RARE DISEASE
F12-related hereditary angioedema with normal C1Inh
F12-related hereditary angioedema with normal C1Inh
F12-related hereditary angioedema with normal C1Inh
Synonyms: F12-related HAE with normal C1 inhibitor, HAE 3, HAE-III, Hereditary angioedema type 3, Hereditary angioneurotic edema type 3, Inherited estrogen-associated angioedema, Inherited estrogen-associated angioneurotic edema, Inherited estrogen-dependent angioedema, Inherited estrogen-dependent angioneurotic edema
Synonyms: F12-related HAE with normal C1 inhibitor, HAE 3, HAE-III, Hereditary angioedema type 3, Hereditary angioneurotic edema type 3, Inherited estrogen-associated angioedema, Inherited estrogen-associated angioneurotic edema, Inherited estrogen-dependent angioedema, Inherited estrogen-dependent angioneurotic edema
Synonyms: F12-related HAE with normal C1 inhibitor, HAE 3, HAE-III, Hereditary angioedema type 3, Hereditary angioneurotic edema type 3, Inherited estrogen-associated angioedema, Inherited estrogen-associated angioneurotic edema, Inherited estrogen-dependent angioedema, Inherited estrogen-dependent angioneurotic edema
Drug discovery
0
drugs
With orphan designations
Overview
F12-related hereditary angioedema (HAE) is an autosomal dominant disorder caused by gain-of-function mutations in the F12 gene, leading to excessive bradykinin production. It manifests as recurrent subcutaneous edema, abdominal pain attacks, and life-threatening airway swelling, with normal C1 inhibitor (C1-INH) levels. Symptoms are often estrogen-exacerbated, triggered by pregnancy or hormonal therapies. Diagnosis requires genetic testing after excluding C1-INH deficiency [1][2][12].
Burden
Episodes cause 15,000–30,000 annual emergency visits in the U.S., with 32.3% experiencing upper airway edema [10][12].
Delayed diagnosis (average 6–10 years) exacerbates morbidity; 68.6% of women report estrogen-dependent exacerbations [2][6][10].
Quality-of-life impacts include anxiety, chronic pain, and reduced productivity [3][12].
Therapies
Acute attacks: Plasma-derived C1-INH (pdC1-INH) or bradykinin B2 receptor antagonists (e.g., icatibant) [3][11][16].
Prophylaxis: Tranexamic acid, danazol, or progestins; estrogen-containing therapies and ACE inhibitors are contraindicated [3][6][12].
Emerging therapies: Anti-FXII monoclonal antibodies (e.g., garadacimab) and siRNA therapies targeting F12 (e.g., ARC-F12) [7][17].
Categories: rare allergic disease, rare genetic diseases, rare systemic and rheumatological diseases
Research Papers
213 drug discovery papers about F12-related hereditary angioedema with normal C1Inh, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
213 drug discovery papers about F12-related hereditary angioedema with normal C1Inh, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-06 | A plain language summary of oral berotralstat for preventive treatment of hereditary angioedema attacks in children: early safety and efficacy results of the ongoing APeX-P study
What is this summary about? This plain language summary describes the interim results (early findings) of an ongoing study called APeX-P, which was published in the Annals of Allergy, Asthma & Immunology journal in 2025. The study looked at berotralstat, an oral (taken by mouth) medication, as a treatment option for hereditary angioedema (HAE) in children. HAE is a rare genetic disease that causes episodes of swelling (attacks) in different parts of the body, which can be serious. Attacks in the tongue and throat can be life-threatening. Berotralstat is taken once a day. Before the APeX-P study, the medication was approved in several countries to help prevent HAE attacks in people aged 12 and older. Berotralstat is now approved for use in people aged 2 and older in the United States. The APeX-P study researchers looked at which doses of berotralstat are appropriate for children aged 2 to under age 12, how children tolerated the medication, and how well berotralstat helps to prevent HAE attacks. The study also assessed children’s experiences and burdens with HAE. What were the results? Most of the children participating in the APeX-P study started having symptoms of HAE before they were 6 years old. Before beginning the study, children experienced burden because of HAE attacks, including missing school and needing emergency medical care because of their symptoms. After taking berotralstat for 12 weeks, children had fewer HAE attacks. The lower rate of attacks continued for up to 48-weeks (about 1 year—the study was still ongoing). This meant that children had fewer days with HAE symptoms. During the first 12 weeks of treatment with berotralstat, 3 HAE attacks (across all children in the study) needed medical care in a doctor’s office, clinic, or hospital. This need for medical care was 86% less than the 22 attacks needing medical care in the 12 weeks before the children started taking the medication. Most children in the study experienced at least 1 side effect after taking berotralstat; only 2 side effects (mild nausea or ‘feeling queasy’ and moderate headache) in 2 children were considered to be caused by the medication. Side effects were mild to moderate except in 1 patient who had an accident and a broken arm that was not caused by the medication. The most common side effects included a common cold, upper respiratory infection (in the nose, throat, or sinuses), or headache. What do the results mean? In the APeX-P study, children taking berotralstat tolerated the treatment well. The interim results show that berotralstat prevented attacks from HAE in young children. How to say (download PDF and double click sound icon to play sound)… APeX-P: AY-peks-pee Berotralstat: bear-oh-TRAL-stat Bradykinin: bray-DEE-ki-nin Hereditary angioedema: huh-REH-duh-tree AN-jee-oh-eh-DEE-muh Kallikrein: kal-uh-KREE-in Prophylaxis: pro-fuh-LACK-sis Angioedema: Swelling in the tissue under the skin. Genetic disease: Diseases caused by changes in a person’s DNA that can develop spontaneously or be passed on from parents to children. Tolerated: To handle a medication without having side effects that are serious or bothersome, or that are manageable enough for patients to continue taking the treatment. This is an abstract of the Plain Language Summary of Publication article. View the full Plain Language Summary PDF of this article to read the full-text Link to original article here
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.
2026-07-12 | 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.
2026-07-11 | 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.
2026-08-06 | A plain language summary of oral berotralstat for preventive treatment of hereditary angioedema attacks in children: early safety and efficacy results of the ongoing APeX-P study
What is this summary about? This plain language summary describes the interim results (early findings) of an ongoing study called APeX-P, which was published in the Annals of Allergy, Asthma & Immunology journal in 2025. The study looked at berotralstat, an oral (taken by mouth) medication, as a treatment option for hereditary angioedema (HAE) in children. HAE is a rare genetic disease that causes episodes of swelling (attacks) in different parts of the body, which can be serious. Attacks in the tongue and throat can be life-threatening. Berotralstat is taken once a day. Before the APeX-P study, the medication was approved in several countries to help prevent HAE attacks in people aged 12 and older. Berotralstat is now approved for use in people aged 2 and older in the United States. The APeX-P study researchers looked at which doses of berotralstat are appropriate for children aged 2 to under age 12, how children tolerated the medication, and how well berotralstat helps to prevent HAE attacks. The study also assessed children’s experiences and burdens with HAE. What were the results? Most of the children participating in the APeX-P study started having symptoms of HAE before they were 6 years old. Before beginning the study, children experienced burden because of HAE attacks, including missing school and needing emergency medical care because of their symptoms. After taking berotralstat for 12 weeks, children had fewer HAE attacks. The lower rate of attacks continued for up to 48-weeks (about 1 year—the study was still ongoing). This meant that children had fewer days with HAE symptoms. During the first 12 weeks of treatment with berotralstat, 3 HAE attacks (across all children in the study) needed medical care in a doctor’s office, clinic, or hospital. This need for medical care was 86% less than the 22 attacks needing medical care in the 12 weeks before the children started taking the medication. Most children in the study experienced at least 1 side effect after taking berotralstat; only 2 side effects (mild nausea or ‘feeling queasy’ and moderate headache) in 2 children were considered to be caused by the medication. Side effects were mild to moderate except in 1 patient who had an accident and a broken arm that was not caused by the medication. The most common side effects included a common cold, upper respiratory infection (in the nose, throat, or sinuses), or headache. What do the results mean? In the APeX-P study, children taking berotralstat tolerated the treatment well. The interim results show that berotralstat prevented attacks from HAE in young children. How to say (download PDF and double click sound icon to play sound)… APeX-P: AY-peks-pee Berotralstat: bear-oh-TRAL-stat Bradykinin: bray-DEE-ki-nin Hereditary angioedema: huh-REH-duh-tree AN-jee-oh-eh-DEE-muh Kallikrein: kal-uh-KREE-in Prophylaxis: pro-fuh-LACK-sis Angioedema: Swelling in the tissue under the skin. Genetic disease: Diseases caused by changes in a person’s DNA that can develop spontaneously or be passed on from parents to children. Tolerated: To handle a medication without having side effects that are serious or bothersome, or that are manageable enough for patients to continue taking the treatment. This is an abstract of the Plain Language Summary of Publication article. View the full Plain Language Summary PDF of this article to read the full-text Link to original article here
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.
2026-07-12 | 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.
2026-07-11 | 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.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
0 orphan drug designations.
0 orphan drug designations.
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI's forecasts to outperform average preclinical success rates. Whether you're expanding your R&D pipeline, evaluating a partnership, or simply have a question — we'd love to hear from you.