Hereditary Angioedema (HAE)

Hereditary angioedema (HAE) is a rare disorder characterized by recurrent episodes of severe swelling in the face, limbs, respiratory system, and gastrointestinal tract. Variations in the SERPING1 and F12 genes result in a deficiency or the dysfunction of C1-esterase inhibitor proteins, which lead to the release of excessive amounts of bradykinin, an increase in vascular permeability, and the leakage of fluid through vascular walls into the surrounding tissues.¹

Treatments During Acute Attacks

The treatment of acute attacks of HAE has advanced during the last 2 decades, after the US Food and Drug Administration (FDA) approved several pharmacological agents to manage HAE attacks. Before these medications were approved, the treatment of acute attacks consisted of supportive care, such as tracheostomy, endotracheal intubation, fluid administration, transfusions, and pain management.² 

Cinryze

In 2008, the FDA approved Cinryze^®, a nanofiltered C1-esterase inhibitor concentrate, mainly for the prevention of HAE attacks; however, clinical trials proved that Cinryze is also efficacious during acute HAE attacks.³ In 2 randomized clinical trials, Cinryze decreased the duration and frequency of acute HAE attacks.⁴ 

Read more about Cinryze

Berinert

In 2009, the FDA approved Berinert, a C1-esterase inhibitor concentrate, to treat acute attacks affecting the face and abdomen of adults and adolescents with type 1 or 2 HAE. According to the randomized IMPACT-1 clinical trial, Berinert reduced acute symptoms rapidly, with a median time to symptom relief of 30 minutes.^3,5

In 2012, the FDA approved the use of Berinert for acute laryngeal HAE attacks. Later, in 2016, the FDA approved the use of Berinert in children younger than 12 years. It also approved self-administration by patients after they had received sufficient training from a healthcare provider.³ 

Read more about Berinert

Kalbitor

In 2009, the FDA approved Kalbitor^® (ecallantide), a recombinant kallikrein inhibitor that decreases the rate of C1-esterase inhibitor catabolism, for the management of acute HAE attacks in patients 16 years or older. When used concurrently with C1 inhibitor concentrates like Berinert and Cinryze, Kalbitorr improved their efficacy.³

The safety and efficacy of 30 mg of ecallantide were confirmed in 2 randomized controlled trials, EDEMA3 and EDEMA4. Ecallantide comes with a black box warning from the FDA because anaphylaxis has occurred following multiple administrations; therefore, it must be administered by a healthcare provider capable of treating anaphylaxis.^2,3    

In 2010, in another randomized controlled trial, ecallantide in comparison with placebo effectively improved patient-reported treatment outcome scores and symptom complex severity scores within 4 hours after administration in 71 patients presenting with an acute attack of HAE.⁶

In 2013, results from an open-label continuation study showed that multiple administrations of ecallantide for recurrent acute HAE attacks did not alter the efficacy of the drug. Anaphylaxis developed in only 6 of 147 patients during ecallantide administration, resulting in a safety profile that corresponded to findings in previous clinical studies.⁷  

Read more about Kalbitor

Firazyr

In 2011, the FDA approved Firazyr^® (icatibant), a selective bradykinin B₂-receptor antagonist, for the management of acute HAE attacks in adults. The efficacy and safety of icatibant as a subcutaneously administered treatment for angioedema were confirmed in 3 randomized controlled trials (FAST-1, FAST-2, and FAST-3).³ 

In FAST-3, in 88 adults with acute HAE attacks, icatibant reduced subcutaneous or abdominal symptoms by 50% within a median of 2 hours after administration, compared with 19.8 hours for placebo. Complete symptom relief was achieved after a median of 8 hours in the icatibant group (n=43) vs 36 hours in the placebo group (n=45). Icatibant also reduced the need for additional rescue medications—required by only 3 patients (7%) in the icatibant group vs 18 patients (40%) in the placebo group.^3,8

Ruconest

Developed by Pharming Technologies B.V., Ruconest^® (C1 Esterase Inhibitor [Recombinant]) is a recombinant C1 esterase inhibitor that treats acute attacks associated with hereditary angioedema (HAE) in both adults and adolescents.¹¹ Ruconest received European Medicines Agency (EMA) approval in 2010 and US Food and Drug Administration (FDA) approval in 2014.^11,12 

Read more about Ruconest

Prophylactic Treatments

Because HAE attacks are not histamine-mediated responses, antihistamines have no prophylactic effect. In addition to Cinryze, currently used prophylactic treatments include the following:

• Danazol: an attenuated, synthetic 17ɑ-alkylated androgen 
• Epsilon-aminocaproic acid and tranexamic acid: antifibrinolytic agents
• Takhzyro^® (lanadelumab): a monoclonal antibody targeting kallikrein
• Fresh frozen plasma (FFP) infusions, especially within 24 hours before surgical or dental procedures.⁹

In 2018, the FDA approved lanadelumab on the basis of results from the HELP clinical trial (officially published in 2020), which demonstrated effective long-term prophylaxis against acute HAE attacks. Among the 113 enrolled patients with HAE who completed the 26-week study, lanadelumab reduced the average number of monthly HAE attacks by 92.8% in those with fewer than 2 monthly attacks at baseline and by 88.2% in those with 2 to 3 monthly attacks at baseline. The HAE attack rate in the lanadelumab group averaged between 0.41 and 0.76, whereas the attack rate in the placebo group averaged approximately 2.04.^9,10

References

1. Hereditary angioedema. MedlinePlus. Accessed June 24, 2022.
2. Duffey H, Firszt R. Management of acute attacks of hereditary angioedema: role of ecallantide. J Blood Med. 2015;6:115-123. doi:10.2147/JBM.S66825
3. Frank MM. Hereditary angioedema treatment and management. Medscape. Updated August 30, 3018. Accessed June 24, 2022.
4. 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/NEJMoa0805538
5. Keating GM. Human C1-esterase inhibitor concentrate (Berinert). BioDrugs. 2009;23(6):399-406. doi:10.2165/11201100-000000000-00000
6. Cicardi M, Levy RJ, McNeil DL, et al. Ecallantide for the treatment of acute attacks in hereditary angioedema. N Engl J Med. 2010;363(6):523-531. doi:10.1056/NEJMoa0905079
7. Lumry WR, Bernstein JA, Li HH, et al. Efficacy and safety of ecallantide in treatment of recurrent attacks of hereditary angioedema: open-label continuation study. Allergy Asthma Proc. 2013;34(2):155-161. doi:10.2500/aap.2013.34.3653
8. Lumry WR, Li HH, Levy RJ, et al. Results from FAST-3: A phase III randomized, double-blind, placebo-controlled, multicenter study of subcutaneous icatibant in patients with acute hereditary angioedema (HAE) attacks. J Allergy Clin Immunol. 2011;127(2):AB1. doi:10.1016/j.jaci.2011.01.004
9. Frank MM. Hereditary angioedema treatment and management: prophlylactic treatment. Medscape. Updated August 30, 2018. Accessed June 24, 2022.
10. Riedl MA, Maurer M, Bernstein JA, et al. Lanadelumab demonstrates rapid and sustained prevention of hereditary angioedema attacks. Allergy. 2020;75(11):2879-2887. doi:10.1111/all.14416
11. Ruconest. Prescribing information. Pharming Healthcare Inc; 2020. Accessed June 10, 2022.
12. Ruconest. European Medicines Agency. Updated March 11, 2021. Accessed June 10, 2022.

Reviewed by Kyle Habet, MD, on 6/26/2022.

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Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT

Maria Arini Lopez, PT, DPT, CSCS, CMTPT, CIMT is a freelance medical writer and Doctor of Physical Therapy from Maryland. She has expertise in the therapeutic areas of orthopedics, neurology, chronic pain, gastrointestinal dysfunctions, and rare diseases especially Ehlers Danlos Syndrome.