Novel Variants and Treatment Insights.
Hereditary angioedema with normal C1 inhibitor (HAE-nC1-INH) is a rare and genetically heterogeneous disorder with an incomplete molecular understanding. This study aimed to identify novel genetic variants associated with HAE-nC1-INH, characterize their clinical manifestations, and evaluate real-world treatment responses. Whole-exome sequencing of 27 HAE patients, including eight with HAE-nC1-INH, identified four previously unreported MYOF variants and additional pathogenic variants in KNG1 and HS3ST6, expanding the genetic spectrum of the disease. MYOF variants were associated with recurrent edema episodes, often with prolonged duration. The HS3ST6 variant was linked to refractory angioedema with non-resolving lower extremity involvement, highlighting atypical, persistent clinical phenotypes beyond the classical self-limiting presentation of HAE. Lanadelumab effectively reduced attack frequency in most patients; however, the variability in treatment response, particularly in MYOF and HS3ST6 carriers, highlights the need for individualized therapeutic approaches. These findings provide new insights into the genetic and clinical complexity of HAE-nC1-INH and emphasize the importance of genetic testing in refining diagnosis and optimizing treatment strategies, contributing to a more precise understanding of hereditary angioedema.
other
2025-10-17 | Unraveling angioedema: diagnostic challenges and emerging therapies.
Bradykinin-mediated angioedema comprises rare but potentially life-threatening disorders, most notably hereditary angioedema (HAE) due to C1 inhibitor (C1-INH) deficiency or dysfunction. Diagnosis is often difficult, as these conditions can resemble urticaria variants, leading to misdiagnosis and delays in care. Distinguishing features are critical, since bradykinin-mediated forms do not respond to antihistamines or corticosteroids. This review summarizes the differential diagnoses of angioedema, including urticaria variants, cheilitis granulomatosa, and hypocomplementemic urticarial vasculitis, highlighting clinical and diagnostic clues. Particular focus is given to HAE-its subtypes (Type I, Type II, and normal C1-INH), pathophysiology, presentation, and genetic basis. Acquired angioedema and drug-induced forms, such as ACE inhibitor-associated angioedema, are also discussed. The therapeutic landscape is rapidly evolving, spanning acute and prophylactic approaches. Options include C1-INH concentrate, kallikrein inhibitors, bradykinin receptor antagonists, and factor XII inhibitors. While these advances expand treatment opportunities, they also complicate decision-making for patients and physicians. Furthermore, emerging CRISPR-based gene editing therapies represent innovative approaches that pose complex ethical dilemmas, and their long-term safety and efficacy have yet to be established. Although novel therapies reduce attack frequency, their true impact on quality of life is not fully established. Comparative effectiveness data are limited, long-term safety-particularly of gene-based therapies-is unknown, and the real-world utility of new oral on-demand agents for acute therapy is uncertain, especially in severe pharyngeal or laryngeal attacks that may hinder swallowing. Current guidelines remain unclear on the need for short-term prophylaxis in patients already receiving effective long-term prophylactic therapy. In conclusion, despite major therapeutic advances, persistent challenges and unanswered questions underscore the need for pragmatic, patient-centered, long-term studies to optimize care.
2025-09-04 | Status quo and future developments in the diagnosis and treatment of hereditary angioedema.
Hereditary angioedema (HAE) is a rare hereditary disease characterized by edema, which can be life-threatening in case of swelling in the larynx. The most common form of HAE is caused by a mutation of the SERPING1 gene and is characterized by a deficiency (type I) or loss of function (type II) of the C1 inhibitor (C1-INH), leading to excessive production of bradykinin. In contrast, the HAE-nC1-INH entity is associated with a normal C1-INH protein and is caused by mutations in other genes. Because HAE is a rare and often underdiagnosed disease, it may take years from symptom onset to diagnosis. The angioedema attacks cause suffering and affect both the ability to work and quality of life (QoL). The treatment of HAE includes attack treatment (on-demand), short-term prophylaxis (e.g., before medical procedures), and long-term prophylaxis. Four first-line treatment options for long-term prophylaxis are available, effectively preventing attacks and supporting the guideline goal of complete disease control. Further treatment options, including CRISPR/Cas9-based gene therapy, are under development and promise to provide individually tailored treatment for patients. This review aims to provide an overview of the clinical presentation, diagnosis, and treatment of HAE.
2024-07-03 | Normalization of C1 Inhibitor in a Patient with Hereditary Angioedema.
Hereditary angioedema is a potentially life-threatening autosomal dominant condition, causing attacks of angioedema due to failure to regulate bradykinin. Nearly all cases of hereditary angioedema are caused by mutations in the gene encoding C1 inhibitor, SERPING1. C1 inhibitor is a multifunctional protein produced in the liver that regulates the kallikrein-kinin system at multiple points. An infant with genetically confirmed hereditary angioedema and low C1 inhibitor levels (but without previous episodes of angioedema) underwent liver transplantation for biliary atresia, an unrelated condition. Liver transplantation led to normalization of the C1 inhibitor level and function. To our knowledge, this represents the first patient to be potentially cured of hereditary angioedema.
2022-12-06 | Isolated angioedema: A review of classification and update on management.
To review the various types of angioedema including diagnosis and treatment. PubMed search of articles in the English language of various types of angioedema. Articles on the subject matter were selected and reviewed. Herein, a case-based approach is presented for discussing the major types of angioedema, including the following: hereditary angioedema types I and II and normal complement, acquired angioedema, angiotensin-converting enzyme-induced angioedema, and histaminergic and nonhistaminergic angioedema. Emerging treatments of hereditary angioedema including targets of prekallikrein, DNA vector technology replacing C1-INH protein, and CRIPSR technology targeting prekallikrein among many others are explored. In addition, other causes and mimickers of angioedema are briefly reviewed. Finally, a novel algorithm is proposed to help guide the treating physician through the workup and management of patients with suspected idiopathic angioedema unresponsive to conventional therapy with antihistamines. Over the years, many strides have been made in both understanding the pathophysiology of various types of angioedema and expansion of treatment options. It is important for clinicians to be aware of current and emerging treatment options. We provide a novel practical algorithm to guide clinicians in challenging cases of idiopathic angioedema refractory to antihistamines.
small molecules
2026-08-22 | Real-World Safety and Effectiveness of Icatibant in Patients With Hereditary Angioedema (HAE): Post-Marketing Surveillance in Japan.
Hereditary angioedema (HAE) is a rare, autosomal dominant, life-threatening disease characterized by recurrent attacks of swelling of the face, upper airway, gastrointestinal tract, limbs, and/or genitalia. Genetic mutations of the SERPING1 gene encoding the C1-inhibitor (C1-INH) plasma protein are associated with HAE-C1INH. HAE is also observed in patients with normal C1-INH (HAE-nC1INH). Icatibant is a selective bradykinin B2 receptor antagonist for treatment of acute attacks of HAE. Here we report safety and effectiveness data from a post-marketing, open-label, multicenter observational study of icatibant conducted in Japan (ClinicalTrials.gov ID: NCT04057131). Patients with HAE in Japan who initiated icatibant between November 2018 and June 2020 were enrolled; surveillance was completed in April 2023. In the Safety Analysis Set (n = 155), most patients were women (n = 116, 74.84%) and HAE types included HAE-C1INH-Type 1 (n = 83, 53.55%), HAE-C1INH-Type 2 (n = 9, 5.81%), unclassified HAE-C1INH (n = 16, 10.32%), and HAE-nC1INH (n = 22, 14.19%). Overall, 19 patients (12.26%) experienced adverse drug reactions (ADRs), most of which were mild in severity (n = 18, 11.61%). The most common ADRs were general disorders and administration site conditions (n = 18, 11.61%). No serious ADRs or ADRs of special interest other than hypersensitivity and injection site reaction were reported. In the Effectiveness Analysis Set (n = 100), 97 patients (97.00%) received 30 mg of icatibant. Among 417 HAE attacks, 234 were treated with icatibant alone and 48 with icatibant plus other. Among attacks treated with icatibant alone, median (interquartile range) time to first symptom relief was 60.0 (30.0-270.0) min, and median time to complete resolution of symptoms was 710.0 (148.5-1440.0) min. In conclusion, in this study of the real-world use of icatibant, no new safety concerns were reported. Icatibant was effective in providing early symptom relief for HAE attacks across a broad spectrum of patients, including patients with HAE-nC1INH, who were not included in previous clinical trials.
2026-08-20 | Diagnostic delay, SERPING1 allelic heterogeneity, and real-world lanadelumab prophylaxis in Chinese patients with hereditary angioedema due to C1 inhibitor deficiency.
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. 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. 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. 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.
2026-06-26 | Clinical experience with berotralstat in patients with hereditary angioedema: an Italian case series from the ITACA cohort.
Background. Recent advancements in hereditary angioedema (HAE) management have focused mainly on long-term prophylaxis (LTP), aiming to achieve total disease control and normalize patients' lives. The latest international guidelines recommend as first-line options for LTP plasma-derived C1-INH, lanadelumab, and berotralstat. Berotralstat is a highly selective inhibitor of plasma kallikrein and the first licensed oral therapy for HAE, to be taken once daily. Given the limited clinical experience with berotralstat in Italy, members of the Italian Network for Hereditary and Acquired Angioedema (ITACA) here present and discuss some representative clinical cases treated with berotralstat in their institutions to provide practical guidance for the use of this medication. Methods. Three main topics were identified, (I) the switch from injectable medications to new oral therapies, with a focus on shared decision-making, (II) the switch from androgens to berotralstat, and (III) the management of comorbid patients, with a focus on polypharmacy. Results. The Italian experience to date indicates that (I) the decision on LTP should be always shared with patients and, given the importance for patients of administration route, berotralstat should always be considered and proposed; (II) an overlap period between androgens and berotralstat, with progressive tapering of androgens, is the more appropriate strategy when planning this shift; (III) potential drug-drug interactions must be evaluated in patients on multiple medications, with berotralstat showing a good safety profile in this perspective. Conclusions. Patient engagement, awareness of androgen risks, transition strategies and drug-interaction evaluation are essential to guide individualized LTP choices.
2026-06-22 | Ex vivo bradykinin as a functional biomarker for angioedema with normal C1-inhibitor.
Bradykinin-mediated angioedema (AE-BK) remains diagnostically challenging particularly in patients with normal C1-inhibitor, where diagnosis primarily relies on clinical criteria. Routine laboratory tests can identify complement deficiency in hereditary angioedema due to C1-inhibitor deficiency (HAE-C1INH) but not directly assess kallikrein-kinin system dysregulation underlying these conditions. We sought to investigate potential associations between BK generation following ex vivo cold activation and clinical phenotypes of AE-BK, with or without C1-inhibitor deficiency. Functional total BK generation ex vivo was quantified using a validated LC-MS/MS assay in cold-activated EDTA blood samples from 181 individuals: 46 with HAE-C1INH, 68 with recurrent angioedema and normal C1-inhibitor clinically suspected to be AE-BK, and 67 controls. A subset of patients in both angioedema groups was receiving long-term prophylaxis with plasma kallikrein inhibitors. Elevated total BK following ex vivo activation was observed in most patients not on long-term prophylaxis (90.3% of HAE-C1INH; 57.4% of suspected AE-BK). Serial measurements demonstrated marked BK increases during acute angioedema episodes and stable levels during remission. Total BK levels correlated with plasma kallikrein activity and were reduced toward the reference range in patients receiving long-term prophylaxis with plasma kallikrein inhibitor therapy in both AE-BK subtypes. The measurement of ex vivo BK generation by LC-MS/MS is associated with clinical features of AE-BK and with pharmacologic inhibition of kallikrein-kinin system. These observations suggest that this assay may have a role in pathophysiology-based patient stratification and treatment monitoring for AE-BK, though further prospective multicenter studies are warranted to clarify its diagnostic performance and clinical utility.
2026-02-22 | Management of pregnancy, delivery and breast-feeding in hereditary angioedema: an analysis of 15 pregnancies with conventional treatment approaches and a case of Lanadelumab use.
BACKGROUND: The course of hereditary angioedema (HAE) during pregnancy varies greatly. Limited treatment options complicate the management of HAE in this period. This study aimed to examine the clinical progression of HAE throughout the perinatal period in relation to management strategies. Additionally, we reported the first documented case of Lanadelumab (Takhzyro) therapy during pregnancy in a patient with HAE. RESULTS: We performed an observational study at the University Hospital Zurich (a tertiary treatment center), in which we included 7 HAE female HAE patients. We analyzed 15 pregnancies of these women. The average maternal age at delivery was 33 years (range: 21–41), and the average gestational age was 40 + 3/7 weeks. Fourteen deliveries were spontaneous, with one requiring vacuum extraction. There were no miscarriages during the study period. Maternal C1-INH levels averaged 0.09 g/l (range: 0.04–0.16), and functional activity averaged 28% (range: 17–42%). Of the 15 newborns, 8 were HAE-positive. Their mean birth weight was 3170 g (±546), compared to 3618 g (±225) in HAE-negative children. No significant complications or adverse outcomes were observed in either group. Attack frequency during pregnancy increased in 4 cases, decreased in 7, and remained unchanged in 4. Most women (60%) received plasma-derived C1-inhibitor (Berinert) for acute management; 27% used it prophylactically during pregnancy. One patient received combination therapy with Lanadelumab/Takhzyro® and Berinert®, showing good tolerability and effectiveness. The pregnancy proceeded without complications and the child was born healthy at term with normal birth weight. CONCLUSIONS: The variable evolution of HAE symptoms during pregnancy highlights the need for flexible and personalized treatment plans. Plasma-derived C1-inhibitor remains the recommended treatment during pregnancy due to its favorable therapeutic and safety profile. The first documented use of Lanadelumab during pregnancy was well tolerated and linked to positive outcomes for both mother and newborn. Although these findings are promising, further research is necessary to confirm the safety and effectiveness of Lanadelumab in this setting.
proteins
2025-12-17 | Treatment of Hereditary Angioedema With Plasma-Derived C1 Inhibitor: A Review.
Hereditary angioedema (HAE) is clinically characterized by recurrent episodes of localized edema. HAE typically occurs due to a deficiency of functional C1 inhibitor (C1INH, HAE-C1INH); in addition, several types of HAE with normal quantity and activity of C1INH (HAE-nC1INH) have recently been classified, which occur due to different gene mutations. C1INH plays an integral role in the kallikrein-kinin system, where a deficiency of functional C1INH results in overproduction of bradykinin leading to subcutaneous and submucosal edema. Plasma-derived C1INH (pdC1INH) replacement therapy for hereditary angioedema has been in use clinically for over 40 years and has been developed for both intravenous and subcutaneous administrations. In this review, we provide an in-depth overview of the efficacy and safety of pdC1INH in clinical trials and real-world studies, and guideline recommendations for pdC1INH replacement therapy as a first-line treatment for on-demand therapy, short-term prophylaxis, and long-term prophylaxis in patients with HAE-C1INH Type 1 and 2, including special patient populations.
2025-11-05 | C1 esterase inhibitor (C1-INH) response as a supportive diagnostic criterion for patients with suspected hereditary angioedema with normal C1-INH.
Diagnosis of hereditary angioedema (HAE) with normal C1INH level (HAE-nl-C1INH) is based on several criteria, including either an associated genetic variant identified or family history of recurrent angioedema plus lack of high-dose antihistamine response. A rapid, durable response to bradykinin-targeted medication is considered supportive, and this study aimed to evaluate the use of recombinant human C1 esterase inhibitor (rhC1-INH) in this regard. A retrospective medical records review was conducted for angioedema/HAE codes. Thirty-one patients with HAE-nl-C1INH were identified (female, 87.1%; mean age, 46.2 years; range, 16-74 years). All patients had experienced recurrent angioedema, with documentation of antihistamine and/or mast cell-targeted therapy ineffectiveness and normal/near-normal laboratory data. Genetic testing (n = 9) found no known pathogenic variants of HAE. Diagnosis of HAE-nl-C1INH was confirmed in the 31 patients via a favorable response after intravenous rhC1-INH (weight-based; maximum, 4200 U) during an angioedema attack. Only 30.0% (9/30) of patients with documented information had been aware of a family history of recurrent angioedema/HAE. In conclusion, reliance on a family history of recurrent angioedema as a diagnostic criterion may delay accurate diagnosis and access to effective treatment. These results support that responsiveness to C1-INH replacement therapy may also be a useful supportive diagnostic criterion for HAE-nl-C1INH.
2024-02-15 | Hereditary Angioedema With a Normal Complement Level.
Hereditary angioedema (HAE) is an uncommon autosomal dominant disorder, characterized by episodes of oropharyngeal, gastrointestinal, and subcutaneous tissue swelling, often accompanied by discomfort. HAE is primarily associated with mutations in the SERPING1 gene, resulting in insufficient levels or impaired function of C1 esterase inhibitor (C1-INH), an important regulatory protein of the complement system. While types 1 and 2 HAE are well-established entities caused by quantitative and qualitative defects in C1-INH, respectively, the emergence of type 3 HAE, also known as estrogen-dependent HAE, has expanded our understanding of this complex disorder. In this case, a 2-year-old girl with Down syndrome visited the ER after experiencing lip and tongue swelling following the ingestion of ground pepper. Her laboratory results showed that her complement levels were within normal limits despite clinical symptoms. This situation leads to the specific variant of hereditary angioedema called hereditary angioedema with a normal C1 esterase inhibitor (HAE-NI-C1-INH). Although there are currently no approved treatments, positive responses have been seen to her use of C1-INH concentrate and tranexamic acid to alleviate both immediate and delayed symptoms.
2023-12-12 | Patient outcomes associated with subcutaneous C1INH prophylaxis for hereditary angioedema: a retrospective analysis.
Real-world data on subcutaneous C1INH (C1INH[SC]) usage and patient-level impacts on hereditary angioedema (HAE)-related outcomes and quality of life (QoL) are both lacking and challenging to generate using conventional study methodologies. Using a hybrid study design involving patient interviews supplemented by retrospective medical chart data review, we conducted a real-world assessment of the impact of C1INH(SC) prophylaxis on HAE attack patterns, QoL, and on-demand medication use. The study was conducted at seven US sites and included 36 adults with HAE who had been treated with C1INH(SC) long-term prophylaxis following ≥ 12 months of on-demand management only. Patients underwent 30-min interviews, facilitated and analyzed by a trained qualitative research specialist. Medical records were reviewed for 12 months before (pre-index) and after (post-index) initiation of C1INH(SC). Using interview data with descriptive terms converted to numerical values, we compared pre- versus post-index attack frequency, severity, and rescue medication usage. Mean (SD) annualized attack frequency per patient decreased 82.0%, from 38.8 (38.8) attacks/year pre-index to 7.0 (15.3) attacks/year (P < 0.001); the median number of attacks decreased by 97.0% (30 pre-index to 1 post-index). For 20 patients, the annualized attack rate after starting C1INH(SC) prophylaxis was ≤ 1 attack/year; 12 of these patients reported 0 attacks. Mean (SD) attack severity (scale: 0 = none/mild to 4 = very severe) decreased from 2.3 (0.7) pre-index to 0.9 (0.9) post-index (P < 0.001). Mean/median rescue medication use decreased by 77.2%/96.3%. Improved QoL was narratively described for many domains. These real-world findings indicate that long-term prophylaxis with C1INH(SC) markedly improves important factors that contribute to the goal of achieving total disease control and normalization of patients' lives, including fewer and less severe attacks, less rescue medication usage, and improved QoL.
2023-11-30 | Plasma-derived C1 esterase inhibitor pharmacokinetics and safety in patients with hereditary angioedema.
Over 40 years of use demonstrates that complement 1 esterase inhibitor (C1-INH) concentrate is effective and well tolerated for acute edema attacks and prophylaxis in patients with hereditary angioedema. OCTA-C1-INH is a new stable, virus-inactivated, nanofiltrated concentrate of C1-INH derived from human plasma. We investigated the pharmacokinetics and safety profile of new C1-INH in people with hereditary angioedema during an attack-free period. In this prospective, multicenter, open-label, single-arm study, adults with hereditary angioedema type I/II received a single intravenous dose of 20 IU/kg C1-INH. Blood samples were taken ≤30 minutes before infusion, and 0, 0.25, 1, 2, 6, 12, 24, 48, 72, 120, 144, and 168 hours after infusion. The primary end point was assessing the pharmacokinetic parameters of C1-INH measured by C1-INH activity. Safety end points were also examined. Twenty patients received a single dose of 20 IU/kg new C1-INH with a mean (standard deviation) total dose of 1457.3 (356.51) IU. Mean (standard deviation) area under the curve normalized by dose was 51.6 (17.9) h∙IU/mL/IU, maximum blood concentration was 1.14 (0.989) IU/mL, incremental recovery was 0.0466 (0.051) (IU∙kg)/(IU∙mL), half-life was 0.598 (0.716) hours, and time to maximum concentration was 0.598 (0.716) hours. No thromboembolic events were recorded. No treatment-emergent adverse events were rated as severe/serious. PK parameters of new C1-INH were in line with those reported for other C1-INH concentrates. New C1-INH demonstrated a favorable safety profile in patients with C1-INH deficiency. Further studies are warranted to determine the effectiveness and longer-term safety of new C1-INH.
oligonucleotides
2021-12-07 | Leveraging Genetics for Hereditary Angioedema: A Road Map to Precision Medicine.
Biochemical studies performed during the last decades resulted in the development of various innovative medicinal products for hereditary angioedema (HAE). These therapeutic agents target the production or the function of bradykinin-the main mediator of HAE due to C1-inhibitor (C1-INH) deficiency. However, despite these remarkable achievements, current knowledge cannot provide convincing explanations for the clinical variability of the disease. As a consequence, treatment indications apply for drugs available for C1-INH deficiency. The advent of high-throughput next-generation sequencing technologies may assist in covering the missing part of our understanding of HAE pathogenesis. During the last 3 years alone, several new entities were added to the already described genotypes. The recent discovery of four novel target genes expands our understanding of other causes which may explain recurrent angioedema in individuals and families with normal C1-INH activity. Furthermore, new genetic technologies allowed the recognition of deep intronic variants associated with the disease, and elegant functional studies characterized new variants for the C1-INH gene. Thus, evidence has been provided regarding pathogenetic aspects remaining obscure for many years, such as the defective intracellular transport of mutant C1-INH, and environmental effect on the disease expression. Therefore, it seems that the stage for Precision Medicine era in HAE management is ready. Disease endotypes are expected to be uncovered and specified targets for therapeutic intervention will be detected, promising a more effective, individualized management of the disease.
2020-09-11 | Study of angiopoietin and plasminogen genes in hereditary angioedema.
To investigate the presence of the Angiopoietin 1 (ANGPT1) and Plasminogen (PLG) mutations in patients with Hereditary Angioedema (HAE) and normal C1 esterase inhibitor (C1-INH) levels, who do not harbor the F12 gene mutation. Patients clinically diagnosed with HAE but without C1-INH deficiency or dysfunction and F12 gene mutation were evaluated. DNA extraction, quantification, and dilution were performed at a concentration of 100 ng/µL, followed by a DNA amplification (PCR) for molecular evaluation of exon 2 of the ANGPT1 gene and exon 9 of the PLG gene for identification of mutations c.807G>T / p.A119S and c.988A>G / p.K330E, respectively. The PCR product was evaluated in 1% agarose gel electrophoresis. Sequencing was performed using the Sanger method. The electropherograms were analyzed using the FASTA® program. DNA samples from 15 women were sequenced. Their ages ranged from 10 to 60 years and the normal C1 esterase and C4 inhibitor serum levels ranged from 22 to 39 mg/dL and from 10 to 40 mg/dL, respectively. No mutations were detected in the analyzed exons of ANGPT1 and PLG. However, a single-nucleotide polymorphism (SNP) was detected in two homozygotic and five heterozygotic patients. Further studies are needed to evaluate these SNPs and scrutinize their potential for use as molecular markers of HAE and as novel therapeutic targets.
1999-01-07 | Regulation of C1 inhibitor synthesis.
The primary biologic roles of C1 inhibitor (C1-INH) are the regulation of activation of the classical complement pathway and of the contact system of kinin formation. Heterozygosity for deficiency or dysfunction of C1-INH results in hereditary angioedema (HAE). This deficiency results in loss of homeostasis with unregulated complement and contact system activation. Due to the consequent C1-INH consumption, plasma levels of C1-INH in patients with HAE are decreased below 50% of normal. In addition, diminished synthesis contributes to the lowered levels in some patients. The hepatocyte is the primary source of C1-INH, although a number of other cell types, including peripheral blood monocytes, microglial cells, fibroblasts, endothelial cells, the placenta, and megakaryocytes also synthesize and secrete the protein both in vivo and in vitro. Interferon-gamma and alpha (IFN), colony stimulating factor-1, interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) all induce C1-INH synthesis in a variety of cell types. The IFN-response elements in the 5'-flanking region and in the first intron have been partially characterized, as have several of the promoter elements that direct basal transcription of the gene. However, although androgen therapy, in vivo, results in an increase in C1-INH plasma levels, a direct effect of androgens on C1-INH synthesis has not been convincingly demonstrated. Although the C1-INH gene contains a potential glucocorticoid/androgen response element, this element does not appear to respond to androgen. Continued analysis of the transcriptional regulation of the C1-INH gene may lead to new approaches to therapy of HAE.
antibodies
2026-03-08 | Open-label phase 1b/2 trial of navenibart, a long-acting plasma kallikrein inhibitor for hereditary angioedema.
Hereditary angioedema (HAE), characterized by unpredictable, painful, recurrent swelling events (HAE attacks), poses a significant health care burden. This phase 1b/2 trial (ALPHA-STAR) assessed the safety, efficacy, pharmacokinetics, pharmacodynamics, and immunogenicity of navenibart, a novel long-acting monoclonal antibody targeting plasma kallikrein. This global, dose-ranging, proof-of-concept trial assigned adults with HAE due to C1 inhibitor deficiency (HAE-C1INH) sequentially to 3 cohorts: 450 mg as a single dose on day 1 (cohort 1); 600 mg on day 1 and 300 mg on day 84 (cohort 2); or 600 mg on days 1 and 28 (cohort 3). Study assessments lasted up to 9 months (6 months after final dose). Primary end points included safety, secondary end points included clinical outcomes, and exploratory end points included quality of life. Twenty-nine participants received navenibart and completed the trial. There were no severe or serious treatment-emergent adverse events, and no treatment-emergent adverse events led to discontinuation. The most common treatment-emergent adverse events were headache, nasopharyngitis, and urinary tract infection. Rapid reductions in HAE attack rates (including moderate and severe attacks) versus baseline were observed in all cohorts. Overall, the mean (standard deviation) time-normalized monthly attack rate was reduced from 2.23 (1.46) at baseline to 0.31 (0.48) after treatment with navenibart. The overall mean (median) reduction in time-normalized monthly attack rate was 86.3% (95.4%) compared with baseline. Participants had improved Angioedema Quality of Life total scores, with a mean decrease ranging 21.0 to 30.3 points. Navenibart was well tolerated and substantially reduced HAE attacks, providing support for every-3-month and every-6-month administration of navenibart to prevent HAE attacks.
2026-01-14 | Patient-reported disease burden and health care utilization of HAE-nl-C1INH: insights from a real-world survey.
Hereditary angioedema (HAE), a rare genetic disorder, is classified into 3 types: Type 1 (low C1 esterase inhibitor [C1-INH]), Type 2 (dysfunctional C1-INH), and HAE-nl-C1INH (normal C1-INH levels). This study aimed to compare characteristics among individuals with HAE Type 1/2 and HAE-nl-C1INH. A cross-sectional online survey was conducted (June 2020-September 2021) among adults with HAE to capture various patient-specific data and health care utilization. Statistical analyses included Fisher exact test, t test, and odds ratios (OR) with 95% confidence intervals (CI). Eighty-nine participants were included (HAE Type 1/2, n = 44; HAE-nl-C1INH, n = 45). No significant differences in demographics, treatment characteristics, and HAE triggers were observed between groups. Participants with HAE-nl-C1INH were less likely to be diagnosed before 18 years of age (4% vs. 32%; OR, 0.10; 95% CI, 0.02-0.50) and had higher odds of experiencing frequent HAE attacks (47% vs. 14%; OR, 5.5; 95% CI, 2.0-15.7) than those with HAE Type 1/2. Participants with HAE-nl-C1INH also had increased odds of orofacial-laryngeal swelling (31% vs. 16%; OR, 2.3; 95% CI, 1.1-4.7), more frequent doctor visits (> 1 visit/month: 31% vs. 11%; OR, 3.5; 95% CI, 1.1-10.8), and more concomitant conditions (93% vs. 77%; OR, 3.8; 95% CI, 1.6-9.2). The total health-related quality of life score was significantly worse in participants with HAE-nl-C1INH (53.6 vs. 38.2; p = 0.0001). Participants with HAE-nl-C1INH experience a significantly greater disease burden than those with HAE Type 1/2, emphasizing the need for improved diagnosis, targeted treatment strategies, and a deeper understanding of the prevalence and pathophysiology of HAE-nl-C1INH.
2025-12-03 | Management of hereditary angioedema with normal C1Inh: a series of 163 French patients.
The diagnosis of hereditary angioedema with a normal C1Inh was genetic. The two most frequent pathogenic variants are found in the FXII and PLG genes. Their management is similar to that of HAE patients with C1Inh deficiency but without evidence-based medicine. The French Reference Centre for Angioedema (CREAK) Our center identified all patients with HAE with a normal C1Inh to evaluate their therapeutic management. This was a national retrospective study conducted in our center the CREAK network. A total of 287 patients were identified with an F12 pathogenic variant (133 families), 38 with PLG (12 families) and one patient with KNG1. Among these patients, 111 patients with HAE-FXII and 19 patients with HAE-PLG were symptomatic. More women than men were symptomatic (86.3% vs. 30.8%, respectively) (p < 0,0001). The mean age at first attack was 24 ± 12 years. 49% of patients with HAE-FXII were estrogen dependent (vs. 0% HAE-PLG, p < 0,01). 91% of patients with HAE-PLG needed to receive at least one attack of icatibant with 100% efficacy. 67% of patients with HAE-FXII were treated at least once: 56% with icatibant and 54% with C1Inh concentrate (during pregnancy). 12,6% of patients with HAE-FXII and 47,4% of patients with HAE-PLG required long-term prophylactic treatment: 66,7% of patients HAE-PLG who were taking tranexamic acid were attack-free (vs. 37,5 3% of HAE-FXII patients). 100% of patients with HAE-FXII treated with lanadelumab were completely asymptomatic (vs. 25% of patients with HAE-PLG). HAE patients with a normal C1inh have specific clinical features, including a later age at first attack than HAE patients with a normal C1inh, high sensitivity to estrogens of HAE-FXII and the location of the HAE-PLG on the tongue. The treatments used for HAE patients with C1Inh deficiency appear to be effective and safe. Low-dose progestin-only pills are good contraceptive options.
2025-09-06 | Insights From the First 820 Patients From the Brazilian Multicenter Registry of Hereditary Angioedema: The Key Role of Genetic Testing and Targeted Therapies.
Hereditary angioedema (HAE) is a rare autosomal dominant disorder with a prevalence of 1:50,000 individuals. Delayed diagnosis and deaths from asphyxia still occur. To identify knowledge and management gaps regarding clinical, genetic, and therapeutic aspects of HAE in Brazil, aiming to improve patient care and outcomes. A Brazilian multicenter HAE registry was established, with patients' data included by treating physicians using the REDCap (Research Electronic Data Capture) platform. Of the 820 patients with HAE enrolled, 68.8% were female. Most (72.4%) experienced HAE due to C1 inhibitor deficiency (HAE-C1INH), whereas 19.4% had HAE with normal C1INH caused by variants in the F12 gene (HAE-FXII). Onset of symptoms occurred earlier in HAE-C1INH as compared with HAE-FXII (mean 11.2 years vs 19.4 years, respectively), and time for diagnosis was shorter in patients younger than 18 years, as compared with those 18 years and older (mean 1.8 years vs 14.5 years, respectively). Regarding treatment, 52.8% received first-line on-demand therapies (icatibant or plasma-derived C1INH [pdC1INH]). Only 4.8% used first-line options for long-term prophylaxis (LTP), such as lanadelumab or subcutaneous/intravenous pdC1INH. Attenuated androgens were used for LTP in 52% of patients, with adverse effects reported for 34.8%. Brazilian patients with HAE share common aspects with global patients, including predominance in women, and HAE-C1INH as the most common subtype. Available genetic testing allowed for identification of a notable proportion of HAE-FXII (19.4% of the patients). Despite recent advances, access to first-line therapies for LTP of HAE attacks remains limited.
2025-08-26 | Expanding the Genetic and Clinical Spectrum of Hereditary Angioedema with Normal C1 Inhibitor: Novel Variants and Treatment Insights.
Hereditary angioedema with normal C1 inhibitor (HAE-nC1-INH) is a rare and genetically heterogeneous disorder with an incomplete molecular understanding. This study aimed to identify novel genetic variants associated with HAE-nC1-INH, characterize their clinical manifestations, and evaluate real-world treatment responses. Whole-exome sequencing of 27 HAE patients, including eight with HAE-nC1-INH, identified four previously unreported MYOF variants and additional pathogenic variants in KNG1 and HS3ST6, expanding the genetic spectrum of the disease. MYOF variants were associated with recurrent edema episodes, often with prolonged duration. The HS3ST6 variant was linked to refractory angioedema with non-resolving lower extremity involvement, highlighting atypical, persistent clinical phenotypes beyond the classical self-limiting presentation of HAE. Lanadelumab effectively reduced attack frequency in most patients; however, the variability in treatment response, particularly in MYOF and HS3ST6 carriers, highlights the need for individualized therapeutic approaches. These findings provide new insights into the genetic and clinical complexity of HAE-nC1-INH and emphasize the importance of genetic testing in refining diagnosis and optimizing treatment strategies, contributing to a more precise understanding of hereditary angioedema.
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2025-10-17 | Unraveling angioedema: diagnostic challenges and emerging therapies.
Bradykinin-mediated angioedema comprises rare but potentially life-threatening disorders, most notably hereditary angioedema (HAE) due to C1 inhibitor (C1-INH) deficiency or dysfunction. Diagnosis is often difficult, as these conditions can resemble urticaria variants, leading to misdiagnosis and delays in care. Distinguishing features are critical, since bradykinin-mediated forms do not respond to antihistamines or corticosteroids. This review summarizes the differential diagnoses of angioedema, including urticaria variants, cheilitis granulomatosa, and hypocomplementemic urticarial vasculitis, highlighting clinical and diagnostic clues. Particular focus is given to HAE-its subtypes (Type I, Type II, and normal C1-INH), pathophysiology, presentation, and genetic basis. Acquired angioedema and drug-induced forms, such as ACE inhibitor-associated angioedema, are also discussed. The therapeutic landscape is rapidly evolving, spanning acute and prophylactic approaches. Options include C1-INH concentrate, kallikrein inhibitors, bradykinin receptor antagonists, and factor XII inhibitors. While these advances expand treatment opportunities, they also complicate decision-making for patients and physicians. Furthermore, emerging CRISPR-based gene editing therapies represent innovative approaches that pose complex ethical dilemmas, and their long-term safety and efficacy have yet to be established. Although novel therapies reduce attack frequency, their true impact on quality of life is not fully established. Comparative effectiveness data are limited, long-term safety-particularly of gene-based therapies-is unknown, and the real-world utility of new oral on-demand agents for acute therapy is uncertain, especially in severe pharyngeal or laryngeal attacks that may hinder swallowing. Current guidelines remain unclear on the need for short-term prophylaxis in patients already receiving effective long-term prophylactic therapy. In conclusion, despite major therapeutic advances, persistent challenges and unanswered questions underscore the need for pragmatic, patient-centered, long-term studies to optimize care.
2025-09-04 | Status quo and future developments in the diagnosis and treatment of hereditary angioedema.
Hereditary angioedema (HAE) is a rare hereditary disease characterized by edema, which can be life-threatening in case of swelling in the larynx. The most common form of HAE is caused by a mutation of the SERPING1 gene and is characterized by a deficiency (type I) or loss of function (type II) of the C1 inhibitor (C1-INH), leading to excessive production of bradykinin. In contrast, the HAE-nC1-INH entity is associated with a normal C1-INH protein and is caused by mutations in other genes. Because HAE is a rare and often underdiagnosed disease, it may take years from symptom onset to diagnosis. The angioedema attacks cause suffering and affect both the ability to work and quality of life (QoL). The treatment of HAE includes attack treatment (on-demand), short-term prophylaxis (e.g., before medical procedures), and long-term prophylaxis. Four first-line treatment options for long-term prophylaxis are available, effectively preventing attacks and supporting the guideline goal of complete disease control. Further treatment options, including CRISPR/Cas9-based gene therapy, are under development and promise to provide individually tailored treatment for patients. This review aims to provide an overview of the clinical presentation, diagnosis, and treatment of HAE.
2024-07-03 | Normalization of C1 Inhibitor in a Patient with Hereditary Angioedema.
Hereditary angioedema is a potentially life-threatening autosomal dominant condition, causing attacks of angioedema due to failure to regulate bradykinin. Nearly all cases of hereditary angioedema are caused by mutations in the gene encoding C1 inhibitor, SERPING1. C1 inhibitor is a multifunctional protein produced in the liver that regulates the kallikrein-kinin system at multiple points. An infant with genetically confirmed hereditary angioedema and low C1 inhibitor levels (but without previous episodes of angioedema) underwent liver transplantation for biliary atresia, an unrelated condition. Liver transplantation led to normalization of the C1 inhibitor level and function. To our knowledge, this represents the first patient to be potentially cured of hereditary angioedema.
2022-12-06 | Isolated angioedema: A review of classification and update on management.
To review the various types of angioedema including diagnosis and treatment. PubMed search of articles in the English language of various types of angioedema. Articles on the subject matter were selected and reviewed. Herein, a case-based approach is presented for discussing the major types of angioedema, including the following: hereditary angioedema types I and II and normal complement, acquired angioedema, angiotensin-converting enzyme-induced angioedema, and histaminergic and nonhistaminergic angioedema. Emerging treatments of hereditary angioedema including targets of prekallikrein, DNA vector technology replacing C1-INH protein, and CRIPSR technology targeting prekallikrein among many others are explored. In addition, other causes and mimickers of angioedema are briefly reviewed. Finally, a novel algorithm is proposed to help guide the treating physician through the workup and management of patients with suspected idiopathic angioedema unresponsive to conventional therapy with antihistamines. Over the years, many strides have been made in both understanding the pathophysiology of various types of angioedema and expansion of treatment options. It is important for clinicians to be aware of current and emerging treatment options. We provide a novel practical algorithm to guide clinicians in challenging cases of idiopathic angioedema refractory to antihistamines.
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