3 breakthrough HAE treatments in 2025 that could transform hereditary angioedema care

Hereditary angioedema (HAE) is a rare but potentially life-threatening disorder characterized by recurrent episodes of swelling affecting the skin, gastrointestinal tract, and airway.¹ These attacks can cause severe pain, functional impairment, and, in the case of laryngeal involvement, airway obstruction requiring urgent intervention. Unlike histamine-mediated angioedema, HAE attacks do not respond to standard allergy treatments, such as antihistamines or corticosteroids, necessitating targeted therapies that address the underlying bradykinin-driven pathway.

While treatment options have advanced significantly in recent years, many patients continue to experience breakthrough attacks, treatment burden, and anxiety related to the unpredictability of the disease. The approval of several novel therapies in 2025 marks a pivotal moment for HCPs and patients alike, offering new opportunities to improve disease control, reduce attack frequency and severity, and tailor management strategies to individual needs. These developments represent a significant step toward addressing long-standing gaps in care and improving outcomes for those living with HAE.

Garadacimab: factor XIIa inhibitor for long-term prevention

The FDA has approved garadacimab as a preventive therapy for HAE.² Garadacimab is a monoclonal antibody that inhibits factor XIIa, a plasma protein central to the cascade driving episodes of oedema. The therapy is approved for adults and adolescents aged 12 years and older and is delivered once monthly as a quick subcutaneous self-injection through an autoinjector.

Lead author of the VANGUARD trial, Dr Timothy Craig (Pennsylvania State University, Hershey, PA, USA) said:²

“Unlike other HAE treatments that target downstream mediators, Andembry inhibits factor XIIa at the top of the HAE cascade and provides sustained protection against attacks”.

Results from the phase III VANGUARD trial (NCT04656418) showed that patients who received garadacimab remained 62% attack-free throughout treatment, while median reductions in overall HAE attacks exceeded 99% compared to placebo.³ The therapy also lowered the number of HAE attacks requiring on-demand medication and reduced moderate-to-severe attacks, compared to placebo. The most common side effects reported were nasopharyngitis and abdominal pain.

Interim data from an open-label extension study (NCT04739059) demonstrated durable efficacy and a favourable safety profile, supporting its use as a long-term prophylactic option.^4,5

Dr Timothy Craig speaking on the approval:²

“It offers both clinical impact and convenience for patients living with this unpredictable and potentially life-threatening disease”.

Sebetralstat: first and only oral on-demand treatment

Sebetralstat is a plasma kallikrein inhibitor recently approved by the FDA and MHRA for the on-demand treatment of HAE attacks in patients aged 12 and over.^6,7 Sebetralstat has also maintained its orphan drug designation in Europe, with regulatory review due by the EMA in October 2025.⁷ This approval has particular significance as sebetralstat is the first and only oral on-demand treatment for HAE; furthermore, this is the first approval of an on-demand treatment for this indication in 10 years.

Investigator for the KONFIDENT trial, Prof. Marc A. Riedl (University of California, San Diego, CA, USA) said:⁶

“Having an oral option empowers patients to treat attacks early, which aligns with treatment guidelines and advances our goal as physicians to reduce the overall burden of disease”.

Approval was supported by the phase III KONFIDENT trial (NCT05259917) and the open-label extension study KONFIDENT-S (NCT05505916).^8,9 In the phase III study, sebetralstat 300 mg and 600 mg demonstrated faster symptom relief, reduction in attack severity and complete resolution compared to placebo.⁸ Furthermore, a higher percentage of patients had complete attack resolution within 24 hours in the sebetralstat arm. Sebetralstat had a similar safety profile to placebo, with no reported serious adverse events relating to treatment. In the extension study, sebetralstat continued to reduce attacks quickly, while no new safety concerns were observed.⁹

Trial investigator, Dr Mauro Cancian (University of Padua, Italy) said of the EMA decision:⁷

“Oral sebetralstat has the potential to change that, giving patients the ability to treat attacks early, with confidence, in a way that fits their lifestyle.”

Donidalorsen: RNA-based therapy with flexible dosing

Donidalorsen has been approved by the FDA for the prevention of HAE attacks in patients aged 12 years and over.¹⁰ Donidalorsen is an RNA-targeted medicine, which inhibits the production of prekallikrein (PKK), a protein involved in the pathway for HAE attacks. The therapy is designed to be delivered once every 4 or 8 weeks as a self-administered, subcutaneous autoinjector.¹¹ The approval was supported by the findings from the phase III OASIS-HAE trial (NCT05139810) and the open-label extension study, OASISplus (NCT04307381).^12,13

OASIS-HAE and OASISplus trial investigator, Dr Marc Riedl (University of California, San Diego, CA, USA) said:¹⁰

“Dawnzera is positioned to help meet patient needs, providing substantial and sustained reduction of HAE attacks, continued improvement over time and reduced burden of treatment”.

In the OASIS-HAE trial, patients received donidalorsen every 4 or 8 weeks for 24 weeks, and had an 81% (p<0.001) and 55% (p= 0.004) reduction in monthly HAE rate compared to placebo, respectively. Furthermore, between week 5 and 25, patients in both dose groups reported a larger reduction in monthly attack rates when compared to placebo, while the 4-weekly group also experienced an 89% reduction in moderate-to-severe HAE attacks.

In the OASISplus study, both dose groups had a 94% reduction in total mean attack rate at 1 year. In addition, patients who were previously treated with lanadelumab or berotralstat had a 62% reduction in mean HAE attack rate at week 16 when receiving donidalorsen every 4 weeks. The most commonly reported adverse events were injection site reactions, upper respiratory tract infection, urinary tract infection and abdominal discomfort.

Emerging therapies: what’s next for HAE?

Other investigational treatments currently in clinical trials include deucrictibant, an oral bradykinin B2 receptor antagonist, which is being investigated as an on-demand and prophylactic therapy for HAE in the RAPIDe-3 (NCT06343779) and CHAPTER-3 phase III trials (NCT06669754), respectively.¹⁴ Navenibart is another prophylactic investigational therapy in phase III trials (ALPHA-ORBIT; NCT06842823) following positive results from the ALPHA-STAR phase Ib/II trial.¹⁵ Navenibart is a long-acting monoclonal antibody inhibitor of plasma kallikrein, with the potential for dosing every 3 to 6 months. A CRISPR-Cas9-based gene-editing therapy is also in early stage trials with the aim of achieving lifelong control of HAE attacks after a single dose (NCT05120830).¹⁶

HAE management is entering a transformative era with multiple new approvals in 2025. These therapies provide clinicians with new tools to prevent and treat attacks more effectively, while offering patients greater flexibility, convenience, and control over their condition. By targeting earlier points in the HAE cascade, introducing oral and less frequent dosing options, and expanding preventive strategies, these innovations address long-standing unmet needs and have the potential to reduce both the physical and psychological burden of HAE. Looking ahead, ongoing research, including gene-editing approaches, signals the possibility of even more profound, durable solutions that could ultimately transform long-term disease management and patient outcomes.

References

1. Pines JM, Poarch K, Hughes S. Recognition and Differential Diagnosis of Hereditary Angioedema in the Emergency Department. J Emerg Med. 2021;60:35–43.
2. Healio. FDA approves garadacimab-gxii as prophylaxis for hereditary angioedema. 2025. [Press release]. Available at: https://www.healio.com/news/allergy-asthma/20250709/fda-approves-garadacimabgxii-as-prophylaxis-for-hereditary-angioedema (accessed 1 September 2025).
3. 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;401:1079–1090.
4. 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;80:545–556.
5. ClinicalTrials.gov. Long-term Safety and Efficacy of CSL312 (Garadacimab) in the Prophylactic Treatment of Hereditary Angioedema Attacks. ClinicalTrials.gov identifier: NCT04739059. Available at: https://clinicaltrials.gov/study/NCT04739059 (accessed 1 September 2025).
6. AJMC. FDA Approves Sebetralstat for Hereditary Angioedema. 2025. [Press release]. Available at: https://www.ajmc.com/view/fda-approves-sebetralstat-for-hereditary-angioedema (accessed 2 September 2025).
7. Angioedema News. Sebetralstat gets to keep orphan drug status for HAE in Europe 2025. [Press release]. Available at: https://angioedemanews.com/news/sebetralstat-maintains-orphan-drug-status-hae-european-union/ (accessed 2 September 2025).
8. Riedl MA, Farkas H, Aygören-Pürsün E, et al; KONFIDENT investigators. Oral sebetralstat for on-demand treatment of hereditary angioedema attacks. N Engl J Med. 2024;391:32–43.
9. 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. 2025; in press. Doi: 10.1016/j.jaip.2025.08.020.
10. Healio. FDA approves donidalorsen for hereditary angioedema attack prevention. 2025. [Press release]. Available at: https://www.healio.com/news/allergy-asthma/20250826/fda-approves-donidalorsen-for-hereditary-angioedema-attack-prevention (accessed 4 September 2025).
11. DAWNZERA™ (donidalorsen) approved in the U.S. as first and only RNA-targeted prophylactic treatment for hereditary angioedema. 2025. [Press release]. Available at: https://www.businesswire.com/news/home/20250818615141/en/ (accessed 4 September 2025).
12. Riedl MA, Tachdjian R, Lumry WR, et al. Efficacy and Safety of Donidalorsen for Hereditary Angioedema. N Engl J Med. 2024;391:21–31.
13. Riedl M, Bernstein J, Bordone L, et al. Hereditary Angioedema Disease Control After Switching To Donidalorsen From Prior Long-Term Prophylaxis: Results From The OASISplus Open-Label Extension Study. J Allergy Clin Immunol. 2025;155:AB194.
14. Angiodema news. Deucrictibant for hereditary angioedema. 2025. [Press release]. Available at: https://angioedemanews.com/pha121/ (accessed 4 September 2025).
15. Astria therapeutics. Navenibart (STAR-0215). Available at: https://astriatx.com/our-science/our-pipeline/star-0215/ (accessed 4 September 2025).
16. Longhurst HJ, Lindsay K, Petersen RS, et al. CRISPR-Cas9 In Vivo Gene Editing of KLKB1 for Hereditary Angioedema. N Engl J Med. 2024;390:432–441.

Cite: 3 breakthrough HAE treatments in 2025 that could transform hereditary angioedema care. touchIMMUNOLOGY. 5 September 2025.

Editor: Victoria Smith, Senior Content Editor.

Disclosures: This article was created by the touchIMMUNOLOGY team utilizing AI as an editorial tool (ChatGPT (GPT-4o) [Large language model]. https://chat.openai.com/chat.) The content was developed and edited by human editors. No funding was received in the publication of this article.

Related content

• Breakthrough treatments for hereditary angioedema revealed at EAACI 2024
• Lanadelumab for paediatric patients with hereditary angioedema – the SPRING Study
• Why are so many physicians burning out, and how can we break the cycle?

SIGN UP to TouchIMMUNOLOGY!

Register Register

Join our global community today for access to thousands of peer-reviewed articles, expert insights, and learn-on-the-go education across 150+ specialties, plus concise email updates and newsletters so you never miss out.