RARE DISEASE
Hereditary angioedema with C1Inh deficiency
Hereditary angioedema with C1Inh deficiency
Hereditary angioedema with C1Inh deficiency
Synonyms: HAE with C1 inhibitor deficiency, HAE with C1Inh deficiency, Hereditary angioneurotic edema with C1 inhibitor deficiency, Hereditary angioneurotic edema with C1Inh deficiency
Synonyms: HAE with C1 inhibitor deficiency, HAE with C1Inh deficiency, Hereditary angioneurotic edema with C1 inhibitor deficiency, Hereditary angioneurotic edema with C1Inh deficiency
Synonyms: HAE with C1 inhibitor deficiency, HAE with C1Inh deficiency, Hereditary angioneurotic edema with C1 inhibitor deficiency, Hereditary angioneurotic edema with C1Inh deficiency
Drug discovery
7
drugs
With orphan designations
Overview
Hereditary angioedema with C1 inhibitor deficiency (C1-INH-HAE) is a rare autosomal dominant disorder caused by SERPING1 mutations, leading to quantitative (type I) or qualitative (type II) C1-INH deficiency. This results in unregulated bradykinin production, causing recurrent subcutaneous/submucosal edema involving the skin, gastrointestinal tract, and upper airways. Life-threatening laryngeal edema occurs in 30–50% of untreated cases. Diagnosis requires serum C4 and functional C1-INH testing. Management includes acute therapies (C1-INH concentrates, icatibant) and long-term prophylaxis (C1-INH, kallikrein inhibitors, androgens) [1][2][10][12].
Burden
Mortality: Up to 30% lifetime risk of fatal laryngeal edema without prompt treatment [5][15].
Morbidity: 30% undergo unnecessary abdominal surgeries due to misdiagnosis; 70% report anxiety/depression [2][4][9].
Economic impact: Frequent ED visits, absenteeism, and reduced productivity (50% experience work/school impairment) [4][9][14].
Therapies
Acute attacks: C1-INH replacement (IV/SC), bradykinin B2 receptor antagonists (icatibant), and recombinant kallikrein inhibitors (ecallantide) [5][6][8][13].
Prophylaxis: Long-term C1-INH therapy, subcutaneous kallikrein inhibitors (lanadelumab), oral plasma kallikrein inhibitors (berotralstat), and attenuated androgens (danazol) [3][5][8][13].
Emerging therapies: Antisense oligonucleotides targeting prekallikrein and monoclonal antibodies against factor XIIa [9][13].
Categories: rare allergic disease, rare genetic diseases, rare systemic and rheumatological diseases
Research Papers
1,130 drug discovery papers about Hereditary angioedema with C1Inh deficiency, with 6 first-in-class and 13 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,130 drug discovery papers about Hereditary angioedema with C1Inh deficiency, with 6 first-in-class and 13 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-11 | Hereditary Angioedema Presenting as Recurrent Abdominal Pain: A Diagnostic Challenge
Background: This case report highlights the importance of prompt recognition of hereditary angioedema (HAE) in patients with recurrent abdominal attacks that may mimic surgical emergencies and lead to unnecessary interventions. Case Presentation: A 29-year-old man presented with severe recurrent abdominal pain associated with loose stools. Each episode lasted 3-5 days and resolved spontaneously. Further enquiry revealed a 16-year history of recurrent angioedema involving the face, lips, oral cavity, dorsum of both hands, and large joints of the lower limbs, with multiple episodes each year. The long-standing symptoms and diagnostic delay raised strong clinical suspicion of C1 esterase inhibitor (C1-INH) deficiency. Contrast-enhanced computed tomography of the abdomen and subsequent colonoscopy were performed during an attack. Laboratory evaluation showed low serum C4, low quantitative C1-INH levels, and markedly reduced C1-INH functional activity, findings consistent with Type 1 HAE. The patient was subsequently started on tranexamic acid. At follow-up, he was clinically improved, with complete resolution of symptoms and no recurrence of attacks. Conclusion: This case highlights the importance of recognising abdominal attacks in patients with C1-INH deficiency. Such attacks can be debilitating, may mimic surgical emergencies, and may contribute to prolonged diagnostic delay. Careful recognition of the recurrent pattern of abdominal symptoms together with non-pruritic, non-pitting angioedema and appropriate biochemical testing can support timely diagnosis and help avoid unnecessary interventions.
2026-08-08 | Lanadelumab Use for Hereditary Angioedema Long-Term Prophylaxis Over the Last 7 Years: A Narrative Review of Clinical and Real-World Data.
Hereditary angioedema (HAE) is a rare genetic disease characterized by unpredictable, painful cutaneous and/or subcutaneous swelling attacks; laryngeal attacks can be fatal. For many patients, long-term prophylaxis (LTP) is critical for disease control and quality of life.Lanadelumab, a plasma kallikrein inhibitor, was approved for HAE LTP for adults and adolescents in 2018 and for children aged ≥ 2 years in 2023; it is currently one of the guideline-recommended, first-line LTP options. By integrating 7 years of cumulative clinical trial and real-world data, this narrative review summarizes lanadelumab long-term effectiveness and safety in adult, adolescent, and pediatric HAE populations. Outcomes in 41 peer-reviewed publications were evaluated, including 5 clinical trials involving 262 lanadelumab-treated patients and 28 real-world studies comprising ~ 700 patients. Across clinical trials, lanadelumab reduced attack rates by up to 100%, with an average of 24.9-27.3 patient-reported attack-free days per 28-day period. These findings were largely corroborated by real-world data, including 2 large observational studies with > 100 patients each. Patient-reported disease control and health-related quality of life improved consistently across both settings. The main treatment-related adverse events across studies were injection site reactions. Treatment persistence was generally high in clinical practice. Unmet needs remain for specific populations, including pregnant or lactating patients and those without access to guideline-recommended LTP. Future research should address real-world outcomes in pediatric patients, extended dosing intervals in well-controlled disease, transitions from other LTP therapies, and cost-effectiveness. Overall, sustained effectiveness, safety, and quality-of-life benefits of lanadelumab reinforce its role as a cornerstone of HAE management.
2026-08-05 | Diagnostic delay, SERPING1 allelic heterogeneity, and real-world lanadelumab prophylaxis in Chinese patients with hereditary angioedema due to C1 inhibitor deficiency
Background Hereditary angioedema due to C1 inhibitor deficiency (HAE-C1INH) is a rare and potentially life-threatening bradykinin-mediated disorder most commonly associated with pathogenic variants in SERPING1 . Data from Chinese patients remain limited, particularly regarding diagnostic delay, SERPING1 allelic heterogeneity, and real-world use of lanadelumab prophylaxis. Methods In this single-center retrospective observational study, we reviewed 10 consecutive unrelated index patients with confirmed HAE-C1INH managed at Henan Provincial People’s Hospital from January 2022 to May 2026. Clinical data, complement results, and SERPING1 Sanger sequencing findings were analyzed. Variants were classified according to ACMG/AMP criteria. Seven patients received lanadelumab long-term prophylaxis. Annualized attack rates and Angioedema Control Test scores before and during prophylaxis were compared using the Wilcoxon signed-rank test. Results The cohort included 6 females and 4 males, with a mean age of 32.8 ± 9.9 years. Nine patients had HAE-C1INH type 1 and one had type 2. The mean age at symptom onset was 21.7 ± 11.1 years, and the mean diagnostic delay was 9.4 ± 7.0 years. All patients had recurrent peripheral edema, 7 had abdominal attacks, and 6 had facial and/or laryngeal involvement. One patient required emergency tracheotomy. Serum C4 was reduced during attacks in all patients, and C1q levels were normal. Ten distinct heterozygous SERPING1 variants were identified, including 3 frameshift variants, 6 missense variants, and 1 in-frame deletion. Among the 7 patients receiving lanadelumab, the median annualized attack rate decreased from 11 (IQR, 7–23) to 0 (IQR, 0–1) attacks/year, and the median AECT score increased from 3 (IQR, 2–4) to 13 (IQR, 13–13). No serious adverse events were recorded. Conclusions This single-center retrospective study showed substantial diagnostic delay, marked SERPING1 allelic heterogeneity, and favorable real-world outcomes with lanadelumab prophylaxis in Chinese patients with HAE-C1INH. Earlier complement testing and access to appropriate genetic testing may shorten diagnostic delay. Larger prospective studies are needed to define individualized long-term prophylaxis strategies in Chinese patients.
2026-08-04 | [Current and future therapies for bradykinin-mediated angioedema].
Bradykinin-mediated angioedema, particularly hereditary angioedema due to C1 esterase inhibitor deficiency or dysfunction (HAE-C1INH), is caused by dysregulation of the kallikrein-kinin system with excessive bradykinin generation and subsequent increased vascular permeability. Modern HAE management is based on three major therapeutic strategies: on-demand treatment, short-term prophylaxis (STP), and long-term prophylaxis (LTP). On-demand treatment options include plasma-derived and recombinant C1 inhibitor (C1INH) concentrates, the bradykinin B2 receptor antagonist icatibant, and, more recently, the first orally available plasma kallikrein inhibitor, sebetralstat. Short-term prophylaxis prior to invasive medical procedures is performed as replacement therapy by intravenous administration of C1INH concentrates. The goal of long-term prophylaxis is complete disease control with reduction of attack frequency and/or severity and improvement of quality of life. LTP therapies include subcutaneous and intravenous C1INH preparations, the oral kallikrein inhibitor berotralstat, the anti-kallikrein monoclonal antibody lanadelumab, the factor XIIa inhibitor garadacimab, and the antisense oligonucleotide donidalorsen. Currently under development are the oral bradykinin B2 receptor antagonist deucrictibant, which is intended for both on-demand treatment and long-term prophylaxis in different formulations, long-acting antibodies, such as navenibart, and CRISPR/Cas9-based gene-editing therapies, such as NTLA-2002 with potential functional curative properties. In particular, orally available and long-acting therapies are expected to improve adherence, self-management, and quality of life in affected patients.
2026-07-28 | 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)
2026-08-11 | Hereditary Angioedema Presenting as Recurrent Abdominal Pain: A Diagnostic Challenge
Background: This case report highlights the importance of prompt recognition of hereditary angioedema (HAE) in patients with recurrent abdominal attacks that may mimic surgical emergencies and lead to unnecessary interventions. Case Presentation: A 29-year-old man presented with severe recurrent abdominal pain associated with loose stools. Each episode lasted 3-5 days and resolved spontaneously. Further enquiry revealed a 16-year history of recurrent angioedema involving the face, lips, oral cavity, dorsum of both hands, and large joints of the lower limbs, with multiple episodes each year. The long-standing symptoms and diagnostic delay raised strong clinical suspicion of C1 esterase inhibitor (C1-INH) deficiency. Contrast-enhanced computed tomography of the abdomen and subsequent colonoscopy were performed during an attack. Laboratory evaluation showed low serum C4, low quantitative C1-INH levels, and markedly reduced C1-INH functional activity, findings consistent with Type 1 HAE. The patient was subsequently started on tranexamic acid. At follow-up, he was clinically improved, with complete resolution of symptoms and no recurrence of attacks. Conclusion: This case highlights the importance of recognising abdominal attacks in patients with C1-INH deficiency. Such attacks can be debilitating, may mimic surgical emergencies, and may contribute to prolonged diagnostic delay. Careful recognition of the recurrent pattern of abdominal symptoms together with non-pruritic, non-pitting angioedema and appropriate biochemical testing can support timely diagnosis and help avoid unnecessary interventions.
2026-08-08 | Lanadelumab Use for Hereditary Angioedema Long-Term Prophylaxis Over the Last 7 Years: A Narrative Review of Clinical and Real-World Data.
Hereditary angioedema (HAE) is a rare genetic disease characterized by unpredictable, painful cutaneous and/or subcutaneous swelling attacks; laryngeal attacks can be fatal. For many patients, long-term prophylaxis (LTP) is critical for disease control and quality of life.Lanadelumab, a plasma kallikrein inhibitor, was approved for HAE LTP for adults and adolescents in 2018 and for children aged ≥ 2 years in 2023; it is currently one of the guideline-recommended, first-line LTP options. By integrating 7 years of cumulative clinical trial and real-world data, this narrative review summarizes lanadelumab long-term effectiveness and safety in adult, adolescent, and pediatric HAE populations. Outcomes in 41 peer-reviewed publications were evaluated, including 5 clinical trials involving 262 lanadelumab-treated patients and 28 real-world studies comprising ~ 700 patients. Across clinical trials, lanadelumab reduced attack rates by up to 100%, with an average of 24.9-27.3 patient-reported attack-free days per 28-day period. These findings were largely corroborated by real-world data, including 2 large observational studies with > 100 patients each. Patient-reported disease control and health-related quality of life improved consistently across both settings. The main treatment-related adverse events across studies were injection site reactions. Treatment persistence was generally high in clinical practice. Unmet needs remain for specific populations, including pregnant or lactating patients and those without access to guideline-recommended LTP. Future research should address real-world outcomes in pediatric patients, extended dosing intervals in well-controlled disease, transitions from other LTP therapies, and cost-effectiveness. Overall, sustained effectiveness, safety, and quality-of-life benefits of lanadelumab reinforce its role as a cornerstone of HAE management.
2026-08-05 | Diagnostic delay, SERPING1 allelic heterogeneity, and real-world lanadelumab prophylaxis in Chinese patients with hereditary angioedema due to C1 inhibitor deficiency
Background Hereditary angioedema due to C1 inhibitor deficiency (HAE-C1INH) is a rare and potentially life-threatening bradykinin-mediated disorder most commonly associated with pathogenic variants in SERPING1 . Data from Chinese patients remain limited, particularly regarding diagnostic delay, SERPING1 allelic heterogeneity, and real-world use of lanadelumab prophylaxis. Methods In this single-center retrospective observational study, we reviewed 10 consecutive unrelated index patients with confirmed HAE-C1INH managed at Henan Provincial People’s Hospital from January 2022 to May 2026. Clinical data, complement results, and SERPING1 Sanger sequencing findings were analyzed. Variants were classified according to ACMG/AMP criteria. Seven patients received lanadelumab long-term prophylaxis. Annualized attack rates and Angioedema Control Test scores before and during prophylaxis were compared using the Wilcoxon signed-rank test. Results The cohort included 6 females and 4 males, with a mean age of 32.8 ± 9.9 years. Nine patients had HAE-C1INH type 1 and one had type 2. The mean age at symptom onset was 21.7 ± 11.1 years, and the mean diagnostic delay was 9.4 ± 7.0 years. All patients had recurrent peripheral edema, 7 had abdominal attacks, and 6 had facial and/or laryngeal involvement. One patient required emergency tracheotomy. Serum C4 was reduced during attacks in all patients, and C1q levels were normal. Ten distinct heterozygous SERPING1 variants were identified, including 3 frameshift variants, 6 missense variants, and 1 in-frame deletion. Among the 7 patients receiving lanadelumab, the median annualized attack rate decreased from 11 (IQR, 7–23) to 0 (IQR, 0–1) attacks/year, and the median AECT score increased from 3 (IQR, 2–4) to 13 (IQR, 13–13). No serious adverse events were recorded. Conclusions This single-center retrospective study showed substantial diagnostic delay, marked SERPING1 allelic heterogeneity, and favorable real-world outcomes with lanadelumab prophylaxis in Chinese patients with HAE-C1INH. Earlier complement testing and access to appropriate genetic testing may shorten diagnostic delay. Larger prospective studies are needed to define individualized long-term prophylaxis strategies in Chinese patients.
2026-08-04 | [Current and future therapies for bradykinin-mediated angioedema].
Bradykinin-mediated angioedema, particularly hereditary angioedema due to C1 esterase inhibitor deficiency or dysfunction (HAE-C1INH), is caused by dysregulation of the kallikrein-kinin system with excessive bradykinin generation and subsequent increased vascular permeability. Modern HAE management is based on three major therapeutic strategies: on-demand treatment, short-term prophylaxis (STP), and long-term prophylaxis (LTP). On-demand treatment options include plasma-derived and recombinant C1 inhibitor (C1INH) concentrates, the bradykinin B2 receptor antagonist icatibant, and, more recently, the first orally available plasma kallikrein inhibitor, sebetralstat. Short-term prophylaxis prior to invasive medical procedures is performed as replacement therapy by intravenous administration of C1INH concentrates. The goal of long-term prophylaxis is complete disease control with reduction of attack frequency and/or severity and improvement of quality of life. LTP therapies include subcutaneous and intravenous C1INH preparations, the oral kallikrein inhibitor berotralstat, the anti-kallikrein monoclonal antibody lanadelumab, the factor XIIa inhibitor garadacimab, and the antisense oligonucleotide donidalorsen. Currently under development are the oral bradykinin B2 receptor antagonist deucrictibant, which is intended for both on-demand treatment and long-term prophylaxis in different formulations, long-acting antibodies, such as navenibart, and CRISPR/Cas9-based gene-editing therapies, such as NTLA-2002 with potential functional curative properties. In particular, orally available and long-acting therapies are expected to improve adherence, self-management, and quality of life in affected patients.
2026-07-28 | 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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Drug Discovery Landscape
7 orphan drug designations for Hereditary angioedema with C1Inh deficiency, including 3 approved therapies.
7 orphan drug designations for Hereditary angioedema with C1Inh deficiency, including 3 approved therapies.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Adeno-Associated Viral Vector encoding C1 Esterase Inhibitor | gene therapies | FDA | 2018-08-22 | — | Adverum Biotechnologies, Inc. |
berotralstat [Orladeyo] | small molecules | FDA | 2017-11-01 | 2025-12-11 | BioCryst Pharmaceuticals, Inc. |
berotralstat [ORLADEYO™] | small molecules | FDA | 2017-11-01 | 2020-12-03 | BioCryst Pharmaceuticals, Inc. |
Conestat alfa [Ruconest] | proteins | EMA | 2001-05-11 | — | Pharming Group N.V. |
recombinant human C1-esterase inhibitor | proteins | FDA | 1999-02-23 | — | Pharming Group N.V. |
C1-esterase inhibitor (recombinant) [RUCONEST] | proteins | FDA | 1999-02-23 | 2014-07-16 | Pharming Group N.V. |
C1 esterase inhibitor (human) | proteins | FDA | 1996-08-21 | — | Alpha Therapeutic Corporation |
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