When you have hereditary angioedema (HAE), recurrent attacks of swelling can be not only traumatic but also life-threatening. Swelling in your face or throat can close your airways. Attacks in your stomach come with pain, nausea, vomiting, and other symptoms. Swollen hands and feet can make it hard to do many everyday activities.
Your HAE symptoms likely started by your early teens. But because HAE is a rare genetic condition, it can take many years to get the right diagnosis and treatment. Without the right treatment, your HAE attacks could happen often and last for days. Fortunately, there are now several medicines approved to treat HAE. Recent advances in treatment mean you can live a normal life with the right treatment plan in place. HAE medicines work to stop or prevent your attacks by reducing excess levels of the substance called bradykinin that's behind your swelling in different ways.
Symptoms of HAE can vary from one person to the next. Not everyone responds to medications for HAE the same way either. You'll need a tailored plan to treat and prevent your attacks. Let your doctor know all the ways your HAE symptoms are affecting you. Talk to them about the best plan for you, how your current treatment plan is working, and whether it might be time to try something new.
Which Bradykinin Inhibitors Are Used to Treat Hereditary Angioedema?
Doctors use medicines in different classes to treat your acute HAE attacks or keep them at bay. What they all have in common is they block or inhibit excess bradykinin in different ways. Your treatment options may include:
Bradykinin B2 receptor antagonist
Kallikrein inhibitors
C1 esterase inhibitors
Activated Factor XII (FXIIa) inhibitor
Other medications that have been used to treat HAE complications include:
- Fresh frozen plasma
- Epinephrine
- Antifibrinolytics, such as tranexamic acid
How Do Bradykinin Inhibitors Work?
When you have HAE, it's usually because of changes in a gene encoding the production of a protein in your blood. It's called C1 inhibitor (C1-INH). Another name for HAE is C1 inhibitor deficiency. Sometimes it happens because the C1-INH protein doesn't work the way it should. While rare, it's possible to have it for other reasons, too.
The deficiency or abnormal functioning of that C1-INH enzyme causes your body to make and release too much of another substance, called bradykinin. Bradykinin has an important role in controlling inflammation. This substance makes your blood vessels relax and open wider to increase blood flow. When your blood vessels relax too much, they can become leaky, leading to swelling, or edema, in your hands, feet, stomach, intestines, airways, and throat. Medicines in different drug classes treat HAE in different ways, but they all block or lower excess levels of bradykinin to stop or prevent your swelling.
Bradykinin B2 receptor antagonist. A drug in this class lowers inflammation and swelling by blocking the receptor that binds bradykinin.
Kallikrein inhibitors. Medicines in this class work in another way, by blocking an enzyme called kallikrein. When C1-INH levels are low, kallikrein produces too much bradykinin. So, blocking this enzyme can help to prevent your body from making too much bradykinin.
There is a new type of drug that falls into this category that reduces the production of prekallikrein (PKK), a precursor of plasma kallikrein. By lowering PKK levels, donidalorsen also prevents the overproduction of bradykinin.
C1 esterase inhibitors. Drugs in this class inhibit bradykinin by replacing the C1 esterase inhibitors you're lacking. These enzymes are important natural inhibitors of kallikrein.
Activated factor XII (FXIIa) inhibitor. The new HAE medicine garadacimab-gxii works in a different way, by blocking FXIIa at the top of the bradykinin pathway. Factor XIIa is responsible for producing kallikrein. By blocking this factor, it lowers kallikrein so that your body makes less bradykinin.
How Effective Are Bradykinin Inhibitors?
HAE treatments generally work well to stop or prevent attacks. For example, one trial found the bradykinin receptor antagonist icatibant helped with symptoms in five minutes to two hours. Complete resolution of symptoms typically happened within 48 hours.
A clinical trial of the kallikrein inhibitor ecallantide found it helped with attacks in 72.5% of cases. That's compared to 25% of people who got a placebo instead. By comparison, a clinical trial of lanadelumab showed it led to an 87% reduction in attacks. Most people taking it in the study didn't have any attacks.
A study of one C1 esterase inhibitor found that 75% of those who took it had relief of symptoms within an hour. In a clinical trial, the factor XIIa inhibitor garadacimab reduced HAE attacks by more than 99% in most people. It also helped people avoid on-demand treatment for attacks. More than half of those taking the medicine were attack-free while on the treatment.
Some treatments are approved only for adults, while others are approved for younger people with HAE. Talk to your doctor about which treatment they recommend for you and how well you can expect them to work.
How Do You Take Bradykinin Inhibitors?
Most treatments to lower bradykinin you'll take through an IV or a shot. You'll likely be able to give it to yourself at home. You can take berotralstat (Orladeyo) and sebetralstat (Ekterly) through an oral capsule. Some treatments are used to help when you get an attack, while others can help to prevent attacks if you take them regularly. Thinking about how you'd prefer to take your medicines may help you to make the best treatment decision for you.
Are Bradykinin Inhibitors Safe?
Yes. Bradykinin-lowering medicines are generally well tolerated and safe to take. Talk to your doctor about any questions or concerns you have about taking your medicine safely. You'll need to consider:
Allergies. Let your doctor know if you think you've had a reaction to your medicine or if you have any other known allergies.
Your age. Not all medicines for HAE have been tested in young children or older people.
Pregnancy and breastfeeding. HAE medicines haven't been tested in women who are pregnant or breastfeeding. Talk to your doctor about the benefits and potential risks.
Other medicines. Let your doctor know about any other medicines or supplements you're taking to avoid any drug interactions.
What Are the Possible Side Effects of Bradykinin Inhibitors?
Any medicine can come with side effects. The side effects of your HAE treatment will depend on which medicine or medicines you're taking. Let your doctor know right away if you're having any new or concerning symptoms that you think may be related to your bradykinin inhibitors.
Some common side effects may include:
- Injection site reactions
- Fever
- Headache
- Muscle aches
- Stomach pain
- Stuffy or runny nose
- Chest congestion
- Sore throat
- Tiredness
- Dizziness
- Trouble breathing
- Pain around your eyes
- Vomiting
- Rash
Will Insurance Cover the Cost?
Your out-of-pocket costs and prescription drug coverage will depend on the type of health insurance you have. Your doctor may need to get prior authorization for you to take certain medicines or to switch from one medicine to another. Check with your insurance company to find out which HAE medicines they'll cover. If your medicine isn't covered, ask your doctor if another option is available or where you may be able to get financial assistance to help with your costs.
Clinical Trials of Bradykinin Inhibitors for Hereditary Angioedema
Researchers are studying new bradykinin-lowering medicines for HAE. For example, one study is testing an oral soft capsule called deucrictibant for on-demand treatment of HAE attacks in adolescents and adults. Deucrictibant is a B2 receptor antagonist. Small trials have shown this medicine may be able to safely treat and prevent angioedema attacks.
Ask your doctor if you should consider enrolling in a clinical trial. You can search for clinical trials in HAE near you at ClinicalTrials.gov.
5 Things to Consider When Choosing a Treatment
How you'd like to deliver the medicine. Drugs to reduce bradykinin levels to stop or prevent your HAE attacks can be taken as shots you give yourself under the skin or intravenously. Some bradykinin inhibitors are available as an oral pill. Talk to your doctor about which option might work best for you.
On demand vs. long-term prevention. Some bradykinin inhibitors are taken only when you need them to stop an attack, while others can help to reduce the number of attacks you have and how often they happen over time. Some medicines you'll take every day, while others you'll need less often. Talk to your doctor about your treatment preferences and concerns. Treatments generally work best when you have a plan in place to ensure you're taking them as prescribed.
Treatment monitoring. It's important to follow up with your doctor when you're in treatment for HAE. Your doctor can review and adjust your medicines as needed to make sure they're working as well as they can to keep your symptoms and attacks at bay. Ask about any new treatment options that may be available. When your symptoms are well controlled, it might be enough to see your doctor once or twice a year. See your doctor more often if you're having frequent attacks to see if you should consider changing your medication or dosing.
Side effects or safety concerns. HAE treatments are generally well tolerated. They also can protect you from potentially life-threatening HAE attacks. But the side effects you can expect may vary, depending on which medicines you're taking. Talk to your doctor about any side effects or safety concerns that you may need to consider in your treatment decisions.
Your out-of-pocket costs. Some bradykinin inhibitor medicines for HAE will cost more than others. But your out-of-pocket costs will depend on your health insurance and what it will cover. Make sure you understand your treatment options and their costs. Ask if you may be eligible for financial assistance. Many drug companies and other organizations offer financial assistance and help with health insurance premiums, therapy administration costs, travel costs, copays, and more.
Show Sources
SOURCES:
Cleveland Clinic: "Hereditary Angioedema."
The Journal of Allergy and Clinical Immunology In Practice: "US HAEA Medical Advisory Board 2020 Guidelines for the Management of Hereditary Angioedema."
U.S. Hereditary Angioedema Association: "Treatments."
StatPearls: "Physiology, Bradykinin."
World Allergy Organization Journal: "Hereditary Angioedema Therapy: Kallikrein Inhibition and Bradykinin Receptor Antagonism."
Allergy: "Long‐term prevention of hereditary angioedema attacks with lanadelumab: The HELP OLE Study."
FDA: "Danocrine."
Ionis: "Dawnzera."
Mayo Clinic: "Icatibant," "Garadacimab-gxii," "C1 esterase inhibitor, human."
Patient Advocate Foundation: "Understanding drug tiers."
ClinicalTrials.gov: "Study of Oral Deucrictibant Soft Capsule for On-Demand Treatment of Angioedema Attacks in Adolescents and Adults With Hereditary Angioedema (RAPIDe-3)."
The Journal of Allergy and Clinical Immunology: "Deucrictibant for angioedema due to acquired C1-inhibitor deficiency: A randomized-controlled trial."
The Assistance Fund: "Hereditary Angioedema Financial Assistance Program."