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)
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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.
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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.
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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.
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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.
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