RARE DISEASE
Hereditary angioedema
Hereditary angioedema
Hereditary angioedema
Synonyms: Familial angioneurotic edema, HAE, Hereditary angioneurotic edema, Hereditary bradykinine-induced angioedema, Hereditary non histamine-induced angioedema
Synonyms: Familial angioneurotic edema, HAE, Hereditary angioneurotic edema, Hereditary bradykinine-induced angioedema, Hereditary non histamine-induced angioedema
Synonyms: Familial angioneurotic edema, HAE, Hereditary angioneurotic edema, Hereditary bradykinine-induced angioedema, Hereditary non histamine-induced angioedema
Drug discovery
25
drugs
With orphan designations
Overview
Hereditary angioedema (HAE) is a rare autosomal dominant disorder caused by C1 esterase inhibitor (C1-INH) deficiency or dysfunction, leading to excessive bradykinin production and recurrent episodes of subcutaneous/submucosal swelling. Attacks involve extremities, abdomen, or airways (potentially fatal laryngeal edema). Diagnosis requires serum C4, antigenic/functional C1-INH testing, often delayed due to symptom overlap with common conditions [1][6][10].
Categories: rare allergic disease, rare genetic diseases, rare systemic and rheumatological diseases
Research Papers
1,742 drug discovery papers about Hereditary angioedema, with 1 first-in-class and 13 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,742 drug discovery papers about Hereditary angioedema, with 1 first-in-class and 13 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-07-12 | 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.
2026-07-08 | What are the current treatment options for managing acute attacks of hereditary angioedema?
Current treatment options for acute attacks of hereditary angioedema include C1-esterase inhibitors, icatibant, ecallantide, and the newly approved oral medication sebetralstat, expanding the range of effective and accessible treatments.
2026-07-07 | Living-Donor Kidney Transplantation Between Mother and Son With Clinically Confirmed Hereditary Angioedema.
Hereditary angioedema (HAE) is a rare autosomal dominant disorder resulting from SERPING1-related C1-inhibitor deficiency. Surgical stress and airway manipulation may precipitate life-threatening attacks. Experience with kidney transplantation in patients with HAE remains extremely limited. We describe a 19-year-old male with end-stage kidney disease secondary to congenital obstructive uropathy and nephrolithiasis, who underwent successful living-donor kidney transplantation from his mother, also diagnosed with HAE type I. Because danazol is unavailable in Argentina, both donor and recipient received compounded stanozolol 2 mg daily, starting 5 days preoperatively and continuing for 5 days postoperatively. Fresh frozen plasma (FFP, 10 mL/kg) was administered before extubation to raise C1-inhibitor levels, and icatibant was kept on standby for rescue. Neither donor nor recipient experienced perioperative angioedema. Both had uneventful recoveries, with the recipient maintaining stable graft function over 10 months of follow-up (latest serum creatinine 1.4 mg/dL). This report demonstrates that living-donor kidney transplantation between two individuals affected by HAE can be performed safely with individualized prophylaxis and multidisciplinary coordination.
2026-05-26 | Molecular mechanisms for subtype selectivity of kinin receptors' antagonists.
The kinin receptors B1R and B2R act as key regulators within the kallikrein-kinin system, mediating vasodilation, inflammation, and pain. Antagonists targeting these receptors have shown therapeutic potential in the treatment of angioedema, pancreatitis, and asthma. However, the molecular mechanisms underlying subtype selectivity of kinin receptors' antagonists remain unclear. Here we report three cryo-electron microscopy (cryo-EM) structures of B1R in complex with the peptide antagonist R715 and small-molecule antagonist ELN441958, as well as B2R in complex with small-molecule antagonist Win64338. Together with functional assays and molecular docking, these structures unveil the molecular basis of antagonist binding modes in kinin receptors. Three non-conserved residues at the bottom of the ligand binding pocket are identified to confer the antagonist selectivity to B1R and B2R. Furthermore, our results reveal a shared mechanism for antagonism in both B1R and B2R, wherein the antagonist binding restricts the conformational changes of the toggle switch tryptophan residue. Collectively, these insights lay the foundation for the structure-based design of selective antagonists targeting B1R and B2R.
2026-05-15 | Lanadelumab safety, efficacy, and pharmacokinetics in patients aged ≥12 with hereditary angioedema in China: an open-label, multicenter study.
Lanadelumab is a plasma kallikrein inhibitor approved in many countries, including China, for the long-term prophylaxis of hereditary angioedema (HAE). The primary objective was safety evaluation of lanadelumab for HAE long-term prophylaxis in a Chinese patient population. Secondary objectives included efficacy, pharmacokinetics, pharmacodynamics, and immunogenicity evaluations. This open-label, prospective, phase 3, post-approval commitment study included patients in China aged ≥12 years with HAE due to C1 inhibitor deficiency (HAE-C1INH) (NCT05460325). Eligible patients with ≥1 HAE attack in the 4-week run-in period received subcutaneous lanadelumab 300 mg every 2 weeks during days 0-182 for 14 doses in total. Twenty patients were enrolled (median age, 38 years; 7 male), and all completed the study. No treatment-emergent adverse events (TEAEs) were fatal, led to treatment discontinuation, or were of special interest. Fifteen (75%) patients reported ≥1 TEAE during the study, most commonly COVID-19 infection (50%). Nine (45%) patients reported treatment-related TEAEs, most frequently injection site pain (20%) and swelling (15%). Injection site reactions occurred in 25% of patients. Mean ± SD monthly rate of investigator-confirmed attacks decreased by 99.1% during days 0-182 versus run-in (0.04 ± 0.14 vs 2.50 ± 1.44). Eighteen (90%) patients were attack free during days 0-182; 2 patients experienced a total of 4 mild and 1 moderate investigator-confirmed HAE attacks. Lanadelumab pharmacokinetics, pharmacodynamics, and immunogenicity in Chinese patients were consistent with other patient populations. These findings in patients with HAE in China are consistent with the profile of lanadelumab established in patients from other regions, supporting its use as first-line long-term prophylaxis.
gene therapies
2026-07-28 | Status of Current Clinical Trials on Therapy for Hereditary Angioedema 2309515
Abstract Introduction Hereditary angioedema (HAE) is a rare autosomal dominant deficiency or dysfunction of C1 esterase inhibitor, resulting in dysregulated kallikrein—bradykinin signaling and potentially life-threatening angioedema. While existing C1-INH products and kallikrein inhibitors have improved disease control, new clinical trials aim to further reduce treatment burden and achieve durable prophylaxis through novel therapeutic strategies. Methods Active and recruiting HAE clinical trials were identified through the trial registry on clinicaltrials.gov. Results A total of twenty-two trials were identified, eleven of which are recruiting as of December 2025, and eleven others that are active but no longer recruiting. The sole drug in phase 4 is CSL312 (Garadacimab), a fully human IgG4 monoclonal antibody targeting activated factor XIIa. Drugs in phase 3 include: NTLA-2002, a single-dose intravenous gene therapy targeting inactivation of the KLKB1 gene; Navenibart, an IgG1 monoclonal antibody inhibiting activated kallikrein; OCTA-C1-INH, a virus-inactivated, nanofiltrated, highly purified concentrate of C1-INH derived from pooled human plasma; ADX-324, an siRNA therapy to reduce hepatic production of prekallikrein (PKK); Donidalorsen, an antisense oligonucleotide targeted against hepatic PKK mRNA; Sebetralstat and berotralstat, both plasma kallikrein inhibitors that reduce production of bradykinin; and deucrictibant, a competitive bradykinin B2 receptor antagonist. Drugs in phase 2 are: BW-20805, another siRNA therapy targeting human hepatic PKK mRNA; and BMN 331, an AAV5-based gene therapy that introduces the SERPING1 gene which encodes wild-type human C1INH protein. Conclusion Advances in gene therapy, biologics, RNA interference therapeutics, and improved replacement strategies hold promise for transforming both rescue and prophylactic management for HAE. Ongoing evaluation of safety, durability of response, and real-world applicability will be critical in defining the future standard of care for HAE. Funding Source n/a Topic Categories Translational and Interventional Immunology (TI)
2026-07-27 | Lonvoguran ziclumeran: a CRISPR-CAS9-based gene therapy for the treatment of hereditary angioedema.
Hereditary angioedema (HAE) is a rare genetic disorder characterized by recurrent swelling caused by dysregulation of the kallikrein-kinin pathway. Although current therapies effectively reduce attack frequency, treatment remains lifelong. Lonvoguran ziclumeran (Lonvo-z; NTLA-2002) is the first systemically administered in vivo CRISPR/Cas9 gene-editing therapy designed to provide durable suppression of plasma kallikrein through permanent disruption of the KLKB1 gene. This review summarizes the pathophysiology and current management of HAE, the development of Lonvo-z, its lipid nanoparticle delivery platform, and the technical advances enabling in vivo genome editing. Preclinical studies and clinical evidence, including early-phase trials and the Phase 3 HAELO study, are reviewed with emphasis on efficacy, safety and clinical implications. Lonvo-z represents a major milestone in precision medicine and the clinical application of systemic genome editing. A single administration has produced sustained reductions in plasma kallikrein levels and HAE attack frequency. Although long-term follow-up is ongoing, current evidence supports its potential as the first one-time disease-modifying treatment for HAE and a landmark advance in CRISPR-based therapeutics.
2026-06-21 | Modeling Hereditary Angioedema With Personalized EPSC-Derived Hepatocytes: A CRISPR-Validated Platform for Mutation-Specific Mechanisms and Therapeutic Innovation.
Hereditary angioedema (HAE) with C1 esterase inhibitor (C1INH) deficiency is caused by pathogenic SERPING1 mutations that disrupt production of the plasma protease inhibitor C1INH. However, the molecular mechanisms and consequences of patient-specific mutations remain poorly understood due to the lack of physiologically relevant human models. Here, we established a personalized, isogenic, stem-cell-derived hepatocyte platform to investigate the underlying mutation-specific mechanisms of HAE. Specifically, peripheral blood mononuclear cell (PBMC)-expanded erythroblasts from four representative HAE-C1INH-Type1 patients containing distinct point, insertion, deletion, or large fragment SERPING1 mutations were reprogrammed into expanded potential stem cells (EPSCs) and further differentiated into hepatocyte-like cells (HLCs). These HLCs exhibited appropriate transcriptional transitions, mature hepatic features, and C1INH secretion comparable to that observed in human plasma. All patient-derived HLCs demonstrated impaired C1INH secretion with mutation-specific differences in both SERPING1 transcription and intracellular accumulation. Moreover, to verify that the mutations directly drive the phenotype, we performed CRISPR/Cas9-mediated genome repair, which restored SERPING1 mRNA expression and C1INH secretion. Conversely, identical patient mutations installed into healthy EPSCs showed the same transcriptional and secretory defects, confirming sufficiency. Collectively, we have established a robust human hepatocyte model that accurately recapitulates key hepatocyte-specific aspects of HAE pathophysiology and provides a scalable foundation for investigation of future precision therapies.
2026-03-11 | 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.
2025-11-14 | 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.
proteins
2026-07-25 | Hereditary Angioedema: On-demand Treatment and Long-term Prophylaxis - A Global Reality.
Hereditary Angioedema (HAE) is a rare disorder of recurrent swellings of the subcutaneous and/or mucosal tissues due to defects in the contact system regulation of bradykinin production. The swellings can be disfiguring, cause debilitating abdominal pain, or be fatal with laryngeal obstruction. Over the last decade there has been immense successes in management of HAE owing to development of drugs targeting the contact system. This review focuses on management of HAE due to C1-INH deficiency/dysfunction including a global perspective which is under-represented in the literature. HAE with normal C1-INH is outside the scope of this article. The review provides summaries of clinical trials that has led to licensing of new HAE medications and discusses access to these modern drugs from a global perspective.
2026-06-30 | Dental Procedures for Hereditary Angioedema Patients: What Happens in Real Life?
ObjectiveDental procedures are known to be potential trigger for attacks in hereditary angioedema (HAE). Therefore, we aimed to demonstrate the potential of dental procedures to trigger HAE attacks through real-life experiences.MethodThe files of 57 patients diagnosed with HAE type I-II and followed up at the Immunology Allergy Diseases Outpatient Clinic between January 1, 2018, and April 4, 2025, were examined.ResultsThe study included 44 patients, and prophylaxis was administered to 27.3%, 26.7%, and 8.3% of those who underwent tooth extraction, filling, and root canal treatment, respectively. The frequency of attacks after tooth extraction was reduced in patients who received prophylaxis compared to those who did not receive prophylaxis, but this reduction was statistically insignificant (33.3% in those who did not receive prophylaxis vs. 22.2% in those who did). When comparing patients who experienced attacks without prophylaxis after tooth extraction with those who did not receive prophylaxis, it was observed that the group experiencing attacks was predominantly female (p=0.079). Attacks occurring after tooth extraction were not statistically significantly associated with attack triggers.ConclusionMost HAE patients do not receive prophylaxis before dental procedures. Given the risk of fatal laryngeal attacks, it is important to carefully assess patients for their prophylaxis needs before dental procedures, and to raise awareness among both patients and dentists regarding the risk of attacks despite prophylaxis.
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.
2026-05-20 | Post Hoc Analysis of Recombinant C1 Inhibitor Clinical Data Using Contemporary Endpoints for Hereditary Angioedema.
Contemporary trials of medications to treat hereditary angioedema (HAE) attacks define efficacy endpoints using Patient Global Impression of Severity (PGI-S) and Patient Global Impression of Change (PGI-C) scales; these differ from the visual analog scale (VAS) and treatment effect questionnaire (TEQ) used in legacy recombinant human C1 esterase inhibitor (rhC1-INH) studies. This post hoc analysis aimed to evaluate pooled rhC1-INH trial data, mapped to contemporary HAE clinical trial endpoints and designs. Pooling data from three rhC1-INH trials for acute HAE attacks (NCT00225147, NCT01188564, NCT00262301), this analysis applied results from a bookmarking study to convert TEQ and VAS measurements to PGI-S and PGI-C scales. Kaplan-Meier estimates were calculated for time to complete resolution (TTCR; defined as "none" on PGI-S) and time to onset of symptom relief (TOSR; defined as "a little better" on PGI-C at ≥ 2 consecutive time points within 12 h). Log-rank tests were used to determine differences between treatment groups. Across trials, 48 and 60 patients received rhC1-INH 50 U/kg and placebo, respectively. The most common attack locations were peripheral (47.9% and 41.7%, respectively) and abdominal (35.4% and 35.0%, respectively). Baseline attack severity was either severe or very severe in all patients. Median [95% confidence interval (CI)] TOSR was 0.75 h (0.55-1.50) with rhC1-INH and 8.00 h (3.00-8.05) with placebo (P < 0.001). Median (95% CI) TTCR was 4.50 h (3.55-5.50) with rhC1-INH and 24.00 h (16.00- > 24.00) with placebo (P < 0.001). This post hoc analysis confirmed that rhC1-INH, compared with placebo, is associated with significantly shorter TOSR and TTCR of HAE attacks. ClinicalTrials.gov: NCT00225147, NCT01188564, NCT00262301.
2026-05-03 | Comparative Efficacy of Recombinant C1 Inhibitor Versus Sebetralstat for On-Demand Treatment of Hereditary Angioedema Attacks: A Matching-Adjusted Indirect Treatment Comparison.
Prompt and effective on-demand treatment is critical in hereditary angioedema (HAE). Although multiple on-demand therapies are available, including recombinant human C1 esterase inhibitor (rhC1-INH) and sebetralstat, no head-to-head efficacy trials exist. A series of indirect treatment comparisons evaluated the relative efficacy of US Food and Drug Administration-approved doses of intravenous rhC1-INH (50 U/kg for patients weighing < 84 kg; 4200 U otherwise) vs oral sebetralstat (600 mg) for the on-demand treatment of HAE attacks. Patient-level data from rhC1-INH trials (C1 1310, C1 1205, and C1 1304 [placebo only]) were reweighted to match aggregate baseline characteristics (i.e., prophylaxis use, pooled attack location) from the sebetralstat KONFIDENT trial; matching variables were identified from a validated, clinician-informed study of treatment effect modifiers. In the primary analysis, time to complete resolution (TTCR) and redosing were compared using unanchored matching-adjusted indirect comparisons. TTCR subgroup analyses were performed for variables not matched for in the primary analysis due to population differences (i.e., attack severity, time to treatment). Scenario and sensitivity analyses were performed to support TTCR results; a scenario analysis was performed to support redosing results. Hazard ratios (HRs) and odds ratios (ORs), with 95% confidence intervals (CIs), were estimated using a weighted Cox proportional hazards model and a weighted logistic regression model, respectively. In the primary analysis, rhC1-INH was associated with a statistically significant 4.5-fold increased likelihood of achieving complete resolution (HR 4.52; 95% CI 2.84-7.18) and a significant 82% reduction in redosing (OR 0.18; 95% CI 0.06-0.53) vs sebetralstat. Similar results for TTCR were observed in subgroup analyses of patients with severe/very severe baseline attacks and patients receiving earlier treatment (within the median time to treatment). Scenario and sensitivity analyses confirmed the robustness of these findings. rhC1-INH provides significantly faster symptom resolution and lower redosing rates vs sebetralstat.
antibodies
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.
2026-06-03 | A novel SERPING1 splice-site variant (c.1029 + 2T > A) causing hereditary angioedema type I: functional characterization and clinical analysis.
Hereditary angioedema (HAE) is a rare autosomal dominant disorder predominantly caused by mutations in the SERPING1 gene, which encodes C1 esterase inhibitor (C1-INH). HAE is characterized by recurrent self-limiting episodes of subcutaneous and submucosal edema that can be life-threatening when the upper airway is involved. Diagnostic delays and misdiagnoses are common due to the clinical overlap with allergic and histamine-mediated angioedema. Identification and functional characterization of novel SERPING1 variants is essential for refining the mutational spectrum of this disease, enhancing molecular diagnostics, and guiding individualized therapeutic strategies. A 31-year-old female with a ten-year history of recurrent angioedema was diagnosed with HAE type I based on reduced serum C4, C1-INH antigen levels, and C1-INH functional activity. Sanger sequencing of the SERPING1 gene was performed to identify the causative variant. Functional characterization of the identified splice-site variant was conducted using reverse transcription-PCR (RT-PCR) on patient-derived peripheral blood RNA and an in vitro minigene splicing assay in HEK293T cells. A retrospective analysis of seven HAE patients was performed, including clinical characterization, laboratory profiling, genetic analysis, and treatment outcomes. A novel heterozygous splice-site variant, c.1029 + 2T > A, was identified at the canonical splice donor site of intron 6 of SERPING1. RT-PCR revealed reduced wild-type transcript expression and an aberrant transcript resulting from complete exon 6 skipping (c.890_1029del), predicted to cause a frameshift and premature termination codon (p.Ala297Glyfs*25). The minigene assay confirmed that the mutant construct produced no detectable canonical transcript; instead, three aberrant splice isoforms were identified, with exon 6 skipping as the predominant event. Long-term prophylactic treatment with Lanadelumab (300 mg subcutaneously every two weeks) achieved zero breakthrough attacks over a six-month follow-up period. In the retrospective cohort of seven patients, six were classified as type I and one as type II HAE. Seven distinct variants of the SERPING1 gene were identified. Among these patients, five received long-term prophylaxis with Lanadelumab, which resulted in significant reductions in the frequency of attacks. We identified and functionally characterized a novel SERPING1 splice-site variant, c.1029 + 2T > A, which disrupts canonical mRNA splicing, primarily through exon 6 skipping, leading to C1-INH haploinsufficiency and type I HAE. Our retrospective analysis expands the mutational spectrum of SERPING1 and demonstrates the clinical efficacy of Lanadelumab as a long-term prophylactic therapy. These findings underscore the importance of integrating genetic testing and functional validation in the diagnosis and management of HAE.
2026-05-21 | The Neglected Older Adults in Hereditary Angioedema: Insights From the ITACA Registry.
Hereditary Angioedema due to C1-inhibitor deficiency (HAE-C1INH) is a rare disease that affects individuals of all ages, however, older adults have never been characterized in terms of disease severity, comorbidities, and treatments. The aim was to identify the clinical characteristics of and therapeutic approaches in HAE-C1INH patients aged 65 and older. Data from the ITACA (Italian network for Hereditary and Acquired Angioedema) Registry were prospectively collected for 10-month. Data from 647 HAE-C1INH, patients including 343 females (53%), were collected: 114 patients (17.6%) were aged 65 and older (68 females; 58.6%). Group mean age was 74.3 ± 7.5 years, mean age at first-symptom-onset was 19 ± 15 years, and mean age at diagnosis was 45.6 ± 14.3 years. Common comorbidities were: hypertension (59.6%), dyslipidaemia (28.9%), coronary artery disease (14.0%), diabetes (14.0%), endocrinopathies (14.0%), neoplasia (12.3%) and B/C hepatitis (11.4%). Half of the older patients (49%) experienced at least one attack during the study period, and 8 patients (7%) had an attack frequency of > 0.5 attacks/month. Long-term prophylaxis (LTP) was the treatment of choice in 45 patients (39.5%) and represented 15.9% of overall LTP prescriptions: 60% were treated with lanadelumab, 22.2% with attenuated androgens, 13.3% with berotralstat, and 4.5% with sub-cutaneous C1INH concentrate. Gender differences were not detected in any of the variables analyzed. Older patients with HAE-C1INH constitute a relevant subgroup, characterized by persistent disease activity and comorbidities. The availability of new therapies and guideline recommendations are driving an increase in LTP use, although shifting from older non-specific treatments, especially androgens, is still incomplete.
2026-04-14 | Factor XII in Thrombosis and Thromboinflammation: From Molecular Biology to Clinical Translation.
Factor XII (FXII) is a central mediator at the intersection of coagulation, fibrinolysis, inflammation, and immunity. It is activated upon contact with negatively charged surfaces, triggering the intrinsic coagulation pathway and driving thrombus formation and stabilization. Beyond clotting, FXII contributes to activation of the kallikrein-kinin system, generation of bradykinin, and modulation of inflammatory and immune responses. Congenital FXII deficiency does not increase bleeding risk, highlighting its unique role and making FXII inhibition an attractive strategy for anticoagulation and immune modulation with a potentially superior safety profile. Preclinical studies provide compelling evidence for this concept. In models of ischemic stroke and traumatic brain injury, FXII blockade significantly reduced infarct volume, improved neurological outcomes, and attenuated neuroinflammation without increasing hemorrhage. Similarly, in extracorporeal circulation and vascular stent implantation, FXII inhibition prevented thrombus formation and reduced fibrin deposition, achieving effects comparable to heparin but with markedly lower bleeding risk. Several classes of FXII inhibitors are currently in development, including antisense oligonucleotides, peptides, recombinant proteins, and monoclonal antibodies. Among them, Ixodes ricinus contact phase inhibitor (Ir-CPI) and recombinant human albumin-fused Infestin-4 (rHA-Infestin-4) have demonstrated strong antithrombotic efficacy in animal models. Most notably, garadacimab, a monoclonal anti-FXIIa antibody, has completed phase 3 trials and received regulatory approval for hereditary angioedema (HAE) prophylaxis, where it markedly reduces attack frequency with a favorable safety profile. This review summarizes current knowledge on FXII biology and evaluates its translational potential as a novel target for anticoagulant and anti-inflammatory therapies.
2026-03-31 | [Consensus of Mexican experts on long-term prophylaxis in patients with hereditary angioedema in Mexico].
Hereditary angioedema (HAE) is a rare, potentially life-threatening genetic disorder characterized by recurrent, bradykinin-mediated swelling episodes, with substantial impact on morbidity, quality of life, and healthcare resource use. Targeted agents have reshaped long-term prophylaxis (LTP); however, effective implementation depends on clinical decision-making as well as health-system access and structural constraints. To comprehensively describe HAE long-term prophylaxis management in Mexico, focusing on the diagnostic approach, LTP use, treatment access and availability, perceived disease control, and applicability of clinical recommendations, based on structured national expert opinion. We conducted a descriptive and analytical evaluation of Mexico-specific data derived from a structured Delphi process involving clinicians experienced in HAE management. Assessed domains included diagnostic testing practices, selection and prescribing frequency of LTP therapies, use of non-recommended treatments, funding sources, medication availability issues, access barriers, and clinicians' perceptions regarding disease control and guideline applicability. Experts reported strong conceptual alignment with current clinical recommendations. LTP prescribing was predominantly concentrated on lanadelumab, with limited use of C1-INH concentrates and no reported use of berotralstat. Despite reported public coverage, frequent barriers related to availability and cost constrained effective access and treatment continuity. Clinical guidelines were perceived as highly applicable; however, a gap between recommended care and feasible real-world implementation was consistently acknowledged. HAE prophylaxis management in Mexico appears aligned with contemporary standards, yet sustained and individualized implementation remains limited by structural access and supply constraints. Key priorities include strengthening timely diagnosis, ensuring continuous access to targeted therapies, and standardizing follow-up in routine clinical care.
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.
2026-03-10 | Donidalorsen for hereditary angioedema: Long-term results from a 4-year, phase 2, open-label extension study.
Hereditary angioedema (HAE) is a rare disorder caused by kallikrein-kinin system dysregulation. Donidalorsen is a prekallikrein-directed antisense oligonucleotide that can rebalance this system by reducing prekallikrein production and is indicated for prophylaxis to prevent HAE attacks in patients 12 years of age and older. To report results from a 4-year, phase 2, open-label extension study of donidalorsen (NCT04307381). The study on-treatment period included fixed (weeks 0-12) and flexible (weeks 16-208) treatment periods. Patients received donidalorsen 80 mg subcutaneously every 4 weeks (Q4W) in the fixed treatment period and could receive 80 mg every 8 weeks (Q8W) in the flexible treatment period if attack free for greater than or equal to 12 weeks or 100 mg Q4W if disease was not adequately controlled. End points are summarized through the end of the study (week 208). Of 17 patients with HAE-C1INH-type 1 or HAE-C1INH-type 2, 13 (76%) completed 4 years of treatment (median exposure: 3.99 years). Eight patients changed to donidalorsen Q8W; 5 stayed on Q8W to study completion. One patient received 100 mg Q4W. Mean monthly HAE attack rates decreased by 97% overall from baseline to the on-treatment period, with 97% (Q4W) and 83% (Q8W) decreases to the flexible treatment period. The median longest attack-free interval was 990 days. No serious treatment-emergent adverse events (TEAEs) occurred. One patient (6%) (100 mg Q4W) discontinued due to a TEAE (injection-site discoloration). Seven patients (41%) reported treatment-related TEAEs; the only treatment-related TEAEs reported in more than 1 patient were injection-site reactions. In this 4-year study, donidalorsen led to sustained reductions in monthly HAE attack rate with an acceptable safety profile. ClinicalTrials.gov Identifier: NCT04307381 (https://www. gov/study/NCT04307381).
2026-03-02 | Donidalorsen for Long-Term Prophylaxis of Hereditary Angioedema Attacks: Results from the OASISplus Open-Label Extension Cohort at Year 1.
Donidalorsen, a prekallikrein-directed antisense oligonucleotide indicated for prophylaxis of hereditary angioedema (HAE) attacks in patients aged ≥12 years, demonstrated efficacy and acceptable safety in the phase 3, placebo-controlled OASIS-HAE trial (NCT05139810). Here, we report 1-year results from the corresponding open-label extension (OLE) cohort of the OASISplus study (NCT05392114). OASISplus included patients who rolled over from OASIS-HAE. Patients who received donidalorsen 80 mg or placebo subcutaneously every 4 weeks (Q4W) in OASIS-HAE received donidalorsen Q4W in OASISplus. Patients who received donidalorsen 80 mg or placebo every 8 weeks (Q8W) in OASIS-HAE received donidalorsen Q8W or Q4W, if not attack-free in the final 8 weeks of OASIS-HAE. The primary endpoint was safety (ie, incidence of treatment-emergent adverse events [TEAEs]). Secondary endpoints included the monthly rate of HAE attacks and Angioedema Quality of Life (AE-QoL). The OLE cohort included 83 patients (Q4W, n=69 [83%]; Q8W, n=14 [17%]). Of these, 75 (90.4%) completed Year 1, and 6 patients receiving donidalorsen Q8W in OASIS-HAE switched to the Q4W dosing group in the OLE. Median donidalorsen exposure was 392.3 days. From Weeks 0 to 52, reductions in mean HAE attack rate from OASIS-HAE baseline were 94% (Q4W) and 95% (Q8W), and patients reported clinically meaningful improvements in mean AE-QoL total score at Week 52 (Q4W, 28.1 points; Q8W, 26.7 points). Twenty-two (27%) patients reported treatment-related TEAEs; none were serious, and injection-site reactions were the most frequently reported. Donidalorsen demonstrated sustained reductions in HAE attack rate, improvements in QoL, and an acceptable safety profile after 1 year of treatment.
small molecules
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.
2026-07-08 | What are the current treatment options for managing acute attacks of hereditary angioedema?
Current treatment options for acute attacks of hereditary angioedema include C1-esterase inhibitors, icatibant, ecallantide, and the newly approved oral medication sebetralstat, expanding the range of effective and accessible treatments.
2026-07-07 | Living-Donor Kidney Transplantation Between Mother and Son With Clinically Confirmed Hereditary Angioedema.
Hereditary angioedema (HAE) is a rare autosomal dominant disorder resulting from SERPING1-related C1-inhibitor deficiency. Surgical stress and airway manipulation may precipitate life-threatening attacks. Experience with kidney transplantation in patients with HAE remains extremely limited. We describe a 19-year-old male with end-stage kidney disease secondary to congenital obstructive uropathy and nephrolithiasis, who underwent successful living-donor kidney transplantation from his mother, also diagnosed with HAE type I. Because danazol is unavailable in Argentina, both donor and recipient received compounded stanozolol 2 mg daily, starting 5 days preoperatively and continuing for 5 days postoperatively. Fresh frozen plasma (FFP, 10 mL/kg) was administered before extubation to raise C1-inhibitor levels, and icatibant was kept on standby for rescue. Neither donor nor recipient experienced perioperative angioedema. Both had uneventful recoveries, with the recipient maintaining stable graft function over 10 months of follow-up (latest serum creatinine 1.4 mg/dL). This report demonstrates that living-donor kidney transplantation between two individuals affected by HAE can be performed safely with individualized prophylaxis and multidisciplinary coordination.
2026-05-26 | Molecular mechanisms for subtype selectivity of kinin receptors' antagonists.
The kinin receptors B1R and B2R act as key regulators within the kallikrein-kinin system, mediating vasodilation, inflammation, and pain. Antagonists targeting these receptors have shown therapeutic potential in the treatment of angioedema, pancreatitis, and asthma. However, the molecular mechanisms underlying subtype selectivity of kinin receptors' antagonists remain unclear. Here we report three cryo-electron microscopy (cryo-EM) structures of B1R in complex with the peptide antagonist R715 and small-molecule antagonist ELN441958, as well as B2R in complex with small-molecule antagonist Win64338. Together with functional assays and molecular docking, these structures unveil the molecular basis of antagonist binding modes in kinin receptors. Three non-conserved residues at the bottom of the ligand binding pocket are identified to confer the antagonist selectivity to B1R and B2R. Furthermore, our results reveal a shared mechanism for antagonism in both B1R and B2R, wherein the antagonist binding restricts the conformational changes of the toggle switch tryptophan residue. Collectively, these insights lay the foundation for the structure-based design of selective antagonists targeting B1R and B2R.
2026-05-15 | Lanadelumab safety, efficacy, and pharmacokinetics in patients aged ≥12 with hereditary angioedema in China: an open-label, multicenter study.
Lanadelumab is a plasma kallikrein inhibitor approved in many countries, including China, for the long-term prophylaxis of hereditary angioedema (HAE). The primary objective was safety evaluation of lanadelumab for HAE long-term prophylaxis in a Chinese patient population. Secondary objectives included efficacy, pharmacokinetics, pharmacodynamics, and immunogenicity evaluations. This open-label, prospective, phase 3, post-approval commitment study included patients in China aged ≥12 years with HAE due to C1 inhibitor deficiency (HAE-C1INH) (NCT05460325). Eligible patients with ≥1 HAE attack in the 4-week run-in period received subcutaneous lanadelumab 300 mg every 2 weeks during days 0-182 for 14 doses in total. Twenty patients were enrolled (median age, 38 years; 7 male), and all completed the study. No treatment-emergent adverse events (TEAEs) were fatal, led to treatment discontinuation, or were of special interest. Fifteen (75%) patients reported ≥1 TEAE during the study, most commonly COVID-19 infection (50%). Nine (45%) patients reported treatment-related TEAEs, most frequently injection site pain (20%) and swelling (15%). Injection site reactions occurred in 25% of patients. Mean ± SD monthly rate of investigator-confirmed attacks decreased by 99.1% during days 0-182 versus run-in (0.04 ± 0.14 vs 2.50 ± 1.44). Eighteen (90%) patients were attack free during days 0-182; 2 patients experienced a total of 4 mild and 1 moderate investigator-confirmed HAE attacks. Lanadelumab pharmacokinetics, pharmacodynamics, and immunogenicity in Chinese patients were consistent with other patient populations. These findings in patients with HAE in China are consistent with the profile of lanadelumab established in patients from other regions, supporting its use as first-line long-term prophylaxis.
gene therapies
2026-07-28 | Status of Current Clinical Trials on Therapy for Hereditary Angioedema 2309515
Abstract Introduction Hereditary angioedema (HAE) is a rare autosomal dominant deficiency or dysfunction of C1 esterase inhibitor, resulting in dysregulated kallikrein—bradykinin signaling and potentially life-threatening angioedema. While existing C1-INH products and kallikrein inhibitors have improved disease control, new clinical trials aim to further reduce treatment burden and achieve durable prophylaxis through novel therapeutic strategies. Methods Active and recruiting HAE clinical trials were identified through the trial registry on clinicaltrials.gov. Results A total of twenty-two trials were identified, eleven of which are recruiting as of December 2025, and eleven others that are active but no longer recruiting. The sole drug in phase 4 is CSL312 (Garadacimab), a fully human IgG4 monoclonal antibody targeting activated factor XIIa. Drugs in phase 3 include: NTLA-2002, a single-dose intravenous gene therapy targeting inactivation of the KLKB1 gene; Navenibart, an IgG1 monoclonal antibody inhibiting activated kallikrein; OCTA-C1-INH, a virus-inactivated, nanofiltrated, highly purified concentrate of C1-INH derived from pooled human plasma; ADX-324, an siRNA therapy to reduce hepatic production of prekallikrein (PKK); Donidalorsen, an antisense oligonucleotide targeted against hepatic PKK mRNA; Sebetralstat and berotralstat, both plasma kallikrein inhibitors that reduce production of bradykinin; and deucrictibant, a competitive bradykinin B2 receptor antagonist. Drugs in phase 2 are: BW-20805, another siRNA therapy targeting human hepatic PKK mRNA; and BMN 331, an AAV5-based gene therapy that introduces the SERPING1 gene which encodes wild-type human C1INH protein. Conclusion Advances in gene therapy, biologics, RNA interference therapeutics, and improved replacement strategies hold promise for transforming both rescue and prophylactic management for HAE. Ongoing evaluation of safety, durability of response, and real-world applicability will be critical in defining the future standard of care for HAE. Funding Source n/a Topic Categories Translational and Interventional Immunology (TI)
2026-07-27 | Lonvoguran ziclumeran: a CRISPR-CAS9-based gene therapy for the treatment of hereditary angioedema.
Hereditary angioedema (HAE) is a rare genetic disorder characterized by recurrent swelling caused by dysregulation of the kallikrein-kinin pathway. Although current therapies effectively reduce attack frequency, treatment remains lifelong. Lonvoguran ziclumeran (Lonvo-z; NTLA-2002) is the first systemically administered in vivo CRISPR/Cas9 gene-editing therapy designed to provide durable suppression of plasma kallikrein through permanent disruption of the KLKB1 gene. This review summarizes the pathophysiology and current management of HAE, the development of Lonvo-z, its lipid nanoparticle delivery platform, and the technical advances enabling in vivo genome editing. Preclinical studies and clinical evidence, including early-phase trials and the Phase 3 HAELO study, are reviewed with emphasis on efficacy, safety and clinical implications. Lonvo-z represents a major milestone in precision medicine and the clinical application of systemic genome editing. A single administration has produced sustained reductions in plasma kallikrein levels and HAE attack frequency. Although long-term follow-up is ongoing, current evidence supports its potential as the first one-time disease-modifying treatment for HAE and a landmark advance in CRISPR-based therapeutics.
2026-06-21 | Modeling Hereditary Angioedema With Personalized EPSC-Derived Hepatocytes: A CRISPR-Validated Platform for Mutation-Specific Mechanisms and Therapeutic Innovation.
Hereditary angioedema (HAE) with C1 esterase inhibitor (C1INH) deficiency is caused by pathogenic SERPING1 mutations that disrupt production of the plasma protease inhibitor C1INH. However, the molecular mechanisms and consequences of patient-specific mutations remain poorly understood due to the lack of physiologically relevant human models. Here, we established a personalized, isogenic, stem-cell-derived hepatocyte platform to investigate the underlying mutation-specific mechanisms of HAE. Specifically, peripheral blood mononuclear cell (PBMC)-expanded erythroblasts from four representative HAE-C1INH-Type1 patients containing distinct point, insertion, deletion, or large fragment SERPING1 mutations were reprogrammed into expanded potential stem cells (EPSCs) and further differentiated into hepatocyte-like cells (HLCs). These HLCs exhibited appropriate transcriptional transitions, mature hepatic features, and C1INH secretion comparable to that observed in human plasma. All patient-derived HLCs demonstrated impaired C1INH secretion with mutation-specific differences in both SERPING1 transcription and intracellular accumulation. Moreover, to verify that the mutations directly drive the phenotype, we performed CRISPR/Cas9-mediated genome repair, which restored SERPING1 mRNA expression and C1INH secretion. Conversely, identical patient mutations installed into healthy EPSCs showed the same transcriptional and secretory defects, confirming sufficiency. Collectively, we have established a robust human hepatocyte model that accurately recapitulates key hepatocyte-specific aspects of HAE pathophysiology and provides a scalable foundation for investigation of future precision therapies.
2026-03-11 | 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.
2025-11-14 | 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.
proteins
2026-07-25 | Hereditary Angioedema: On-demand Treatment and Long-term Prophylaxis - A Global Reality.
Hereditary Angioedema (HAE) is a rare disorder of recurrent swellings of the subcutaneous and/or mucosal tissues due to defects in the contact system regulation of bradykinin production. The swellings can be disfiguring, cause debilitating abdominal pain, or be fatal with laryngeal obstruction. Over the last decade there has been immense successes in management of HAE owing to development of drugs targeting the contact system. This review focuses on management of HAE due to C1-INH deficiency/dysfunction including a global perspective which is under-represented in the literature. HAE with normal C1-INH is outside the scope of this article. The review provides summaries of clinical trials that has led to licensing of new HAE medications and discusses access to these modern drugs from a global perspective.
2026-06-30 | Dental Procedures for Hereditary Angioedema Patients: What Happens in Real Life?
ObjectiveDental procedures are known to be potential trigger for attacks in hereditary angioedema (HAE). Therefore, we aimed to demonstrate the potential of dental procedures to trigger HAE attacks through real-life experiences.MethodThe files of 57 patients diagnosed with HAE type I-II and followed up at the Immunology Allergy Diseases Outpatient Clinic between January 1, 2018, and April 4, 2025, were examined.ResultsThe study included 44 patients, and prophylaxis was administered to 27.3%, 26.7%, and 8.3% of those who underwent tooth extraction, filling, and root canal treatment, respectively. The frequency of attacks after tooth extraction was reduced in patients who received prophylaxis compared to those who did not receive prophylaxis, but this reduction was statistically insignificant (33.3% in those who did not receive prophylaxis vs. 22.2% in those who did). When comparing patients who experienced attacks without prophylaxis after tooth extraction with those who did not receive prophylaxis, it was observed that the group experiencing attacks was predominantly female (p=0.079). Attacks occurring after tooth extraction were not statistically significantly associated with attack triggers.ConclusionMost HAE patients do not receive prophylaxis before dental procedures. Given the risk of fatal laryngeal attacks, it is important to carefully assess patients for their prophylaxis needs before dental procedures, and to raise awareness among both patients and dentists regarding the risk of attacks despite prophylaxis.
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.
2026-05-20 | Post Hoc Analysis of Recombinant C1 Inhibitor Clinical Data Using Contemporary Endpoints for Hereditary Angioedema.
Contemporary trials of medications to treat hereditary angioedema (HAE) attacks define efficacy endpoints using Patient Global Impression of Severity (PGI-S) and Patient Global Impression of Change (PGI-C) scales; these differ from the visual analog scale (VAS) and treatment effect questionnaire (TEQ) used in legacy recombinant human C1 esterase inhibitor (rhC1-INH) studies. This post hoc analysis aimed to evaluate pooled rhC1-INH trial data, mapped to contemporary HAE clinical trial endpoints and designs. Pooling data from three rhC1-INH trials for acute HAE attacks (NCT00225147, NCT01188564, NCT00262301), this analysis applied results from a bookmarking study to convert TEQ and VAS measurements to PGI-S and PGI-C scales. Kaplan-Meier estimates were calculated for time to complete resolution (TTCR; defined as "none" on PGI-S) and time to onset of symptom relief (TOSR; defined as "a little better" on PGI-C at ≥ 2 consecutive time points within 12 h). Log-rank tests were used to determine differences between treatment groups. Across trials, 48 and 60 patients received rhC1-INH 50 U/kg and placebo, respectively. The most common attack locations were peripheral (47.9% and 41.7%, respectively) and abdominal (35.4% and 35.0%, respectively). Baseline attack severity was either severe or very severe in all patients. Median [95% confidence interval (CI)] TOSR was 0.75 h (0.55-1.50) with rhC1-INH and 8.00 h (3.00-8.05) with placebo (P < 0.001). Median (95% CI) TTCR was 4.50 h (3.55-5.50) with rhC1-INH and 24.00 h (16.00- > 24.00) with placebo (P < 0.001). This post hoc analysis confirmed that rhC1-INH, compared with placebo, is associated with significantly shorter TOSR and TTCR of HAE attacks. ClinicalTrials.gov: NCT00225147, NCT01188564, NCT00262301.
2026-05-03 | Comparative Efficacy of Recombinant C1 Inhibitor Versus Sebetralstat for On-Demand Treatment of Hereditary Angioedema Attacks: A Matching-Adjusted Indirect Treatment Comparison.
Prompt and effective on-demand treatment is critical in hereditary angioedema (HAE). Although multiple on-demand therapies are available, including recombinant human C1 esterase inhibitor (rhC1-INH) and sebetralstat, no head-to-head efficacy trials exist. A series of indirect treatment comparisons evaluated the relative efficacy of US Food and Drug Administration-approved doses of intravenous rhC1-INH (50 U/kg for patients weighing < 84 kg; 4200 U otherwise) vs oral sebetralstat (600 mg) for the on-demand treatment of HAE attacks. Patient-level data from rhC1-INH trials (C1 1310, C1 1205, and C1 1304 [placebo only]) were reweighted to match aggregate baseline characteristics (i.e., prophylaxis use, pooled attack location) from the sebetralstat KONFIDENT trial; matching variables were identified from a validated, clinician-informed study of treatment effect modifiers. In the primary analysis, time to complete resolution (TTCR) and redosing were compared using unanchored matching-adjusted indirect comparisons. TTCR subgroup analyses were performed for variables not matched for in the primary analysis due to population differences (i.e., attack severity, time to treatment). Scenario and sensitivity analyses were performed to support TTCR results; a scenario analysis was performed to support redosing results. Hazard ratios (HRs) and odds ratios (ORs), with 95% confidence intervals (CIs), were estimated using a weighted Cox proportional hazards model and a weighted logistic regression model, respectively. In the primary analysis, rhC1-INH was associated with a statistically significant 4.5-fold increased likelihood of achieving complete resolution (HR 4.52; 95% CI 2.84-7.18) and a significant 82% reduction in redosing (OR 0.18; 95% CI 0.06-0.53) vs sebetralstat. Similar results for TTCR were observed in subgroup analyses of patients with severe/very severe baseline attacks and patients receiving earlier treatment (within the median time to treatment). Scenario and sensitivity analyses confirmed the robustness of these findings. rhC1-INH provides significantly faster symptom resolution and lower redosing rates vs sebetralstat.
antibodies
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.
2026-06-03 | A novel SERPING1 splice-site variant (c.1029 + 2T > A) causing hereditary angioedema type I: functional characterization and clinical analysis.
Hereditary angioedema (HAE) is a rare autosomal dominant disorder predominantly caused by mutations in the SERPING1 gene, which encodes C1 esterase inhibitor (C1-INH). HAE is characterized by recurrent self-limiting episodes of subcutaneous and submucosal edema that can be life-threatening when the upper airway is involved. Diagnostic delays and misdiagnoses are common due to the clinical overlap with allergic and histamine-mediated angioedema. Identification and functional characterization of novel SERPING1 variants is essential for refining the mutational spectrum of this disease, enhancing molecular diagnostics, and guiding individualized therapeutic strategies. A 31-year-old female with a ten-year history of recurrent angioedema was diagnosed with HAE type I based on reduced serum C4, C1-INH antigen levels, and C1-INH functional activity. Sanger sequencing of the SERPING1 gene was performed to identify the causative variant. Functional characterization of the identified splice-site variant was conducted using reverse transcription-PCR (RT-PCR) on patient-derived peripheral blood RNA and an in vitro minigene splicing assay in HEK293T cells. A retrospective analysis of seven HAE patients was performed, including clinical characterization, laboratory profiling, genetic analysis, and treatment outcomes. A novel heterozygous splice-site variant, c.1029 + 2T > A, was identified at the canonical splice donor site of intron 6 of SERPING1. RT-PCR revealed reduced wild-type transcript expression and an aberrant transcript resulting from complete exon 6 skipping (c.890_1029del), predicted to cause a frameshift and premature termination codon (p.Ala297Glyfs*25). The minigene assay confirmed that the mutant construct produced no detectable canonical transcript; instead, three aberrant splice isoforms were identified, with exon 6 skipping as the predominant event. Long-term prophylactic treatment with Lanadelumab (300 mg subcutaneously every two weeks) achieved zero breakthrough attacks over a six-month follow-up period. In the retrospective cohort of seven patients, six were classified as type I and one as type II HAE. Seven distinct variants of the SERPING1 gene were identified. Among these patients, five received long-term prophylaxis with Lanadelumab, which resulted in significant reductions in the frequency of attacks. We identified and functionally characterized a novel SERPING1 splice-site variant, c.1029 + 2T > A, which disrupts canonical mRNA splicing, primarily through exon 6 skipping, leading to C1-INH haploinsufficiency and type I HAE. Our retrospective analysis expands the mutational spectrum of SERPING1 and demonstrates the clinical efficacy of Lanadelumab as a long-term prophylactic therapy. These findings underscore the importance of integrating genetic testing and functional validation in the diagnosis and management of HAE.
2026-05-21 | The Neglected Older Adults in Hereditary Angioedema: Insights From the ITACA Registry.
Hereditary Angioedema due to C1-inhibitor deficiency (HAE-C1INH) is a rare disease that affects individuals of all ages, however, older adults have never been characterized in terms of disease severity, comorbidities, and treatments. The aim was to identify the clinical characteristics of and therapeutic approaches in HAE-C1INH patients aged 65 and older. Data from the ITACA (Italian network for Hereditary and Acquired Angioedema) Registry were prospectively collected for 10-month. Data from 647 HAE-C1INH, patients including 343 females (53%), were collected: 114 patients (17.6%) were aged 65 and older (68 females; 58.6%). Group mean age was 74.3 ± 7.5 years, mean age at first-symptom-onset was 19 ± 15 years, and mean age at diagnosis was 45.6 ± 14.3 years. Common comorbidities were: hypertension (59.6%), dyslipidaemia (28.9%), coronary artery disease (14.0%), diabetes (14.0%), endocrinopathies (14.0%), neoplasia (12.3%) and B/C hepatitis (11.4%). Half of the older patients (49%) experienced at least one attack during the study period, and 8 patients (7%) had an attack frequency of > 0.5 attacks/month. Long-term prophylaxis (LTP) was the treatment of choice in 45 patients (39.5%) and represented 15.9% of overall LTP prescriptions: 60% were treated with lanadelumab, 22.2% with attenuated androgens, 13.3% with berotralstat, and 4.5% with sub-cutaneous C1INH concentrate. Gender differences were not detected in any of the variables analyzed. Older patients with HAE-C1INH constitute a relevant subgroup, characterized by persistent disease activity and comorbidities. The availability of new therapies and guideline recommendations are driving an increase in LTP use, although shifting from older non-specific treatments, especially androgens, is still incomplete.
2026-04-14 | Factor XII in Thrombosis and Thromboinflammation: From Molecular Biology to Clinical Translation.
Factor XII (FXII) is a central mediator at the intersection of coagulation, fibrinolysis, inflammation, and immunity. It is activated upon contact with negatively charged surfaces, triggering the intrinsic coagulation pathway and driving thrombus formation and stabilization. Beyond clotting, FXII contributes to activation of the kallikrein-kinin system, generation of bradykinin, and modulation of inflammatory and immune responses. Congenital FXII deficiency does not increase bleeding risk, highlighting its unique role and making FXII inhibition an attractive strategy for anticoagulation and immune modulation with a potentially superior safety profile. Preclinical studies provide compelling evidence for this concept. In models of ischemic stroke and traumatic brain injury, FXII blockade significantly reduced infarct volume, improved neurological outcomes, and attenuated neuroinflammation without increasing hemorrhage. Similarly, in extracorporeal circulation and vascular stent implantation, FXII inhibition prevented thrombus formation and reduced fibrin deposition, achieving effects comparable to heparin but with markedly lower bleeding risk. Several classes of FXII inhibitors are currently in development, including antisense oligonucleotides, peptides, recombinant proteins, and monoclonal antibodies. Among them, Ixodes ricinus contact phase inhibitor (Ir-CPI) and recombinant human albumin-fused Infestin-4 (rHA-Infestin-4) have demonstrated strong antithrombotic efficacy in animal models. Most notably, garadacimab, a monoclonal anti-FXIIa antibody, has completed phase 3 trials and received regulatory approval for hereditary angioedema (HAE) prophylaxis, where it markedly reduces attack frequency with a favorable safety profile. This review summarizes current knowledge on FXII biology and evaluates its translational potential as a novel target for anticoagulant and anti-inflammatory therapies.
2026-03-31 | [Consensus of Mexican experts on long-term prophylaxis in patients with hereditary angioedema in Mexico].
Hereditary angioedema (HAE) is a rare, potentially life-threatening genetic disorder characterized by recurrent, bradykinin-mediated swelling episodes, with substantial impact on morbidity, quality of life, and healthcare resource use. Targeted agents have reshaped long-term prophylaxis (LTP); however, effective implementation depends on clinical decision-making as well as health-system access and structural constraints. To comprehensively describe HAE long-term prophylaxis management in Mexico, focusing on the diagnostic approach, LTP use, treatment access and availability, perceived disease control, and applicability of clinical recommendations, based on structured national expert opinion. We conducted a descriptive and analytical evaluation of Mexico-specific data derived from a structured Delphi process involving clinicians experienced in HAE management. Assessed domains included diagnostic testing practices, selection and prescribing frequency of LTP therapies, use of non-recommended treatments, funding sources, medication availability issues, access barriers, and clinicians' perceptions regarding disease control and guideline applicability. Experts reported strong conceptual alignment with current clinical recommendations. LTP prescribing was predominantly concentrated on lanadelumab, with limited use of C1-INH concentrates and no reported use of berotralstat. Despite reported public coverage, frequent barriers related to availability and cost constrained effective access and treatment continuity. Clinical guidelines were perceived as highly applicable; however, a gap between recommended care and feasible real-world implementation was consistently acknowledged. HAE prophylaxis management in Mexico appears aligned with contemporary standards, yet sustained and individualized implementation remains limited by structural access and supply constraints. Key priorities include strengthening timely diagnosis, ensuring continuous access to targeted therapies, and standardizing follow-up in routine clinical care.
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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.
2026-03-10 | Donidalorsen for hereditary angioedema: Long-term results from a 4-year, phase 2, open-label extension study.
Hereditary angioedema (HAE) is a rare disorder caused by kallikrein-kinin system dysregulation. Donidalorsen is a prekallikrein-directed antisense oligonucleotide that can rebalance this system by reducing prekallikrein production and is indicated for prophylaxis to prevent HAE attacks in patients 12 years of age and older. To report results from a 4-year, phase 2, open-label extension study of donidalorsen (NCT04307381). The study on-treatment period included fixed (weeks 0-12) and flexible (weeks 16-208) treatment periods. Patients received donidalorsen 80 mg subcutaneously every 4 weeks (Q4W) in the fixed treatment period and could receive 80 mg every 8 weeks (Q8W) in the flexible treatment period if attack free for greater than or equal to 12 weeks or 100 mg Q4W if disease was not adequately controlled. End points are summarized through the end of the study (week 208). Of 17 patients with HAE-C1INH-type 1 or HAE-C1INH-type 2, 13 (76%) completed 4 years of treatment (median exposure: 3.99 years). Eight patients changed to donidalorsen Q8W; 5 stayed on Q8W to study completion. One patient received 100 mg Q4W. Mean monthly HAE attack rates decreased by 97% overall from baseline to the on-treatment period, with 97% (Q4W) and 83% (Q8W) decreases to the flexible treatment period. The median longest attack-free interval was 990 days. No serious treatment-emergent adverse events (TEAEs) occurred. One patient (6%) (100 mg Q4W) discontinued due to a TEAE (injection-site discoloration). Seven patients (41%) reported treatment-related TEAEs; the only treatment-related TEAEs reported in more than 1 patient were injection-site reactions. In this 4-year study, donidalorsen led to sustained reductions in monthly HAE attack rate with an acceptable safety profile. ClinicalTrials.gov Identifier: NCT04307381 (https://www. gov/study/NCT04307381).
2026-03-02 | Donidalorsen for Long-Term Prophylaxis of Hereditary Angioedema Attacks: Results from the OASISplus Open-Label Extension Cohort at Year 1.
Donidalorsen, a prekallikrein-directed antisense oligonucleotide indicated for prophylaxis of hereditary angioedema (HAE) attacks in patients aged ≥12 years, demonstrated efficacy and acceptable safety in the phase 3, placebo-controlled OASIS-HAE trial (NCT05139810). Here, we report 1-year results from the corresponding open-label extension (OLE) cohort of the OASISplus study (NCT05392114). OASISplus included patients who rolled over from OASIS-HAE. Patients who received donidalorsen 80 mg or placebo subcutaneously every 4 weeks (Q4W) in OASIS-HAE received donidalorsen Q4W in OASISplus. Patients who received donidalorsen 80 mg or placebo every 8 weeks (Q8W) in OASIS-HAE received donidalorsen Q8W or Q4W, if not attack-free in the final 8 weeks of OASIS-HAE. The primary endpoint was safety (ie, incidence of treatment-emergent adverse events [TEAEs]). Secondary endpoints included the monthly rate of HAE attacks and Angioedema Quality of Life (AE-QoL). The OLE cohort included 83 patients (Q4W, n=69 [83%]; Q8W, n=14 [17%]). Of these, 75 (90.4%) completed Year 1, and 6 patients receiving donidalorsen Q8W in OASIS-HAE switched to the Q4W dosing group in the OLE. Median donidalorsen exposure was 392.3 days. From Weeks 0 to 52, reductions in mean HAE attack rate from OASIS-HAE baseline were 94% (Q4W) and 95% (Q8W), and patients reported clinically meaningful improvements in mean AE-QoL total score at Week 52 (Q4W, 28.1 points; Q8W, 26.7 points). Twenty-two (27%) patients reported treatment-related TEAEs; none were serious, and injection-site reactions were the most frequently reported. Donidalorsen demonstrated sustained reductions in HAE attack rate, improvements in QoL, and an acceptable safety profile after 1 year of treatment.
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Drug Discovery Landscape
25 orphan drug designations for Hereditary angioedema, including 9 approved therapies.
25 orphan drug designations for Hereditary angioedema, including 9 approved therapies.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
small interfering RNA duplex oligonucleotide designed to cleave prekallikrein messenger RNA | RNAs | FDA | 2025-10-02 | — | ADARx Pharmaceuticals, Inc. |
Navenibart | antibodies | EMA | 2024-10-11 | — | Phara |
navenibart | antibodies | FDA | 2024-09-26 | — | Astria Therapeutics, Inc. |
Donidalorsen [Dawnzera] | oligonucleotides | EMA | 2024-02-19 | — | Otsuka Pharmaceutical Netherlands B.V. |
Messenger RNA encoding Cas9, Single guide RNA targeting the human KLKB1 gene | gene editing enzymes | EMA | 2023-11-08 | — | Pharma Gateway AB |
donidalorsen [Dawnzera] | RNAs | FDA | 2023-09-19 | 2025-08-21 | Ionis Pharmaceuticals |
Adeno-associated virus serotype 5 vector encoding C1-esterase inhibitor | gene therapies | EMA | 2022-11-10 | — | Biomarin International Limited |
lipid nanoparticle encapsulating single guide RNA (G012267) targeting the human KLKB1 gene and messenger RNA (mRNA000042) encoding Cas9 | combination | FDA | 2022-09-01 | — | Intellia Therapeutics, Inc. |
Sebetralstat [Ekterly] | small molecules | EMA | 2022-06-21 | 2025-09-18 | Kalvista Pharmaceuticals (Ireland) Limited |
deucrictibant | small molecules | FDA | 2022-03-18 | — | Pharvaris GmbH |
adeno-associated virus serotype 5 (AAV5) vector containing the hSERPING cDNA sequence encoding human C1-esterase inhibitor (C1-INH) | gene therapies | FDA | 2021-12-20 | — | BioMarin Pharmaceutical, Inc. |
Garadacimab [Andembry] | antibodies | EMA | 2021-12-10 | — | CSL Behring GmbH |
sebetralstat [Ekterly] | small molecules | FDA | 2021-09-07 | 2025-07-03 | KalVista Pharmaceuticals Ltd |
garadacimab-gxii [Andembry] | antibodies | FDA | 2020-04-30 | 2025-06-16 | CSL Behring |
Berotralstat [Orladeyo] | small molecules | EMA | 2018-06-27 | — | Biocryst Ireland Limited |
Recombinant human IgG1 kappa light chain monoclonal antibody targeting plasma kallikrein [TAKHZYRO] | antibodies | EMA | 2015-10-09 | 2018-11-26 | Takeda Pharmaceuticals International AG Ireland Branch |
Avoralstat [BCX4161] | small molecules | EMA | 2015-02-12 | — | Biocryst UK Limited |
3-[2-(4-carbamimidoyl-phenylcarbamoyl)-5-methoxy-4-vinyl-phenyl]-6-(cyclopropylmethyl-carbamoyl)-pyridine-2-carboxylic acid | small molecules | FDA | 2014-12-23 | — | BioCryst Pharmaceuticals, Inc. |
Human C1-esterase inhibitor [Cinryze] | proteins | EMA | 2009-10-08 | — | Shire Services |
C1 esterase inhibitor (human) [Cinryze] | proteins | FDA | 2004-07-16 | 2008-10-10 | Takeda Development Center Americas, Inc. |
icatibant [Firazyr] | small molecules | FDA | 2003-11-25 | 2011-08-25 | Takeda Development Center Americas, Inc. |
Icatibant acetate [Firazyr] | peptides | EMA | 2003-02-17 | — | [INACTIVE] Shire Orphan Therapies GmbH |
Ecallantide [Kalbitor] | proteins | EMA | 2002-12-18 | — | [INACTIVE] Dyax |
C1 esterase inhibitor subcutaneous (human) [Haegarda] | proteins | FDA | 1992-10-16 | 2017-06-22 | CSL Behring LLC |
C1 esterase inhibitor (human) [Berinert] | proteins | FDA | 1992-10-16 | 2009-10-08 | CSL Behring LLC |
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