RARE DISEASE
Non-histaminic angioedema
Non-histaminic angioedema
Non-histaminic angioedema
Synonyms: Angioneurotic edema, Bradykinine-induced angioedema, Non histamine-induced angioedema
Synonyms: Angioneurotic edema, Bradykinine-induced angioedema, Non histamine-induced angioedema
Synonyms: Angioneurotic edema, Bradykinine-induced angioedema, Non histamine-induced angioedema
Drug discovery
1
drug
With orphan designation
Overview
Non-histaminic angioedema is a bradykinin-mediated disorder characterized by recurrent subcutaneous/submucosal edema involving the face, extremities, gastrointestinal tract, or airways. It includes hereditary forms (C1 inhibitor deficiency Types I/II, FXII mutation Type III) and acquired variants, distinguished by non-pruritic swelling unresponsive to antihistamines/corticosteroids. Laryngeal edema carries a 25% mortality risk if untreated [1][4][6].
Burden
Mortality: Up to 25% risk of fatal laryngeal edema without timely intervention [1][4].
Healthcare utilization: Frequent ED visits (80,000–112,000 annually in the U.S.) and hospitalizations for abdominal crises or airway obstruction [2][19].
Quality of life: Chronic disability from unpredictable attacks, with diagnostic delays averaging 8–16 years [19][14].
Therapies
Acute attacks: C1 inhibitor concentrates (e.g., Berinert®), icatibant (bradykinin B2 receptor antagonist), or fresh frozen plasma [1][8][12].
Prophylaxis: Tranexamic acid, danazol, or lanadelumab (kallikrein inhibitor) [1][3][8].
Avoid triggers: ACE inhibitors, NSAIDs, estrogen therapies, and procedural stress [2][7].
Categories: rare allergic disease, rare systemic and rheumatological diseases
Research Papers
995 drug discovery papers about Non-histaminic angioedema, with 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
995 drug discovery papers about Non-histaminic angioedema, with 1 next-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-18 | Prekallikrein: the catalytic crossroads of inflammation and thrombosis.
The contact activation pathway, historically considered dispensable for hemostasis, has re-emerged as a critical mediator of thromboinflammation. Plasma prekallikrein, through its activation to kallikrein, links coagulation, inflammation, and vascular biology. This review is timely given increasing interest in targeting the contact system to develop safer antithrombotic therapies that minimize bleeding risk. Emerging preclinical and translational studies demonstrate that prekallikrein contributes to thrombosis, inflammation, and endothelial dysfunction, despite minimal involvement in baseline hemostasis. Animal models reveal context-dependent roles of prekallikrein in arterial and venous thrombosis, while human data confirm that prekallikrein deficiency is not associated with bleeding. Clinical success of prekallikrein inhibition in hereditary angioedema validates the therapeutic relevance of the kallikrein-kinin system. Early-phase studies and related work targeting contact pathway components, particularly factor XI, further support this pathway as a viable antithrombotic target. Collectively, current evidence positions prekallikrein as a promising therapeutic target that may allow selective inhibition of thromboinflammatory processes without impairing hemostasis. Further clinical investigation is needed to define the efficacy and safety of prekallikrein-directed therapies in thrombosis and other inflammatory conditions.
2026-08-15 | Berotralstat Tolerability and Effectiveness in Hereditary Angioedema: Berolife Study Results.
Berotralstat is a first-line once-daily oral prophylactic treatment for hereditary angioedema (HAE). Berolife was designed to evaluate the tolerability and effectiveness of berotralstat in real-world conditions. Berolife is an open-label, multicenter, observational study conducted in France from September 2021 to January 2024. The primary objective was to assess tolerability, and secondary objectives included characterization of the treated population and assessment of berotralstat effectiveness. HAE attack rate was assessed before and after initiation of berotralstat using the paired Wilcoxon rank-sum test. Altogether, 80 patients were enrolled in the study (75 with HAE-C1INH type 1 or 2 and 5 with HAE-nC1INH) and received at least one dose of berotralstat. At baseline, patients had a mean (standard deviation [SD]) age of 40.0 (17.5) years, and most (67.5%) had received prior long-term prophylaxis treatment. The mean (SD) duration of berotralstat treatment was 11.5 (8.5) months. Treatment-related adverse events (AEs) occurred in 45.0% of patients, with gastrointestinal disorders being the most common (diarrhea: 13.8%, abdominal pain: 12.5%, upper abdominal pain: 7.5%). Importantly, no treatment-related serious AEs were reported. A total of 61 patients were treated with berotralstat for ≥ 6 months and evaluated for effectiveness. At 6 months of treatment, a significant reduction in monthly HAE attack rates was observed (mean [SD]: 0.62 [0.66] vs. mean [SD]: 1.25 [1.10] at baseline; p = 0.001). Berotralstat was generally well tolerated with a tolerability profile consistent with prior clinical trials. Significant reductions in monthly HAE attack rates were observed, confirming its effectiveness in real-world settings.
2026-08-04 | [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.
2026-07-12 | Sebetralstat for breakthrough attacks in patients with hereditary angioedema receiving long-term prophylaxis in KONFIDENT-S.
Although long-term prophylaxis (LTP) reduces attack frequency in hereditary angioedema, patients may experience breakthrough attacks. Oral sebetralstat demonstrated favorable safety and efficacy compared with placebo in the randomized phase 3 KONFIDENT trial (NCT05259917), including in patients receiving LTP. The safety and effectiveness of sebetralstat in participants receiving LTP are being assessed in the KONFIDENT-S open-label extension study (NCT05505916). This interim analysis of the KONFIDENT-S study evaluated long-term safety and effectiveness of oral sebetralstat 600 mg for attacks of hereditary angioedema with C1-inhibitor deficiency in participants receiving LTP with lanadelumab, berotralstat, or C1 inhibitor. Efficacy end points included times to beginning of symptom relief, reduction in severity, and complete attack resolution. As of September 14, 2024, 35 participants receiving LTP experienced a mean ± standard deviation of 1.7 ± 1.5 attacks per month and treated 382 attacks with sebetralstat (1.3 ± 1.1 sebetralstat-treated attacks per month). Median (interquartile range) time from attack recognition to sebetralstat administration was 6 (1-40) minutes; time to beginning of symptom relief was 1.3 (0.8 to 3.8) hours, time to reduction in severity was 4.2 (1.3 to >12) hours, and time to complete attack resolution was 14.8 (4.6 to >24) hours. Effectiveness was similar for participants receiving berotralstat, lanadelumab, or C1 inhibitor. No serious or severe treatment-related treatment-emergent adverse events were reported. Sebetralstat was well tolerated and enabled early on-demand treatment of attacks in patients with hereditary angioedema with C1-inhibitor deficiency receiving LTP. Treatment of breakthrough attacks with sebetralstat resulted in rapid symptom relief, reduction in attack severity, and complete attack resolution, regardless of LTP mechanism of action.
2026-07-07 | Isolated angioedema in the emergency department: rarely an allergic reaction.
Angioedema is a common, potentially life-threatening emergency characterized by swelling of subcutaneous or submucosal tissues. While allergic reactions are common, a substantial proportion of ED angioedema presentations, particularly those without urticaria, involve non-allergic, bradykinin-mediated mechanisms. Differentiating between these pathways is critical, as standard anaphylaxis treatments like epinephrine are often ineffective for non-allergic variants. A key clinical indicator is the presence or absence of urticaria; isolated angioedema is rarely an allergy and suggests a bradykinin-driven aetiology. Common non-allergic causes include ACE inhibitors, DPP-IV (dipeptidyl peptidase IV) inhibitors, neprilysin inhibitors and C1-esterase inhibitor deficiencies. Mislabelling these conditions as "allergies" can lead to inappropriate management, unnecessary intubations, and significant patient distress. Diagnostic tools such as serum tryptase, C4 levels, and C1-inhibitor function tests are essential for accurate classification, but the results are not available at the acute moment. Effective treatment requires a targeted approach based on the underlying mechanism, including antihistamines for histamine-mediated reactions and on-demand therapies for bradykinin-mediated hereditary angioedema, such as C1-esterase inhibitor concentrate, icatibant, and the recently approved oral kallikrein inhibitor sebetralstat. This article provides a clinical framework to help emergency physicians identify the correct underlying mechanism. Ultimately, accurate diagnosis facilitates appropriate specialist referral and improves long-term patient outcomes.
proteins
2026-06-17 | Endothelial barrier disorder in hereditary angioedema: molecular mechanisms and therapeutic implications.
Hereditary angioedema (HAE) is a rare genetic disorder characterized by recurrent episodes of vascular leakage and tissue swelling. Although excessive bradykinin generation has long been considered the central pathogenic mechanism, increasing evidence indicates that endothelial cells play a decisive role in determining when and where vascular permeability occurs. This Review summarizes recent advances in endothelial biology relevant to HAE, highlighting how intercellular junctions, the endothelial glycocalyx, and dynamic endothelial activation states cooperatively regulate barrier integrity. Newly identified HAE subtypes caused by pathogenic variants that directly affect endothelial regulatory pathways further support endothelial dysfunction as a key disease mechanism beyond bradykinin excess. By integrating bradykinin-dependent and bradykinin-independent processes within an endothelial-centered framework, this Review proposes a revised conceptual model for HAE pathogenesis and discusses its implications for biomarker discovery and therapeutic strategies aimed at stabilizing the endothelial barrier.
2026-03-16 | Aesthetic interventions in patients with allergic skin diseases: Risk assessment and evidence-based preventive risk management.
The use of aesthetic dermatologic procedures in patients with underlying allergic and inflammatory skin diseases is on the rise, but specific safety considerations are often overlooked. Individuals with hypersensitivity to injectables, chronic inducible urticaria, allergic contact dermatitis, atopic dermatitis, or hereditary angioedema may face an increased risk of adverse reactions triggered by mechanical trauma, injected substances, or disruption of the skin barrier. Adverse reactions to local anesthetics are predominantly non-IgE-mediated. Thus, preventive strategies should focus on selecting the appropriate agents and employing proper injection techniques rather than routine pharmacologic prophylaxis. Botulinum toxin, hyaluronic acid fillers, and hyaluronidase can rarely cause immediate or delayed hypersensitivity reactions. This highlights the need for individualized risk assessment and avoidance of reexposure in confirmed cases. For patients with chronic inducible urticaria, aesthetic procedures can act as physical triggers. Ensuring optimal disease control with preprocedural antihistamines may help reduce this risk. In cases of allergic contact dermatitis and atopic dermatitis, a compromised skin barrier and exposure to device-related allergens may heighten the chances of developing eczematous or infectious complications. Patients with hereditary angioedema require short-term prophylaxis, preferably utilizing C1-inhibitor therapy. With careful evaluation and tailored preventive strategies, aesthetic dermatologic procedures can be performed safely in patients with allergic and inflammatory skin conditions.
2026-02-26 | Angioedema reported with tissue plasminogen activators: A need to communicate on bradykinin- and histamine-mediated mechanisms.
Angioedema (AE) is a potentially life-threatening adverse effect. The mechanism can be either bradykinin- (BK-AE) or histamine-mediated (Hi-AE), each requiring different management. AE are reported with recombinant tissue plasminogen activators (alteplase and tenecteplase), for which an immunoallergic or bradykinic mechanism is suggested. The aim of this study was to describe the characteristics of cases of AE (BK or Hi) reported with rt-PA to the French Regional Pharmacovigilance Centers in order to optimize their identification and management. All cases of AE reported with alteplase or tenecteplase until 30 November, 2023 were analyzed and classified as Hi-AE or BK-AE using the clinical manifestations, the management and the allergological workup. We analyzed 151 cases of AE, with a median time to onset of 1h (IQR=1-2h), all localized at the head. From them, 150 were with alteplase use for acute ischemic stroke (98%) or myocardial infarction (2%), and 1 with tenecteplase. Of them 107 (71%) could be clearly categorized and were classified as 98 (92%) cases of BK-AE and 9 (8%) cases of Hi-AE. When the use of icatibant or C1 esterase inhibitor is specified, it was the 1st-line treatment for 32/47 (68%) patients. The majority of cases of AE reported with rt-PA, are BK-AE involving alteplase. This is consistent with the effects of rt-PA, which activates the kinin pathway by hydrolyzing plasminogen to plasmin, resulting in the formation of bradykinin. Clinicians need to be informed of this mechanism, in order to early prescribe the appropriate treatment, as we detect that it was not systematically used as 1st-line therapy for a lot of cases.
2026-01-11 | Bradykinin reduces wound healing in human umbilical vein endothelial cells via downregulation of vascular endothelial growth factor A.
INTRODUCTION: Hereditary angioedema (HAE) is characterized by acute swelling attacks triggered by abnormally elevated levels of bradykinin. Despite persistently high bradykinin levels, patients experience only intermittent swelling episodes. Many HAE patients, however, report triggers such as trauma preceding angioedema attacks. This suggests the involvement of additional factors, such as mechanical damage to the endothelium. Bradykinin-mediated impairment of wound healing may contribute to swelling development—a concept known as the “second hit” hypothesis. Vascular endothelial growth factors (VEGF) and their receptors play a critical role in endothelial wound healing and have also been implicated in bradykinin-mediated angioedema. This study investigates the influence of bradykinin on endothelial wound healing, with a particular focus on VEGF. MATERIALS AND METHODS: Human umbilical vein endothelial cells were incubated with bradykinin and VEGF. Gene and protein expression were analyzed by real-time polymerase chain reaction, western blotting, and immunocytochemistry. Barrier function was assessed by measuring transendothelial electrical resistance, as well as apparent and water permeability. Proliferation rates were determined using resazurin assays and real-time cell analysis. Cell migration was assessed using invasion and migration assays, and the combined effects were evaluated using scratch assays. RESULTS: Bradykinin treatment led to reduced expression of the VEGFA isoform and its receptor VEGFR-2. VEGFA alone had no effect on bradykinin-induced barrier disruption. However, bradykinin significantly decreased endothelial proliferation and migration, resulting in impaired wound healing. This effect was counteracted by the addition of VEGFA. CONCLUSIONS: VEGFA and its receptor VEGFR-2 are key regulators of endothelial wound healing. Bradykinin impairs wound healing by reducing proliferation and migration, likely through downregulation of VEGFA and VEGFR-2. These findings support the hypothesis that bradykinin-mediated impairment of wound healing may contribute to the episodic nature of swelling attacks in patients with bradykinin-mediated angioedema, in line with the second hit hypothesis.
2025-12-18 | Therapeutic Potential of C1-Inhibitor in Vascular Diseases and Beyond.
C1INH (C1-inhibitor) is a multifunctional SERPIN (serine protease inhibitor) that functions as a major negative regulator of the complement, coagulation, and kallikrein-kinin systems. C1INH products were originally developed for the treatment of hereditary angioedema associated with C1INH deficiency. A growing body of literature indicates that C1INH products may find utility in the management of several other disease states. In this review, we detail the key biological activities of C1INH and consider the pathophysiological role of C1INH targets in many conditions. The therapeutic potential of exogenous C1INH is highlighted in the settings of thromboembolism, ischemia-reperfusion injury, sepsis, transplantation, and coronavirus disease 2019.
antibodies
2026-09-18 | Isolated gastrointestinal hereditary angioedema associated with a pathogenic SERPING1 variant arising de novo: a case report.
Hereditary angioedema (HAE) is a rare genetic disorder typically characterized by cutaneous and submucosal edema. Cases presenting exclusively with gastrointestinal symptoms, devoid of concurrent or historical cutaneous or upper airway manifestations, are uncommon. This atypical presentation poses a considerable diagnostic challenge and often leads to a marked delay in diagnosis, particularly in patients without a family history. We report the case of a 28-year-old female with an over 6-year history of recurrent, self-limiting abdominal pain. During a severe attack, abdominal computed tomography angiography (CTA) revealed jejunal wall edema and ascites, accompanied by a dramatic surge in D-dimer (>20.00 mg/L FEU) and fibrin degradation products (FDP >120.00 mg/L), closely mimicking mesenteric ischemia. However, a retrospective review of medical history identified the persistent consumption of complement C4 (0.03-0.05 g/L). Subsequent testing showed a functional C1 esterase inhibitor (fC1-INH) level of <7.0% and a C1 esterase inhibitor (C1-INH) antigen level of 6.81 μg/mL, confirming type 1 HAE. Whole-exome sequencing (WES) identified the nonsense variant NM_000062.3:c.990C>A, p.(Tyr330Ter), in SERPING1. The variant was not detected in either biological parent, supporting a de novo origin. Under the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) framework, it was classified as pathogenic on the basis of PVS1 and PS2. An abdominal attack in May 2025 resolved rapidly after icatibant administration. Long-term prophylaxis (LTP) with lanadelumab was subsequently initiated following an individualized shared decision-making process. No breakthrough attacks or treatment related adverse events occurred from June 2025 through June 2026. This report highlights that HAE should be considered in patients with recurrent, unexplained, self-limiting abdominal pain, and C4 should be included in the initial evaluation. A negative family history does not exclude HAE.
2026-08-08 | 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.
2026-07-11 | Garadacimab and the future of hereditary angioedema prophylaxis: a step upstream in the bradykinin pathway.
Hereditary angioedema (HAE) is a rare autosomal dominant disorder characterized by recurrent, potentially life-threatening episodes of bradykinin-mediated angioedema affecting the skin, gastrointestinal tract, and upper airway. Despite the availability of several prophylactic therapies, there is a need for effective and convenient treatment options. On 21 June 2024, the U.S. Food and Drug Administration approved Andembry™ (garadacimab-gxii), a first-in-class monoclonal antibody that inhibits activated Factor XII (FXIIa), for prophylaxis of HAE attacks in patients aged ≥12 years. By targeting FXIIa, garadacimab acts upstream in the kallikrein-kinin pathway, suppressing bradykinin generation and preventing vascular permeability associated with angioedema. Clinical trials demonstrated substantial reductions in attack frequency, with the phase 3 VANGUARD study reporting a 91.5% reduction in HAE attacks and that approximately 77% of patients remain attack-free during the study period. Garadacimab is administered as a 200-mg subcutaneous injection once monthly and has a favorable pharmacokinetic profile with an elimination half-life of approximately 18-20 days. Adverse events were generally mild, including headache, nasopharyngitis, and injection-site reactions. The approval of garadacimab represents an important advancement in HAE prophylaxis, offering a novel upstream mechanism, convenient dosing, and potential improvement in quality of life of the patients.
2026-06-09 | Lanadelumab in Hereditary Angioedema: Extending Dose Intervals from Every 2 Weeks to Every 4 Weeks.
Both clinical trial and real-world data demonstrate the effectiveness of lanadelumab long-term prophylaxis (LTP) to prevent hereditary angioedema (HAE) attacks, which may be maintained after dose interval extension from every 2 weeks (Q2W) to every 4 weeks (Q4W) in patients with well-controlled disease (attack free for >6 months). This narrative review summarizes published data on lanadelumab treatment patterns collected from clinical trials and observational studies since US approval in 2018. Disease activity and HAE-related healthcare resource use at baseline and during the first 6 months of lanadelumab treatment may be useful indicators of patients with well-controlled disease who will be eligible for, and may derive benefit from, dose interval extension on lanadelumab. Patients who receive a dose interval extension could benefit from a reduction in treatment burden, but not all patients may be a good fit for interval extension. Although there are inherent limitations related to analyzing small sample sizes for subgroups of patients with a rare disease and for data derived from real-world studies, these data can inform physicians and patients about the characteristics and outcomes of patients who have successfully extended dosing intervals of lanadelumab LTP. This may in turn encourage regular monitoring to facilitate optimization of treatment and outcomes for each patient.
2026-06-08 | Acquired angioedema due to C1 inhibitor deficiency: real-world clinical characteristics and treatment outcomes.
Acquired angioedema due to C1 inhibitor deficiency (AAE-C1INH) is a rare bradykinin-mediated condition that may mimic hereditary angioedema (HAE). Management is largely extrapolated from HAE data. Therefore, retrospective observations in AAE-C1INH are particularly valuable for informing future approaches. This study aimed to evaluate the clinical characteristics, underlying conditions, and treatment outcomes of patients with AAE-C1INH. We conducted a retrospective cohort study of adult patients diagnosed with AAE-C1INH, with a comprehensive review of demographic and clinical features. Among 587 patients with recurrent angioedema, 1.7% had AAE-C1INH. Median onset age was 56.5 years (45.5-66.75), median follow-up was 60.5 months (23.25-66.5), and 20% were female. Clonal hematologic neoplasms were present in 60% of patients and monoclonal gammopathy of undetermined significance in 30%, with angioedema preceding the diagnosis of the underlying condition in 60% of cases. Long-term prophylaxis was required in 50% of patients. Antifibrinolytic agents showed limited efficacy, whereas attenuated androgens were associated with a marked reduction in attack frequency. Rituximab-based therapy effectively controlled angioedema, although relapse occurred during extended follow-up. Complete remission under Bruton's tyrosine kinase (BTK) inhibition was observed despite persistently low complement levels; however, concurrent withdrawal of renin-angiotensin system blockers represents a potential confounder. Complement levels were observed to parallel treatment response in most patients, whereas this association was not observed in the patient receiving a BTK inhibitor. In this rare, well-characterized cohort with extended follow-up, angioedema frequently represented the earliest clinical manifestation of AAE-C1INH, preceding recognition of the underlying disorder. Antifibrinolytic prophylaxis showed limited benefit, whereas attenuated androgens were associated with reduced attack frequency. Furthermore, therapies targeting the underlying lymphoproliferative condition, including rituximab-based regimens and BTK inhibition, were associated with meaningful clinical benefit. These findings support an individualized, etiology-driven management approach and provide practical insights for clinicians managing this rare condition.
gene therapies
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.
2026-03-11 | CRISPR in Medicine: A Systematic Review of Clinical Trials and Therapeutic Applications.
Clustered Regularly Interspaced Short Palindromic Repeats-CRISPR associated protein 9 (CRISPR/Cas9) technology has become a revolutionary tool in medicine, offering substantial potential for treating a wide range of diseases, including hematological disorders, cancers, genetic conditions, and ophthalmological diseases. This systematic review evaluates the efficacy, safety, and applicability of CRISPR/Cas9 in clinical trials. A comprehensive search of the PubMed, Scopus, Web of Science, and Cochrane databases was conducted. All studies, up to November 2024, meeting the eligibility criteria assessing the application of CRISPR for the treatment of diseases were included. A quality assessment of the included studies was conducted using the Cochrane risk of bias tool. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement for systematic reviews and meta-analyses was followed, and a total of 17 studies were included. This systematic review of CRISPR/Cas9 technology focused on its effectiveness and safety across various diseases. In nonmalignant hematological disorders, CRISPR successfully treated β-thalassemia and sickle cell disease, resulting in high transfusion independence and the elimination of disease crises. In malignant hematological disorders, B-cell acute lymphoblastic leukemia, CRISPR-engineered chimeric antigen receptor T (CAR-T) cells achieved an 83.3% complete remission rate. Furthermore, CRISPR-based CAR-T cells showed promising results in B-cell non-Hodgkin's lymphoma. In oncology, lung cancer and other solid tumors are among the diseases that have been safely engineered using CRISPR gene editing technology. For genetic disorders, CRISPR improved vision in retinal degeneration and reduced symptoms in hereditary angioedema and transthyretin amyloidosis with mild side effects. The results demonstrated CRISPR's potential across a wide range of conditions. In conclusion, the findings underscore the potential role of CRISPR/Cas9 technology across a wide range of diseases. However, challenges remain, including optimizing delivery systems, minimizing off-target effects, addressing immunogenicity concerns, and ethical considerations.
2025-12-11 | CRISPR-Cas9 gene editing for hereditary angioedema: current treatments and emerging therapies.
Hereditary angioedema (HAE) is a rare autosomal dominant disorder marked by episodic, non-urticarial swelling due to C1 esterase inhibitor (C1-INH) deficiency or dysfunction, leading to excessive bradykinin-mediated vascular permeability. While current treatments focus on symptomatic control using C1-INH replacement or kallikrein inhibitors, they require frequent administration and do not address the underlying genetic defect. CRISPR-Cas9 gene-editing technologies, particularly the investigational therapy NTLA-2002, offer a transformative approach by targeting the KLKB1 gene to durably reduce plasma kallikrein levels. This narrative review summarizes the pathophysiology and conventional treatments of HAE, and highlights emerging clinical evidence supporting the safety and efficacy of NTLA-2002. Preliminary trials demonstrate substantial reductions in HAE attack frequency and plasma kallikrein, with minimal adverse events. However, concerns about long-term safety, off-target effects, ethical implications, and accessibility remain. CRISPR-based therapeutics such as NTLA-2002 represent a paradigm shift in the management of HAE and underscore the broader potential of in vivo gene editing for genetic disorders.
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.
other
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.
2026-03-14 | 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.
2026-02-02 | Population Pharmacokinetic/Pharmacodynamic Modeling of Donidalorsen, an Antisense Oligonucleotide in Development for Prophylaxis of Hereditary Angioedema.
Hereditary angioedema (HAE) is a rare disorder linked to kallikrein-kinin system dysregulation, which leads to uncontrolled activation of plasma prekallikrein. Donidalorsen is an antisense oligonucleotide designed to selectively degrade prekallikrein messenger RNA and thereby reduce prekallikrein production. We aimed to develop population pharmacokinetic and pharmacokinetic/pharmacodynamic models of donidalorsen and evaluate the impact of potential intrinsic/extrinsic covariates on exposure and prekallikrein response. Plasma donidalorsen and prekallikrein data were obtained from phase 1 to 3 studies in healthy volunteers (NCT03263507, 721744-CS9) and adult and adolescent patients with HAE (NCT04030598, NCT05139810). The evaluated doses were 20, 40, 60, and 80 mg every 4 weeks (Q4W) and 80 mg every 8 weeks (Q8W), administered subcutaneously over 13-21 weeks. Donidalorsen pharmacokinetics were well described by a linear 2-compartment model with first-order absorption. The population terminal elimination half-life was 31.4 days. Prekallikrein was well described by an indirect response model with inhibition of prekallikrein production by donidalorsen. Covariate analysis identified body weight as the main factor affecting pharmacokinetic exposure; however, this effect was not considered clinically significant. The developed population pharmacokinetic/pharmacodynamic model well characterized the donidalorsen exposure-prekallikrein response relationship. Modeling analyses support that no dose adjustment is needed with respect to intrinsic/extrinsic factors in adults and adolescents with HAE. The nearly identical simulated pharmacokinetic or prekallikrein time courses for Q4W versus monthly dosing and for Q8W versus every-2-month dosing regimens support switching to more convenient regimens for patients.
2025-11-10 | Exposure-Response Analysis of Donidalorsen for the Treatment of Hereditary Angioedema.
Hereditary angioedema (HAE) is characterized by recurrent attacks of severe tissue swelling. In the OASIS-HAE phase 3 study (NCT05139810), donidalorsen, an RNA-targeted antisense oligonucleotide that reduces prekallikrein production in the liver, significantly reduced HAE attack rates. To characterize the relationship between prekallikrein concentrations and HAE attack rates following donidalorsen and predict the efficacy of potential dosing regimens, an exposure-response model was developed using data from OASIS-HAE. Simulations were conducted to evaluate the following regimens: 80 mg once every 4 weeks (Q4W), 8 weeks (Q8W), 1 month (Q1M), and 2 months (Q2M), and a switch to Q2M dosing for patients who were attack-free for 3 months on the Q1M regimen. The relationship between prekallikrein concentrations and HAE attack rates was well characterized by a sigmoidal Emax (maximum effect) model with baseline attack rate and baseline prekallikrein concentration included as covariates. The average prekallikrein concentration estimated to result in a 90% reduction in attack rate (EC10) was 47.1 mg/L. Predicted percent reductions in attack rates at steady state were similar for Q4W (84.1%) vs. Q1M (82.9%) and Q8W (72.6%) vs. Q2M (70.2%) dosing. Predicted reductions in attack rate remained similar and clinically meaningful in patients who switched from Q1M to Q2M dosing (94.0% in month 1 and 91.3% in month 2 of the 2-month dosing interval at steady state). Overall, exposure-response analyses supported the efficacy of Q1M and Q2M dosing and indicated that switching to Q2M dosing could be a viable approach for patients who are attack-free on the Q1M regimen.
small molecules
2026-09-18 | Prekallikrein: the catalytic crossroads of inflammation and thrombosis.
The contact activation pathway, historically considered dispensable for hemostasis, has re-emerged as a critical mediator of thromboinflammation. Plasma prekallikrein, through its activation to kallikrein, links coagulation, inflammation, and vascular biology. This review is timely given increasing interest in targeting the contact system to develop safer antithrombotic therapies that minimize bleeding risk. Emerging preclinical and translational studies demonstrate that prekallikrein contributes to thrombosis, inflammation, and endothelial dysfunction, despite minimal involvement in baseline hemostasis. Animal models reveal context-dependent roles of prekallikrein in arterial and venous thrombosis, while human data confirm that prekallikrein deficiency is not associated with bleeding. Clinical success of prekallikrein inhibition in hereditary angioedema validates the therapeutic relevance of the kallikrein-kinin system. Early-phase studies and related work targeting contact pathway components, particularly factor XI, further support this pathway as a viable antithrombotic target. Collectively, current evidence positions prekallikrein as a promising therapeutic target that may allow selective inhibition of thromboinflammatory processes without impairing hemostasis. Further clinical investigation is needed to define the efficacy and safety of prekallikrein-directed therapies in thrombosis and other inflammatory conditions.
2026-08-15 | Berotralstat Tolerability and Effectiveness in Hereditary Angioedema: Berolife Study Results.
Berotralstat is a first-line once-daily oral prophylactic treatment for hereditary angioedema (HAE). Berolife was designed to evaluate the tolerability and effectiveness of berotralstat in real-world conditions. Berolife is an open-label, multicenter, observational study conducted in France from September 2021 to January 2024. The primary objective was to assess tolerability, and secondary objectives included characterization of the treated population and assessment of berotralstat effectiveness. HAE attack rate was assessed before and after initiation of berotralstat using the paired Wilcoxon rank-sum test. Altogether, 80 patients were enrolled in the study (75 with HAE-C1INH type 1 or 2 and 5 with HAE-nC1INH) and received at least one dose of berotralstat. At baseline, patients had a mean (standard deviation [SD]) age of 40.0 (17.5) years, and most (67.5%) had received prior long-term prophylaxis treatment. The mean (SD) duration of berotralstat treatment was 11.5 (8.5) months. Treatment-related adverse events (AEs) occurred in 45.0% of patients, with gastrointestinal disorders being the most common (diarrhea: 13.8%, abdominal pain: 12.5%, upper abdominal pain: 7.5%). Importantly, no treatment-related serious AEs were reported. A total of 61 patients were treated with berotralstat for ≥ 6 months and evaluated for effectiveness. At 6 months of treatment, a significant reduction in monthly HAE attack rates was observed (mean [SD]: 0.62 [0.66] vs. mean [SD]: 1.25 [1.10] at baseline; p = 0.001). Berotralstat was generally well tolerated with a tolerability profile consistent with prior clinical trials. Significant reductions in monthly HAE attack rates were observed, confirming its effectiveness in real-world settings.
2026-08-04 | [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.
2026-07-12 | Sebetralstat for breakthrough attacks in patients with hereditary angioedema receiving long-term prophylaxis in KONFIDENT-S.
Although long-term prophylaxis (LTP) reduces attack frequency in hereditary angioedema, patients may experience breakthrough attacks. Oral sebetralstat demonstrated favorable safety and efficacy compared with placebo in the randomized phase 3 KONFIDENT trial (NCT05259917), including in patients receiving LTP. The safety and effectiveness of sebetralstat in participants receiving LTP are being assessed in the KONFIDENT-S open-label extension study (NCT05505916). This interim analysis of the KONFIDENT-S study evaluated long-term safety and effectiveness of oral sebetralstat 600 mg for attacks of hereditary angioedema with C1-inhibitor deficiency in participants receiving LTP with lanadelumab, berotralstat, or C1 inhibitor. Efficacy end points included times to beginning of symptom relief, reduction in severity, and complete attack resolution. As of September 14, 2024, 35 participants receiving LTP experienced a mean ± standard deviation of 1.7 ± 1.5 attacks per month and treated 382 attacks with sebetralstat (1.3 ± 1.1 sebetralstat-treated attacks per month). Median (interquartile range) time from attack recognition to sebetralstat administration was 6 (1-40) minutes; time to beginning of symptom relief was 1.3 (0.8 to 3.8) hours, time to reduction in severity was 4.2 (1.3 to >12) hours, and time to complete attack resolution was 14.8 (4.6 to >24) hours. Effectiveness was similar for participants receiving berotralstat, lanadelumab, or C1 inhibitor. No serious or severe treatment-related treatment-emergent adverse events were reported. Sebetralstat was well tolerated and enabled early on-demand treatment of attacks in patients with hereditary angioedema with C1-inhibitor deficiency receiving LTP. Treatment of breakthrough attacks with sebetralstat resulted in rapid symptom relief, reduction in attack severity, and complete attack resolution, regardless of LTP mechanism of action.
2026-07-07 | Isolated angioedema in the emergency department: rarely an allergic reaction.
Angioedema is a common, potentially life-threatening emergency characterized by swelling of subcutaneous or submucosal tissues. While allergic reactions are common, a substantial proportion of ED angioedema presentations, particularly those without urticaria, involve non-allergic, bradykinin-mediated mechanisms. Differentiating between these pathways is critical, as standard anaphylaxis treatments like epinephrine are often ineffective for non-allergic variants. A key clinical indicator is the presence or absence of urticaria; isolated angioedema is rarely an allergy and suggests a bradykinin-driven aetiology. Common non-allergic causes include ACE inhibitors, DPP-IV (dipeptidyl peptidase IV) inhibitors, neprilysin inhibitors and C1-esterase inhibitor deficiencies. Mislabelling these conditions as "allergies" can lead to inappropriate management, unnecessary intubations, and significant patient distress. Diagnostic tools such as serum tryptase, C4 levels, and C1-inhibitor function tests are essential for accurate classification, but the results are not available at the acute moment. Effective treatment requires a targeted approach based on the underlying mechanism, including antihistamines for histamine-mediated reactions and on-demand therapies for bradykinin-mediated hereditary angioedema, such as C1-esterase inhibitor concentrate, icatibant, and the recently approved oral kallikrein inhibitor sebetralstat. This article provides a clinical framework to help emergency physicians identify the correct underlying mechanism. Ultimately, accurate diagnosis facilitates appropriate specialist referral and improves long-term patient outcomes.
proteins
2026-06-17 | Endothelial barrier disorder in hereditary angioedema: molecular mechanisms and therapeutic implications.
Hereditary angioedema (HAE) is a rare genetic disorder characterized by recurrent episodes of vascular leakage and tissue swelling. Although excessive bradykinin generation has long been considered the central pathogenic mechanism, increasing evidence indicates that endothelial cells play a decisive role in determining when and where vascular permeability occurs. This Review summarizes recent advances in endothelial biology relevant to HAE, highlighting how intercellular junctions, the endothelial glycocalyx, and dynamic endothelial activation states cooperatively regulate barrier integrity. Newly identified HAE subtypes caused by pathogenic variants that directly affect endothelial regulatory pathways further support endothelial dysfunction as a key disease mechanism beyond bradykinin excess. By integrating bradykinin-dependent and bradykinin-independent processes within an endothelial-centered framework, this Review proposes a revised conceptual model for HAE pathogenesis and discusses its implications for biomarker discovery and therapeutic strategies aimed at stabilizing the endothelial barrier.
2026-03-16 | Aesthetic interventions in patients with allergic skin diseases: Risk assessment and evidence-based preventive risk management.
The use of aesthetic dermatologic procedures in patients with underlying allergic and inflammatory skin diseases is on the rise, but specific safety considerations are often overlooked. Individuals with hypersensitivity to injectables, chronic inducible urticaria, allergic contact dermatitis, atopic dermatitis, or hereditary angioedema may face an increased risk of adverse reactions triggered by mechanical trauma, injected substances, or disruption of the skin barrier. Adverse reactions to local anesthetics are predominantly non-IgE-mediated. Thus, preventive strategies should focus on selecting the appropriate agents and employing proper injection techniques rather than routine pharmacologic prophylaxis. Botulinum toxin, hyaluronic acid fillers, and hyaluronidase can rarely cause immediate or delayed hypersensitivity reactions. This highlights the need for individualized risk assessment and avoidance of reexposure in confirmed cases. For patients with chronic inducible urticaria, aesthetic procedures can act as physical triggers. Ensuring optimal disease control with preprocedural antihistamines may help reduce this risk. In cases of allergic contact dermatitis and atopic dermatitis, a compromised skin barrier and exposure to device-related allergens may heighten the chances of developing eczematous or infectious complications. Patients with hereditary angioedema require short-term prophylaxis, preferably utilizing C1-inhibitor therapy. With careful evaluation and tailored preventive strategies, aesthetic dermatologic procedures can be performed safely in patients with allergic and inflammatory skin conditions.
2026-02-26 | Angioedema reported with tissue plasminogen activators: A need to communicate on bradykinin- and histamine-mediated mechanisms.
Angioedema (AE) is a potentially life-threatening adverse effect. The mechanism can be either bradykinin- (BK-AE) or histamine-mediated (Hi-AE), each requiring different management. AE are reported with recombinant tissue plasminogen activators (alteplase and tenecteplase), for which an immunoallergic or bradykinic mechanism is suggested. The aim of this study was to describe the characteristics of cases of AE (BK or Hi) reported with rt-PA to the French Regional Pharmacovigilance Centers in order to optimize their identification and management. All cases of AE reported with alteplase or tenecteplase until 30 November, 2023 were analyzed and classified as Hi-AE or BK-AE using the clinical manifestations, the management and the allergological workup. We analyzed 151 cases of AE, with a median time to onset of 1h (IQR=1-2h), all localized at the head. From them, 150 were with alteplase use for acute ischemic stroke (98%) or myocardial infarction (2%), and 1 with tenecteplase. Of them 107 (71%) could be clearly categorized and were classified as 98 (92%) cases of BK-AE and 9 (8%) cases of Hi-AE. When the use of icatibant or C1 esterase inhibitor is specified, it was the 1st-line treatment for 32/47 (68%) patients. The majority of cases of AE reported with rt-PA, are BK-AE involving alteplase. This is consistent with the effects of rt-PA, which activates the kinin pathway by hydrolyzing plasminogen to plasmin, resulting in the formation of bradykinin. Clinicians need to be informed of this mechanism, in order to early prescribe the appropriate treatment, as we detect that it was not systematically used as 1st-line therapy for a lot of cases.
2026-01-11 | Bradykinin reduces wound healing in human umbilical vein endothelial cells via downregulation of vascular endothelial growth factor A.
INTRODUCTION: Hereditary angioedema (HAE) is characterized by acute swelling attacks triggered by abnormally elevated levels of bradykinin. Despite persistently high bradykinin levels, patients experience only intermittent swelling episodes. Many HAE patients, however, report triggers such as trauma preceding angioedema attacks. This suggests the involvement of additional factors, such as mechanical damage to the endothelium. Bradykinin-mediated impairment of wound healing may contribute to swelling development—a concept known as the “second hit” hypothesis. Vascular endothelial growth factors (VEGF) and their receptors play a critical role in endothelial wound healing and have also been implicated in bradykinin-mediated angioedema. This study investigates the influence of bradykinin on endothelial wound healing, with a particular focus on VEGF. MATERIALS AND METHODS: Human umbilical vein endothelial cells were incubated with bradykinin and VEGF. Gene and protein expression were analyzed by real-time polymerase chain reaction, western blotting, and immunocytochemistry. Barrier function was assessed by measuring transendothelial electrical resistance, as well as apparent and water permeability. Proliferation rates were determined using resazurin assays and real-time cell analysis. Cell migration was assessed using invasion and migration assays, and the combined effects were evaluated using scratch assays. RESULTS: Bradykinin treatment led to reduced expression of the VEGFA isoform and its receptor VEGFR-2. VEGFA alone had no effect on bradykinin-induced barrier disruption. However, bradykinin significantly decreased endothelial proliferation and migration, resulting in impaired wound healing. This effect was counteracted by the addition of VEGFA. CONCLUSIONS: VEGFA and its receptor VEGFR-2 are key regulators of endothelial wound healing. Bradykinin impairs wound healing by reducing proliferation and migration, likely through downregulation of VEGFA and VEGFR-2. These findings support the hypothesis that bradykinin-mediated impairment of wound healing may contribute to the episodic nature of swelling attacks in patients with bradykinin-mediated angioedema, in line with the second hit hypothesis.
2025-12-18 | Therapeutic Potential of C1-Inhibitor in Vascular Diseases and Beyond.
C1INH (C1-inhibitor) is a multifunctional SERPIN (serine protease inhibitor) that functions as a major negative regulator of the complement, coagulation, and kallikrein-kinin systems. C1INH products were originally developed for the treatment of hereditary angioedema associated with C1INH deficiency. A growing body of literature indicates that C1INH products may find utility in the management of several other disease states. In this review, we detail the key biological activities of C1INH and consider the pathophysiological role of C1INH targets in many conditions. The therapeutic potential of exogenous C1INH is highlighted in the settings of thromboembolism, ischemia-reperfusion injury, sepsis, transplantation, and coronavirus disease 2019.
antibodies
2026-09-18 | Isolated gastrointestinal hereditary angioedema associated with a pathogenic SERPING1 variant arising de novo: a case report.
Hereditary angioedema (HAE) is a rare genetic disorder typically characterized by cutaneous and submucosal edema. Cases presenting exclusively with gastrointestinal symptoms, devoid of concurrent or historical cutaneous or upper airway manifestations, are uncommon. This atypical presentation poses a considerable diagnostic challenge and often leads to a marked delay in diagnosis, particularly in patients without a family history. We report the case of a 28-year-old female with an over 6-year history of recurrent, self-limiting abdominal pain. During a severe attack, abdominal computed tomography angiography (CTA) revealed jejunal wall edema and ascites, accompanied by a dramatic surge in D-dimer (>20.00 mg/L FEU) and fibrin degradation products (FDP >120.00 mg/L), closely mimicking mesenteric ischemia. However, a retrospective review of medical history identified the persistent consumption of complement C4 (0.03-0.05 g/L). Subsequent testing showed a functional C1 esterase inhibitor (fC1-INH) level of <7.0% and a C1 esterase inhibitor (C1-INH) antigen level of 6.81 μg/mL, confirming type 1 HAE. Whole-exome sequencing (WES) identified the nonsense variant NM_000062.3:c.990C>A, p.(Tyr330Ter), in SERPING1. The variant was not detected in either biological parent, supporting a de novo origin. Under the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) framework, it was classified as pathogenic on the basis of PVS1 and PS2. An abdominal attack in May 2025 resolved rapidly after icatibant administration. Long-term prophylaxis (LTP) with lanadelumab was subsequently initiated following an individualized shared decision-making process. No breakthrough attacks or treatment related adverse events occurred from June 2025 through June 2026. This report highlights that HAE should be considered in patients with recurrent, unexplained, self-limiting abdominal pain, and C4 should be included in the initial evaluation. A negative family history does not exclude HAE.
2026-08-08 | 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.
2026-07-11 | Garadacimab and the future of hereditary angioedema prophylaxis: a step upstream in the bradykinin pathway.
Hereditary angioedema (HAE) is a rare autosomal dominant disorder characterized by recurrent, potentially life-threatening episodes of bradykinin-mediated angioedema affecting the skin, gastrointestinal tract, and upper airway. Despite the availability of several prophylactic therapies, there is a need for effective and convenient treatment options. On 21 June 2024, the U.S. Food and Drug Administration approved Andembry™ (garadacimab-gxii), a first-in-class monoclonal antibody that inhibits activated Factor XII (FXIIa), for prophylaxis of HAE attacks in patients aged ≥12 years. By targeting FXIIa, garadacimab acts upstream in the kallikrein-kinin pathway, suppressing bradykinin generation and preventing vascular permeability associated with angioedema. Clinical trials demonstrated substantial reductions in attack frequency, with the phase 3 VANGUARD study reporting a 91.5% reduction in HAE attacks and that approximately 77% of patients remain attack-free during the study period. Garadacimab is administered as a 200-mg subcutaneous injection once monthly and has a favorable pharmacokinetic profile with an elimination half-life of approximately 18-20 days. Adverse events were generally mild, including headache, nasopharyngitis, and injection-site reactions. The approval of garadacimab represents an important advancement in HAE prophylaxis, offering a novel upstream mechanism, convenient dosing, and potential improvement in quality of life of the patients.
2026-06-09 | Lanadelumab in Hereditary Angioedema: Extending Dose Intervals from Every 2 Weeks to Every 4 Weeks.
Both clinical trial and real-world data demonstrate the effectiveness of lanadelumab long-term prophylaxis (LTP) to prevent hereditary angioedema (HAE) attacks, which may be maintained after dose interval extension from every 2 weeks (Q2W) to every 4 weeks (Q4W) in patients with well-controlled disease (attack free for >6 months). This narrative review summarizes published data on lanadelumab treatment patterns collected from clinical trials and observational studies since US approval in 2018. Disease activity and HAE-related healthcare resource use at baseline and during the first 6 months of lanadelumab treatment may be useful indicators of patients with well-controlled disease who will be eligible for, and may derive benefit from, dose interval extension on lanadelumab. Patients who receive a dose interval extension could benefit from a reduction in treatment burden, but not all patients may be a good fit for interval extension. Although there are inherent limitations related to analyzing small sample sizes for subgroups of patients with a rare disease and for data derived from real-world studies, these data can inform physicians and patients about the characteristics and outcomes of patients who have successfully extended dosing intervals of lanadelumab LTP. This may in turn encourage regular monitoring to facilitate optimization of treatment and outcomes for each patient.
2026-06-08 | Acquired angioedema due to C1 inhibitor deficiency: real-world clinical characteristics and treatment outcomes.
Acquired angioedema due to C1 inhibitor deficiency (AAE-C1INH) is a rare bradykinin-mediated condition that may mimic hereditary angioedema (HAE). Management is largely extrapolated from HAE data. Therefore, retrospective observations in AAE-C1INH are particularly valuable for informing future approaches. This study aimed to evaluate the clinical characteristics, underlying conditions, and treatment outcomes of patients with AAE-C1INH. We conducted a retrospective cohort study of adult patients diagnosed with AAE-C1INH, with a comprehensive review of demographic and clinical features. Among 587 patients with recurrent angioedema, 1.7% had AAE-C1INH. Median onset age was 56.5 years (45.5-66.75), median follow-up was 60.5 months (23.25-66.5), and 20% were female. Clonal hematologic neoplasms were present in 60% of patients and monoclonal gammopathy of undetermined significance in 30%, with angioedema preceding the diagnosis of the underlying condition in 60% of cases. Long-term prophylaxis was required in 50% of patients. Antifibrinolytic agents showed limited efficacy, whereas attenuated androgens were associated with a marked reduction in attack frequency. Rituximab-based therapy effectively controlled angioedema, although relapse occurred during extended follow-up. Complete remission under Bruton's tyrosine kinase (BTK) inhibition was observed despite persistently low complement levels; however, concurrent withdrawal of renin-angiotensin system blockers represents a potential confounder. Complement levels were observed to parallel treatment response in most patients, whereas this association was not observed in the patient receiving a BTK inhibitor. In this rare, well-characterized cohort with extended follow-up, angioedema frequently represented the earliest clinical manifestation of AAE-C1INH, preceding recognition of the underlying disorder. Antifibrinolytic prophylaxis showed limited benefit, whereas attenuated androgens were associated with reduced attack frequency. Furthermore, therapies targeting the underlying lymphoproliferative condition, including rituximab-based regimens and BTK inhibition, were associated with meaningful clinical benefit. These findings support an individualized, etiology-driven management approach and provide practical insights for clinicians managing this rare condition.
gene therapies
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.
2026-03-11 | CRISPR in Medicine: A Systematic Review of Clinical Trials and Therapeutic Applications.
Clustered Regularly Interspaced Short Palindromic Repeats-CRISPR associated protein 9 (CRISPR/Cas9) technology has become a revolutionary tool in medicine, offering substantial potential for treating a wide range of diseases, including hematological disorders, cancers, genetic conditions, and ophthalmological diseases. This systematic review evaluates the efficacy, safety, and applicability of CRISPR/Cas9 in clinical trials. A comprehensive search of the PubMed, Scopus, Web of Science, and Cochrane databases was conducted. All studies, up to November 2024, meeting the eligibility criteria assessing the application of CRISPR for the treatment of diseases were included. A quality assessment of the included studies was conducted using the Cochrane risk of bias tool. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement for systematic reviews and meta-analyses was followed, and a total of 17 studies were included. This systematic review of CRISPR/Cas9 technology focused on its effectiveness and safety across various diseases. In nonmalignant hematological disorders, CRISPR successfully treated β-thalassemia and sickle cell disease, resulting in high transfusion independence and the elimination of disease crises. In malignant hematological disorders, B-cell acute lymphoblastic leukemia, CRISPR-engineered chimeric antigen receptor T (CAR-T) cells achieved an 83.3% complete remission rate. Furthermore, CRISPR-based CAR-T cells showed promising results in B-cell non-Hodgkin's lymphoma. In oncology, lung cancer and other solid tumors are among the diseases that have been safely engineered using CRISPR gene editing technology. For genetic disorders, CRISPR improved vision in retinal degeneration and reduced symptoms in hereditary angioedema and transthyretin amyloidosis with mild side effects. The results demonstrated CRISPR's potential across a wide range of conditions. In conclusion, the findings underscore the potential role of CRISPR/Cas9 technology across a wide range of diseases. However, challenges remain, including optimizing delivery systems, minimizing off-target effects, addressing immunogenicity concerns, and ethical considerations.
2025-12-11 | CRISPR-Cas9 gene editing for hereditary angioedema: current treatments and emerging therapies.
Hereditary angioedema (HAE) is a rare autosomal dominant disorder marked by episodic, non-urticarial swelling due to C1 esterase inhibitor (C1-INH) deficiency or dysfunction, leading to excessive bradykinin-mediated vascular permeability. While current treatments focus on symptomatic control using C1-INH replacement or kallikrein inhibitors, they require frequent administration and do not address the underlying genetic defect. CRISPR-Cas9 gene-editing technologies, particularly the investigational therapy NTLA-2002, offer a transformative approach by targeting the KLKB1 gene to durably reduce plasma kallikrein levels. This narrative review summarizes the pathophysiology and conventional treatments of HAE, and highlights emerging clinical evidence supporting the safety and efficacy of NTLA-2002. Preliminary trials demonstrate substantial reductions in HAE attack frequency and plasma kallikrein, with minimal adverse events. However, concerns about long-term safety, off-target effects, ethical implications, and accessibility remain. CRISPR-based therapeutics such as NTLA-2002 represent a paradigm shift in the management of HAE and underscore the broader potential of in vivo gene editing for genetic disorders.
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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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.
2026-03-14 | 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.
2026-02-02 | Population Pharmacokinetic/Pharmacodynamic Modeling of Donidalorsen, an Antisense Oligonucleotide in Development for Prophylaxis of Hereditary Angioedema.
Hereditary angioedema (HAE) is a rare disorder linked to kallikrein-kinin system dysregulation, which leads to uncontrolled activation of plasma prekallikrein. Donidalorsen is an antisense oligonucleotide designed to selectively degrade prekallikrein messenger RNA and thereby reduce prekallikrein production. We aimed to develop population pharmacokinetic and pharmacokinetic/pharmacodynamic models of donidalorsen and evaluate the impact of potential intrinsic/extrinsic covariates on exposure and prekallikrein response. Plasma donidalorsen and prekallikrein data were obtained from phase 1 to 3 studies in healthy volunteers (NCT03263507, 721744-CS9) and adult and adolescent patients with HAE (NCT04030598, NCT05139810). The evaluated doses were 20, 40, 60, and 80 mg every 4 weeks (Q4W) and 80 mg every 8 weeks (Q8W), administered subcutaneously over 13-21 weeks. Donidalorsen pharmacokinetics were well described by a linear 2-compartment model with first-order absorption. The population terminal elimination half-life was 31.4 days. Prekallikrein was well described by an indirect response model with inhibition of prekallikrein production by donidalorsen. Covariate analysis identified body weight as the main factor affecting pharmacokinetic exposure; however, this effect was not considered clinically significant. The developed population pharmacokinetic/pharmacodynamic model well characterized the donidalorsen exposure-prekallikrein response relationship. Modeling analyses support that no dose adjustment is needed with respect to intrinsic/extrinsic factors in adults and adolescents with HAE. The nearly identical simulated pharmacokinetic or prekallikrein time courses for Q4W versus monthly dosing and for Q8W versus every-2-month dosing regimens support switching to more convenient regimens for patients.
2025-11-10 | Exposure-Response Analysis of Donidalorsen for the Treatment of Hereditary Angioedema.
Hereditary angioedema (HAE) is characterized by recurrent attacks of severe tissue swelling. In the OASIS-HAE phase 3 study (NCT05139810), donidalorsen, an RNA-targeted antisense oligonucleotide that reduces prekallikrein production in the liver, significantly reduced HAE attack rates. To characterize the relationship between prekallikrein concentrations and HAE attack rates following donidalorsen and predict the efficacy of potential dosing regimens, an exposure-response model was developed using data from OASIS-HAE. Simulations were conducted to evaluate the following regimens: 80 mg once every 4 weeks (Q4W), 8 weeks (Q8W), 1 month (Q1M), and 2 months (Q2M), and a switch to Q2M dosing for patients who were attack-free for 3 months on the Q1M regimen. The relationship between prekallikrein concentrations and HAE attack rates was well characterized by a sigmoidal Emax (maximum effect) model with baseline attack rate and baseline prekallikrein concentration included as covariates. The average prekallikrein concentration estimated to result in a 90% reduction in attack rate (EC10) was 47.1 mg/L. Predicted percent reductions in attack rates at steady state were similar for Q4W (84.1%) vs. Q1M (82.9%) and Q8W (72.6%) vs. Q2M (70.2%) dosing. Predicted reductions in attack rate remained similar and clinically meaningful in patients who switched from Q1M to Q2M dosing (94.0% in month 1 and 91.3% in month 2 of the 2-month dosing interval at steady state). Overall, exposure-response analyses supported the efficacy of Q1M and Q2M dosing and indicated that switching to Q2M dosing could be a viable approach for patients who are attack-free on the Q1M regimen.
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Drug Discovery Landscape
1 orphan drug designation for Non-histaminic angioedema, including 1 approved therapy.
1 orphan drug designation for Non-histaminic angioedema, including 1 approved therapy.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
lanadelumab-flyo [Takhzyro] | antibodies | FDA | Approved | Takeda Pharmaceuticals U.S.A., Inc. |
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