Preventing HAE Attacks: Current and Emerging Therapeutic Approaches

Written by Margaret Anne Rockwood | Last updated September 9th, 2026
Medically reviewed by Timothy J. Craig, DO

Long-term prophylaxis (LTP) has become the cornerstone of hereditary angioedema (HAE) management for many patients with recurrent or burdensome attacks. The World Allergy Organization/European Academy of Allergy and Clinical Immunology (WAO/EAACI) guidelines for the classification, diagnosis, and treatment of HAE recommend that all patients be routinely assessed for the need for prophylactic therapy, with treatment decisions individualized according to attack frequency, severity, quality of life (QoL), and patient preferences with shared decision-making.

Unlike historical approaches that relied on attenuated androgens, current prophylactic therapies primarily target components of the contact/kallikrein-kinin pathway or replace deficient C1 inhibitor for greater mechanistic precision.

Plasma-Derived C1 Esterase Inhibitor Replacement

Plasma-derived C1 inhibitor (pdC1-INH) replacement restores functional C1 inhibitor levels, suppressing activation of the contact and complement systems. Treatment options include:

Cinryze (Takeda)

• FDA Approval: 2008
• Indication: routine prophylaxis against angioedema attacks in adults, adolescents, and pediatric patients (6 years of age and older) with HAE
• MOA: replaces deficient functional C1 inhibitor
• Route of Administration: intravenous
• Dose: 1,000 IU every 3 to 4 days (≥12 years), 500 IU IV every 3 to 4 days (6 to 11 years), with dose adjustment based on individual response
• Key efficacy: In a pivotal placebo-controlled crossover trial, the inhibitor reduced attack frequency by 50% compared with placebo.
• Common adverse effects: headache, nausea, rash, infusion-site reactions; thrombosis has been reported rarely

 Haegarda (CSL Behring)

• FDA approval: 2017, with pediatric expansion in 2020
• Indication: routine prophylaxis to prevent HAE attacks in patients 6 years of age and older
• MOA: plasma-derived C1 inhibitor replacement
• Route of Administration: subcutaneous
• Dose: 60 IU/kg twice weekly
• Key efficacy: The Phase 3 COMPACT trial demonstrated a median reduction in attack frequency of approximately 95% and a mean of 84% versus placebo, with many participants becoming attack-free during treatment.
• Common adverse effects: Injection-site reactions, hypersensitivity, headache

Plasma Kallikrein Inhibitors

Lanadelumab-flyo (Takhzyro; Takeda)

Lanadelumab is a fully human monoclonal antibody that inhibits active plasma kallikrein, reducing bradykinin production.

• FDA approval: 2018
• Indication: prevention of HAE attacks in patients ≥2 years
• Route of Administration: Subcutaneous
• Dose: 300 mg every 2 weeks (≥12 years); 150 mg every 2 weeks (6 years to <12 years); may extend to every 4 weeks in well-controlled patients. 150 mg every 4 weeks  (2 years to  <6 years).
• Key efficacy: In the Phase 3 HELP trial, lanadelumab reduced mean attack rates by up to 87% versus placebo, with many patients remaining attack-free for extended periods.
• Common adverse effects: Injection-site pain, upper respiratory infections, headache, dizziness

Berotralstat (Orladeyo, BioCryst Pharmaceuticals)

Berotralstat is the first orally administered prophylactic therapy for HAE.

• FDA approval: 2020, with pediatric expansion in 2025
• Indication: prevention of HAE attacks in patients aged ≥2 years
• MOA: oral selective plasma kallikrein inhibitor
• Route of Administration: oral capsule
• Dose: 150 mg once daily with food (≥12 years), weight-based dosing (≥2 years)
• Key efficacy: The Phase 3 APeX-2 trial demonstrated a mean reduction in attacks of 44% compared with placebo, with sustained efficacy during long-term extension studies.
• Common adverse effects: Abdominal pain, nausea, diarrhea, vomiting; gastrointestinal symptoms generally diminish with continued treatment.

RNA-Targeted Therapies

Donidalorsen (Dawnzera, Ionis Pharmaceuticals)

Donidalorsen is a ligand-conjugated antisense oligonucleotide designed to reduce hepatic prekallikrein production through RNA degradation.

• FDA approval: 2025
• Indication: prevention of HAE attacks in adults and pediatric patients ≥12 years
• MOA: Antisense inhibition of prekallikrein synthesis
• Route of Administration: Subcutaneous
• Dose: 80 mg every 4 weeks; dosing every 8 weeks may be considered in appropriate patients.
• Key efficacy: In the Phase 3 OASIS-HAE trial, donidalorsen significantly reduced monthly HAE attack rates by a mean of 81% at 4 weeks and 55% versus placebo, with many participants achieving prolonged attack-free intervals and clinically meaningful improvements in QoL.
• Adverse effects: Injection site reactions were among the most frequently reported. Hypersensitivity reactions were reported in the study

Factor XIIa Inhibitors & Gene Editing Therapies

Garadacimab-gxii (Andembry, CSL Behring)

Garadacimab is a fully human monoclonal antibody directed against activated Factor XII (FXIIa), an upstream initiator of the kallikrein-kinin pathway.

• FDA approval: 2025
• Indication: prophylaxis to prevent HAE attacks  in patients ≥12 years
• MOA: monoclonal antibody targeting activated Factor XII (FXIIa)
• Route of Administration: subcutaneous
• Dose: 200 mg monthly following a 400-mg loading regimen
• Key efficacy: The Phase 3 VANGUARD trial demonstrated approximately 87% reduction in HAE attack frequency compared with placebo.
• Adverse effects: Injection-site reactions and upper respiratory/nasopharyngeal symptoms have been reported.

Several late-stage investigational therapies aim to further reduce treatment burden through less frequent dosing or oral administration.

Navenibart (Astria Therapeutics)

Navenibart is a long-acting monoclonal antibody targeting plasma kallikrein. It is designed to permit substantially less frequent dosing than currently available monoclonal-antibody prophylaxis.

• Status: Phase 3 clinical development
• Proposed Indication: prevention of HAE attacks
• MOA: long-acting monoclonal antibody against plasma kallikrein
• Route of Administration: subcutaneous
• Current evidence: Phase 1b/2 ALPHA-STAR trial data supported advancement of navenibart to Phase 3 clinical ALPHA-ORBIT study in adults and adolescents with type I or II HAE.

Deucrictibant XR (Pharvaris)

Deucrictibant is an investigational oral bradykinin B2 receptor antagonist being developed for both on-demand treatment and prophylaxis. For prophylaxis, an extended-release formulation is being evaluated.

• Status: Phase 3 clinical development
• Proposed indication: bradykinin-mediated angioedema attacks
• MOA: selective bradykinin B2 receptor antagonist
• Route of Administration: oral extended-release tablet
• Dose: once daily in the Phase 3 prophylaxis program
• Key efficacy: Phase 2 CHAPTER-1 demonstrated substantial reductions in HAE attack rates compared with placebo; the CHAPTER-3 Phase 3 prophylaxis study is evaluating once-daily deucrictibant ER versus placebo in patients ≥12 years.

Lonvoguran ziclumeran (lonvo-Z, Intellia Therapeutics)

Lonvoguran ziclumeran is an investigational CRISPR-based gene-editing therapy designed as a one-time treatment for HAE. It targets the KLKB1 gene in liver cells, reducing production of plasma kallikrein and, consequently, bradykinin.

• Status: Phase 3 clinical development
• Proposed indication: prophylaxis of HAE attacks
• MOA: In vivo CRISPR gene editing of KLKB1 to reduce plasma kallikrein production
• Route of Administration: Single intravenous infusion
• Current evidence: The Phase 3 HAELO trial evaluated a single dose of lonvo-Z in people aged 16 years and older with HAE due to C1-INH deficiency. Phase 3 results were published in NEJMin June 2026.

Onvuzosiran (ADX-324, ADARx Pharmaceuticals)

Onvuzosiran is an investigational small interfering RNA (siRNA) therapy designed to provide long-lasting prevention of HAE attacks by reducing production of prekallikrein, the precursor to plasma kallikrein.

• Status: Phase 3 clinical development
• Proposed indication: Prevention of HAE attacks
• MOA: siRNA targeting prekallikrein production
• Route of Administration: Subcutaneous injection
• Current evidence: Phase 1/2 testing supported advancement into the Phase 3 STOP-HAE trial, evaluating multiple aspects of two dose levels of onvuzosiran in adults with type I or type II HAE. The Phase 3 study is recruiting; primary completion is estimated for June 2027. There’s also a Phase 3 extension study.

BW-20805 (Argo Biopharma)

BW-20805 is an investigational siRNA therapy designed to reduce production of prekallikrein, with the goal of providing long-lasting prevention of HAE attacks.

• Status: Phase 2 clinical development
• Proposed indication: Prevention of HAE attacks
• MOA: siRNA-mediated reduction of prekallikrein production
• Route of Administration: Subcutaneous injection
• Dose: Being evaluated with dosing intervals of every three or six months
• Current evidence: The Phase 2 BW-20805-2001 trial is evaluating the efficacy and safety of BW-20805 in adults with HAE.

How to Select a Long-Term Prophylaxis Treatment

Selection of prophylactic therapy should be individualized based on disease burden and patient-specific factors, including:

• age
• attack frequency and severity
• history of laryngeal attacks
• pregnancy considerations
• venous access
• patient preference for oral versus injectable therapy
• ability to self-administer medication
• comorbidities
• insurance coverage

Shared decision-making remains central to therapy selection, as multiple highly effective options are now available with differing dosing schedules and routes of administration.

Importantly, patients receiving prophylaxis should continue to maintain immediate access to on-demand therapy and be prepared for short-term prophylaxis, as breakthrough attacks may still occur despite excellent disease control.

HAE management has evolved dramatically over the past decade with the introduction of targeted therapies that inhibit bradykinin generation or replace deficient C1 inhibitor. Plasma-derived C1 inhibitor replacement, monoclonal antibodies targeting plasma kallikrein or Factor XIIa, oral kallikrein inhibition, and RNA-targeted therapies have significantly reduced attack frequency while improving quality of life for many patients. Emerging therapies such as navenibart and extended-release deucrictibant may further expand individualized prophylactic options while reducing treatment burden.

When to Reconsider Long-term Prophylaxis

Routine follow-up should include reassessment of whether the current management strategy remains effective.

Clinical findings and patient feedback may prompt initiating or modifying long-term prophylaxis. These include:

• increasing attack frequency
• more severe attacks
• recurrent laryngeal episodes
• frequent abdominal attacks
• increased use of rescue medication
• emergency department visits or hospitalization
• persistent impairment in quality of life
• patient dissatisfaction with current disease control
• difficulty accessing or administering on-demand therapy

Conversely, patients with sustained disease control may benefit from adjustments in dosing intervals or treatment selection based on shared decision-making and evolving clinical circumstances.

Sources

• A study of navenibart in participants with hereditary angioedema (ALPHA-ORBIT)—phase 3, NCT06842823. ClinicalTrials.gov. Updated 2026. Accessed August 20, 2026. ClinicalTrials.gov
• Aygören-Pürsün E, Stobiecki M, Valerieva A, et al. Oral deucrictibant for prophylaxis of hereditary angioedema attacks (CHAPTER-1): primary analysis of a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Haematol. 2026;13(4).
• Banerji A, Craig T, Sitz K, et al. Open-label phase 1b/2 trial of navenibart, a long-acting plasma kallikrein inhibitor for hereditary angioedema (ALPHA-STAR). J Allergy Clin Immunol. 2026;157(5):1127-1135.e6.
• Banerji A, Riedl MA, Bernstein JA, et al. Effect of lanadelumab compared with placebo on prevention of hereditary angioedema attacks: a randomized clinical trial. JAMA. 2018;320(20):2108-2121. doi:10.1001/jama.2018.16773
• Berotralstat (Orladeyo)—prescribing information. US Food and Drug Administration.
• C1 esterase inhibitor (human) (Cinryze)—prescribing information. US Food and Drug Administration.
• C1 esterase inhibitor (human) (Haegarda)—prescribing information. US Food and Drug Administration.
• Cohn DM, Gurugama P, Longhurst HJ, et al. Lonvoguran ziclumeran—In vivo CRISPR gene editing in hereditary angioedema. N Engl J Med. Published online June 13, 2026.
• Craig TJ, Reshef A, Li HH, et al. Efficacy and safety of garadacimab, a factor XIIa inhibitor for hereditary angioedema prevention (VANGUARD): a global, multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2023;401(10382):1079-1090. doi:10.1016/S0140-6736(23)00183-0
• Donidalorsen (Dawnzera)—prescribing information. US Food and Drug Administration.
• Garadacimab-gxii (Andembry)—prescribing information. US Food and Drug Administration.
• HAELO: A phase 3 study to evaluate NTLA-2002 in participants with hereditary angioedema—NCT06634420. ClinicalTrials.gov. Updated 2026. Accessed August 20, 2026. ClinicalTrials.gov
• Lanadelumab-flyo (Takhzyro)—prescribing information. US Food and Drug Administration.
• Longhurst H, Cicardi M, Craig T, et al. Prevention of hereditary angioedema attacks with a subcutaneous C1 inhibitor. N Engl J Med. 2017;376(12):1131-1140. doi:10.1056/NEJMoa1613627
• Maurer M, Magerl M, Betschel S, et al. The international WAO/EAACI guideline for the management of hereditary angioedema—the 2021 revision and update. Allergy. 2022;77(7):1961-1990. doi:10.1111/all.15214
• Riedl MA, Tachdjian R, Lumry WR, et al. Efficacy and safety of donidalorsen for hereditary angioedema. N Engl J Med. 2024;391(1):21-31. doi:10.1056/NEJMoa2402478
• Safety, tolerability, pharmacokinetics, and pharmacodynamics of ADX-324 in healthy volunteers and patients with hereditary angioedema—phase 1/2a, NCT05691361. ClinicalTrials.gov. Updated 2026. Accessed August 20, 2026. ClinicalTrials.gov
• STOP-HAE: A phase 3 study of ADX-324 (onvuzosiran) in hereditary angioedema—NCT06960213. ClinicalTrials.gov. Updated 2026. Accessed August 20, 2026. ClinicalTrials.gov
• Study of oral deucrictibant extended-release tablet for prophylaxis against angioedema attacks in adolescents and adults with HAE (CHAPTER-3)—phase 3, NCT06669754. ClinicalTrials.gov. Updated 2026. Accessed August 20, 2026. ClinicalTrials.gov
• Zuraw BL, Busse PJ, White M, et al. Nanofiltered C1 inhibitor concentrate for treatment of hereditary angioedema. N Engl J Med. 2010;363(6):513-522. doi:10.1056/NEJMoa0805537
• Zuraw B, Lumry WR, Johnston DT, et al. Oral once-daily berotralstat for the prevention of hereditary angioedema attacks: a randomized, double-blind, placebo-controlled phase 3 trial. J Allergy Clin Immunol. 2021;148(1):164-172.e9. doi:10.1016/j.jaci.2020.12.027