What new drugs are available for the management of hereditary angioedema?

Background
Hereditary angioedema (HAE) is a rare, autosomal dominant disorder characterized by recurrent episodes of angioedema involving the skin and mucosal tissues of the gastrointestinal tract and upper airway, potentially leading to incapacitating symptoms or fatal airway obstruction.1-3 The frequency of HAE episodes varies widely, ranging from a few episodes per year to multiple attacks each month.2 Episodes typically begin during childhood, worsen during puberty, and may vary in severity over the course of life.3 The estimated prevalence of HAE is approximately 1 in 50,000 individuals.1,3,4

Hereditary angioedema is categorized into 2 primary types: 1) HAE with C1 esterase inhibitor (C1-INH) deficiency (HAE-C1INH) and 2) HAE with normal C1-INH levels (HAE-nl-C1INH).4 HAE-C1INH is associated with mutations in the SERPING1 gene, which encodes the C1-INH protein. This subtype is further divided into Type I (characterized by reduced C1-INH levels) and Type II (characterized by dysfunctional C1-INH), representing approximately 85% and 15% of HAE-C1INH cases, respectively.4,5 In either type, quantitative or qualitative C1-INH deficiency causes uncontrolled activation of the classic complement pathway and the kallikrein–bradykinin system, culminating in recurrent episodes of angioedema.4,6 In contrast to HAE-C1INH, HAE-nl-C1INH is attributed to mutations in genes other than SERPING1, although the pathophysiology remains less well understood.4,7 Despite advancements in the diagnosis of HAE-nl-C1INH, there remains a paucity of data regarding its optimal management.7 Nonetheless, current therapeutic approaches largely mirror those established for HAE-C1INH.

Pharmacological therapies for HAE–C1INH
Various agents are currently approved by the US Food and Drug Administration for preventing and/or treating HAE attacks, summarized in Table 1.8,9 Mechanisms of action vary between these targeted agents; they exert their effects in HAE by reversibly inhibiting plasma kallikrein (berotralstat, ecallantide, lanadelumab, sebetralstat); antagonizing the bradykinin B2 receptor (icatibant); inhibiting activated Factor XII (garadacimab); reducing the production of prekallikrein (donidalorsen); and restoring the function of deficient or dysfunctional C1INH (plasma-derived C1INH and recombinant human C1INH).

Prior to the approval of targeted therapies for HAE, attenuated androgens (e.g., danazol, oxandrolone, stanozolol) were mostly commonly used for long-term prophylaxis of HAE.8,10 These anabolic steroids presumably exert their activity by increasing hepatic C1INH production.10 While effective in reducing the frequency and severity of HAE attacks, their use was limited by significant and potentially serious adverse effects.8,10

Table 1. FDA-approved agents for prevention and treatment of HAE.8,9
UseDrugApproved Age GroupsAdministration
Prophylaxis of HAE attacksBerotralstat (Orladeyo®)Adults and children (12+)PO; self-administered
Plasma-derived human C1-INH (Cinryze®)Adults and children (6+)IV; self-administered
Plasma-derived human C1-INH (Haegarda®)Adults and children (6+)Sub-Q; self-administered
Lanadelumab-flyo (Takhzyro®)Adults and children (2+)Sub-Q; self-administered
Garadacimab-gxii (Andembry®)Adults and children (12+)Sub-Q; self-administered
Donidalorsen (Dawnzera®)Adults and children (12+)Sub-Q; self-administered
Treatment of acute HAE attacksEcallantide (Kalbitor®)Adults and children (12+)Sub-Q; HCP-administered
Icatibant (Firazyr®; generic)AdultsSub-Q; self-administered
Plasma-derived C1-INH (Berinert®)Adults and childrenIV; self-administered
Recombinant human C1-INH (Ruconest®)Adults and children (13+)IV; self-administered
Sebetralstat (Ekterly®)Adults and children (12+)PO; self-administered
Abbreviations: C1-INH=C1 esterase inhibitor; FDA=US Food and Drug Administration; HAE=hereditary angioedema; HCP=healthcare professional; IV=intravenous; PO=oral; Sub-Q=subcutaneous.

New HAE therapies approved in 2025
Among the agents listed in Table 1, garadacimab, donidalorsen, and sebetralstat are newly approved in 2025.11-13 As previously noted, garadacimab and donidalorsen are approved for the prophylactic management of HAE, whereas sebetralstat is approved for treatment of acute HAE attacks. Pivotal clinical trials that led to the approval of these agents are summarized in Table 2.14-19

These new therapies are distinguished by their unique mechanisms of action and/or advantages in administration.8,11-13 Garadacimab is the only FDA-approved therapy that inhibits the start of the HAE cascade by targeting activated factor XII (FXIIa), the first factor in the contact activation system.8,11 Garadacimab offers once-monthly subcutaneous dosing for all patients from the start and is delivered via a citrate-free autoinjector in ≤15 seconds; this formulation is designed for convenient self-administration and sustained long-term protection. Similarly, donidalorsen is designed for self-administration in 10 seconds using a citrate-free, single-use autoinjector.8,12 Donidalorsen is the first and only RNA-targeted prophylactic therapy for HAE that offers the longest time between doses (i.e., every 4 or 8 weeks). Sebetralstat is the first and only FDA-approved oral on-demand treatment for acute HAE attacks.8,13 It is intended to be taken at the onset of symptoms, offering an alternative to injectable therapies.

Due to their recent approval, garadacimab, donidalorsen, and sebetralstat are not mentioned in the current clinical practice guidelines for HAE; however, they are likely to be included in future guideline updates.4,20

Table 2. Pivotal phase 3 studies of garadacimab, donidalorsen, and sebetralstat.14-19
Study DesignSubjectsInterventionsKey Results
Garadacimab

Craig 202314

VANGUARD		Multicenter, randomized, double-blind, placebo-controlled phase 3 trialN=65 patients (≥12 years of age) with type I or type II HAE; mean age, 41.2 years (range, 12 to 69 years)Garadacimab (400 mg sub-Q loading followed by 200 mg monthly) or matching placebo for 6 monthsMean number of investigator-confirmed HAE attacks per month with garadacimab versus placebo: 0.27 versus 2.01; percentage difference in means of -87% (95% CI, -96 to -58; p<0.0001)

Findings from the interim analysis of the ongoing, open-label extension of VANGUARD supports the long-term safety and efficacy of garadacimab over a median exposure period of 13.8 months.15
Donidalorsen

Riedl 202416

OASIS-HAE		Multicenter, randomized, double-blind, placebo-controlled phase 3 trialN=90 patients (≥12 years of age) with type I or type II HAE; mean age, 37 years (range, 12 to 68 years)Donidalorsen (80 mg sub-Q) or placebo once every 4 or 8 weeks for 24 weeksMean attack rate from week 1 to week 25 was 81% lower (95% CI, 65 to 89) in the donidalorsen 4-week group than in the placebo group (p<0.001) and 55% lower (95% CI, 22 to 74) in the donidalorsen 8-week group than in the placebo group (p=0.004)

Findings from the 16-week interim analysis of the ongoing, open-label extension (OASISplus) supports the long-term safety and efficacy of donidalorsen.17
Sebetralstat

Riedl 202418

KONFIDENT		Randomized, double-blind, placebo-controlled, 3-way crossover trialN=136 patients (≥12 years of age) with type I or type II HAE; median age, 39.5 years (range, 25 to 49 years)Sebetralstat (300 mg or 600 mg PO) or placebo (up to 2 administrations)Time to the beginning of symptom relief with sebetralstat 300 mg and 600 mg was faster than with placebo (p<0.001 and p=0.001 for the 2 comparisons, respectively), with median time to symptom relief of 1.61 hours, 1.79 hours, and 6.72 hours, respectively

Findings from the interim analysis of the ongoing, open-label extension (KONFIDENT-S) supports the continued safety and efficacy of sebetralstat; at data cutoff, approximately 84% and 13% of attacks were treated with sebetralstat and placebo, respectively.19
Abbreviations: CI=confidence interval; HAE=hereditary angioedema; PO=oral; Sub-Q=subcutaneous.

Conclusion
The recent approval of garadacimab, donidalorsen, and sebetralstat marks a notable expansion in the therapeutic landscape for HAE, offering greater personalization, improved convenience, and novel mechanisms of action. As these agents become integrated into clinical practice, they have the potential to redefine prophylactic and/or acute management strategies in HAE, addressing limitations of earlier treatments and improving patient quality of life. However, long-term safety, durability of effect, and real-world outcomes remain to be fully established. Furthermore, comparative studies are warranted to guide optimal treatment selection and clarify the relative efficacy, tolerability, and patient preference across available therapies.

References

  1. Abdulkarim A, Craig TJ. Hereditary Angioedema. In: StatPearls. Treasure Island (FL): StatPearls Publishing; May 1, 2023.
  2. Longhurst HJ, Valerieva A. A review of randomized controlled trials of hereditary angioedema long-term prophylaxis with c1 inhibitor replacement therapy: alleviation of disease symptoms is achievable. J Asthma Allergy. 2023;16:269-277. doi:10.2147/JAA.S396338
  3. Gower RG, Busse PJ, Aygören-Pürsün E, et al. Hereditary angioedema caused by c1-esterase inhibitor deficiency: a literature-based analysis and clinical commentary on prophylaxis treatment strategies. World Allergy Organ J. 2011;4(2 Suppl):S9-S21. doi:10.1097/WOX.0b013e31821359a2
  4. Busse PJ, Christiansen SC, Riedl MA, et al. US HAEA medical advisory board 2020 guidelines for the management of hereditary angioedema. J Allergy Clin Immunol Pract. 2021;9(1):132-150.e3. doi:10.1016/j.jaip.2020.08.046
  5. Tutunaru CV, Ică OM, Mitroi GG, et al. Unveiling the complexities of hereditary angioedema. Biomolecules. 2024;14(10):1298. doi:10.3390/biom14101298
  6. Agostoni A, Aygören-Pürsün E, Binkley KE, et al. Hereditary and acquired angioedema: problems and progress: proceedings of the third C1 esterase inhibitor deficiency workshop and beyond. J Allergy Clin Immunol. 2004;114(3 Suppl):S51-S131. doi:10.1016/j.jaci.2004.06.047
  7. Zuraw BL, Bork K, Bouillet L, et al. Hereditary Angioedema with Normal C1 Inhibitor: an Updated International Consensus Paper on Diagnosis, Pathophysiology, and Treatment. Clin Rev Allergy Immunol. 2025;68(1):24. doi:10.1007/s12016-025-09027-4
  8. Approved HAE treatments. US Hereditary Angioedema Association. 2025. Accessed September 17, 2025. https://www.haea.org/pages/p/treatments
  9. DailyMed: National Library of Medicine. National Institutes of Health. 2025 Accessed September 17, 2025. https://dailymed.nlm.nih.gov/dailymed/index.cfm
  10. Horváth HR, Visy B, Kőhalmi KV, et al. A national survey of four decades of hereditary angioedema prophylaxis: Efficacy and safety of old and new drugs. Clin Immunol. 2025;279:110542. doi:10.1016/j.clim.2025.110542
  11. Andembry. Package insert. CSL Behring LLC, Inc.; 2025.
  12. Dawnzera. Package insert. Ionis Pharmaceuticals Inc.; 2025.
  13. Ekterly. Package insert. KalVista Pharmaceuticals, Inc.; 2025.
  14. 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)00350-1
  15. Reshef A, Hsu C, Katelaris CH, et al. Long-term safety and efficacy of garadacimab for preventing hereditary angioedema attacks: Phase 3 open-label extension study. Allergy. 2025;80(2):545-556. doi:10.1111/all.16351
  16. 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
  17. Riedl MA, Bernstein JA, Jacobs JS, et al. Donidalorsen treatment of hereditary angioedema in patients previously on long-term prophylaxis. J Allergy Clin Immunol Pract. 2025;13(9):2381-2389.e3. doi:10.1016/j.jaip.2025.06.018
  18. Riedl MA, Farkas H, Aygören-Pürsün E, et al. Oral sebetralstat for on-demand treatment of hereditary angioedema attacks. N Engl J Med. 2024;391(1):32-43. doi:10.1056/NEJMoa2314192
  19. Farkas H, Anderson J, Bouillet L, et al. Long-term safety and effectiveness of sebetralstat: interim analysis of KONFIDENT-S open-label extension. J Allergy Clin Immunol Pract. Published online August 29, 2025. doi:10.1016/j.jaip.2025.08.020
  20. 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

Prepared by:
Honey Joseph, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

October 2025

The information presented is current as of September 17, 2025. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.