How Is Hereditary Angioedema Treated?

Hereditary angioedema (HAE) is a rare disorder in which a person has recurring, severe swelling. This swelling takes place in the arms, legs, intestines (gut), airways, and face.¹

HAE can be painful. It can cause nausea and vomiting when swelling takes place in the stomach area. When swelling occurs in the airways, it can cause breathing problems and be life-threatening. About 1 in 3 people also develop a non-itchy rash.^1,2

Symptoms usually begin in childhood and get worse in the teen years. Attacks may be triggered by minor surgery, dental work, or stress.^1,3

Without treatment, people with HAE average an attack every 1 to 2 weeks, with each attack lasting 3 to 4 days. How often attacks take place and how long they last varies widely between people, even within the same family.^1,3

What causes hereditary angioedema?

Hereditary angioedema is an autosomal dominant disease. This means that a person needs to inherit only 1 gene, from their mother or their father, to develop the condition.^1,3

HAE has 3 types. Types 1 and 2 are caused by changes (mutations) in the SERPING1 gene. These mutations lead to low levels or poor functioning of the protein C1 inhibitor in the blood. C1 inhibitors help control inflammation in the body. Most people with HAE, about 85 percent, have type 1.^1,3

Some people with type 3 have a mutation in the F12 gene. The F12 gene plays a role in blood clotting and stimulates inflammation. Researchers have identified several more specific mutations that are linked with type 3, including:^1,3

• PLG (Plasminogen)
• ANGPT1 (Angiopoietin-1)
• KNG1 (Kininogen-1)
• HS3ST6 (Heparan sulfate-glucosamine 3-O-sulfotransferase 6)

Who gets hereditary angioedema?

The National Organization for Rare Disorders estimates that 1 in 50,000 to 150,000 individuals is affected by this disorder worldwide. All genders are affected equally. The condition usually begins in childhood.³

Medicines for hereditary angioedema and its complications

There are several treatments approved by the U.S. Food and Drug Administration (FDA) to treat hereditary angioedema. These include:^3,4

• Andembry® – inhibits the top of the HAE cascade and offers once-monthly subcutaneous dosing for all patients from the start
• Berinert® (C1 esterase inhibitor) – an on-demand treatment for swelling in the intestines, face, or throat for both adults and children
• Cinryze® (C1 esterase inhibitor) – to prevent HAE attacks
• Dawnzera™ – RNA-targeted preventative treatment for HAE that offers the longest time between doses, every 4 weeks or 8 weeks
• Ekterly® (sebetralstat) – an oral on-demand treatment for acute attacks of HAE in patients 12 years and older
• Firazyr® – for acute attacks of HAE, approved for adults 18 years and older
• Haegarda® (C1 esterase inhibitor subcutaneous [human]) – to prevent HAE attacks
• Icatibant (generic) – for acute attacks of HAE in adults 18 years of age and older
• Kalbitor® (ecallantide) to treat sudden, life-threatening fluid buildup related to HAE
• Orladeyo® (berotralstat) – to prevent HAE attacks in patients 12 years and older
• Ruconest® (C1 esterase inhibitor [recombinant]) – for sudden or severe attacks
• Takhzyro® (lanadelumab) – for long-term prevention in patients 2 years and older

Only some of these treatments are approved for use in children.³

Other treatments

People with HAE may need short-term treatment before having surgery or dental work done.³

If airway swelling is severe and a person is having trouble breathing, doctors may create a small opening in the throat called a tracheotomy. A tracheotomy is usually temporary. The person may also be given oxygen. With modern on-demand treatments (like Ekterly or Berinert), the need for emergency tracheotomies has significantly decreased.³

Gene therapy

Recent breakthroughs in genetic medicine have introduced the possibility of a "one-and-done" treatment for HAE. Unlike traditional medications that require lifelong injections or pills, gene therapy aims to address the root cause of the disorder at the cellular level.⁵

The most significant advancement has been the clinical rollout of CRISPR/Cas9 gene-editing therapy (such as NTLA-2002). This is an intravenous infusion designed to permanently edit the KLKB1 gene. The therapy "knocks out" the gene responsible for producing prekallikrein. By reducing the levels of plasma kallikrein, the body stops the overproduction of bradykinin – the peptide that causes the debilitating swelling in HAE.⁵

While these therapies began in specialized clinical trials, they have now reached major regulatory milestones. Specialized HAE centers are increasingly offering these genetic interventions to patients with severe phenotypes who previously struggled with treatment adherence or breakthrough attacks.⁵