A Research Guide for
Understanding Hereditary Angioedema

FDA-APPROVED Donidalorsen (brand name: Dawnzera) is the first RNA-targeted therapy for HAE — an antisense medicine that lowers production of prekallikrein, reducing the bradykinin that drives attacks. It is given as a subcutaneous injection every 4 weeks (or every 8 weeks for some patients). In the Phase 3 OASIS-HAE trial it reduced monthly attacks by about 81% versus placebo. FDA-approved in August 2025 for patients aged 12 and older. (See the full Long-Term Prophylaxis section below for details.)

FDA-APPROVED Garadacimab (brand name: Andembry) is the first anti-Factor XIIa monoclonal antibody approved for HAE prophylaxis in adults and pediatric patients aged 12 years and older. FDA approval was granted June 16, 2025. By blocking the kallikrein-kinin cascade at its upstream trigger point (Factor XIIa), garadacimab provides a novel mechanism of action. It is administered as a monthly subcutaneous injection. The VANGUARD trial (NCT04656418) demonstrated significant reduction in attack rates.

FDA-APPROVED Berotralstat was the first oral prophylactic therapy approved for HAE, marking the beginning of the shift from injection-only prevention. In the APeX-2 trial, berotralstat 150 mg daily reduced attack frequency by approximately 44% compared to placebo. While not as potent as injectable options, the convenience of a daily pill has made it an important option, particularly for patients who prefer oral therapy.

FDA-APPROVED Lanadelumab was a breakthrough in HAE prophylaxis. This monoclonal antibody targets plasma kallikrein directly. In the HELP trial, lanadelumab every two weeks reduced attack rates by approximately 87% compared to placebo. Many patients on lanadelumab achieve zero attacks. It is self-administered as a subcutaneous injection every two to four weeks.

INVESTIGATIONAL Deucrictibant is an oral bradykinin B2-receptor antagonist in Phase 3 development (for both on-demand and prophylactic use). It blocks bradykinin at its receptor — the same target as injectable icatibant, but in pill form. It is not yet FDA-approved.

The shift from IV/SC-only prophylaxis toward oral therapies is transforming HAE management. For decades, prophylaxis required regular injections or infusions. Berotralstat (2020) proved that oral prophylaxis was possible, and sebetralstat (Ekterly, 2025) became the first oral on-demand therapy. Donidalorsen (Dawnzera, 2025) added a new once-monthly RNA-targeted prophylactic, and oral deucrictibant is in late-stage development. This wave of new options is making treatment more accessible and less burdensome for patients worldwide.

C4 is the single best screening test for HAE. It is low during attacks and is also low between attacks in the vast majority of HAE Type I and Type II patients. A normal C4 level between attacks makes HAE Type I or II very unlikely (though not impossible during remission periods in mild cases).

Key point: C4 is inexpensive and widely available. If your doctor suspects HAE, this should be the first test ordered.

This measures the amount of C1-inhibitor protein in the blood. In Type I HAE (85% of cases), C1-INH levels are low (typically below 50% of normal). In Type II HAE, C1-INH levels may be normal or even elevated, but the protein does not function properly.

This measures whether the C1-INH protein actually works. It is essential for diagnosing Type II HAE, where C1-INH levels may appear normal but function is reduced (typically below 50% of normal). Both Type I and Type II show low C1-INH function.

Important: Functional assays are more susceptible to handling errors. If results are borderline, repeat testing is recommended. Blood samples should be processed promptly.

C1q is used to distinguish HAE (hereditary) from acquired C1-INH deficiency (AAE). In HAE, C1q is normal. In acquired angioedema due to C1-INH deficiency, C1q is typically low. This distinction matters because the underlying causes and some treatment approaches differ.

Genetic testing for SERPING1 gene mutations (which encodes C1-INH) can confirm HAE Types I and II and is useful for family screening. For HAE with normal C1-INH, genetic testing is essential to identify causative variants in FXII, PLG, ANGPT1, KNG1, MYOF, or HS3ST6. This type of genetic testing is more widely available in Europe.

HAE with normal C1-INH (formerly called HAE Type III) is a distinct condition where all standard complement tests are normal, but patients still experience bradykinin-mediated angioedema attacks. Diagnosis requires:

• A family history of angioedema, OR
• Identification of a known causative genetic variant (FXII, PLG, ANGPT1, KNG1, MYOF, HS3ST6)

This type is predominantly recognized and studied in Europe, where variant-specific genetic testing is more widely available. Estrogen often worsens this form significantly. Most treatments approved for HAE Types I/II are used for HAE with normal C1-INH, though formal approval often does not include this subtype.

Not all angioedema is HAE. Important distinctions include:

• Allergic angioedema: Usually accompanied by hives (urticaria) and itching. Responds to antihistamines and epinephrine. HAE does NOT cause hives.
• ACE inhibitor angioedema: Caused by blood pressure medications that increase bradykinin. Can mimic HAE but starts after medication initiation. Resolves when the medication is stopped.
• Acquired C1-INH deficiency: Similar symptoms to HAE but develops later in life (usually after age 40). Often associated with lymphoproliferative disorders. Distinguished by low C1q levels (C1q is normal in HAE).
• Idiopathic angioedema: Recurrent angioedema without an identifiable cause. May involve histamine or bradykinin pathways. Complement testing is normal. Often responds partially to antihistamines.

Because HAE is autosomal dominant, all first-degree relatives (parents, siblings, children) of a diagnosed patient should be tested. Testing should include C4, C1-INH level, and C1-INH function.

• Children can be tested as early as age 1 year, but results should be confirmed after age 4 because complement levels can be unreliable in infancy
• Up to 25% of HAE patients have de novo mutations with no family history
• Presymptomatic identification allows early treatment planning and emergency preparedness

• What type of HAE do I have (Type I, Type II, or HAE with normal C1-INH)?
• Have all my first-degree relatives been screened?
• Is my C1q level normal (to rule out acquired C1-INH deficiency)?
• Should I have genetic testing, especially if complement tests are normal?
• Are any of my current medications (particularly ACE inhibitors or estrogen-containing drugs) potentially worsening my attacks?
• Do you have experience treating HAE patients, or should I be referred to a specialist?

FDA-APPROVED Sebetralstat (brand name: Ekterly, from KalVista) was FDA-approved in July 2025 and is the first and only oral (pill) on-demand treatment for HAE attacks — the first new type of on-demand therapy in more than a decade. It is a plasma kallikrein inhibitor that you swallow at the first sign of an attack, for patients aged 12 and older.

• Form: Oral tablet — no needle, no mixing, no refrigeration.
• Onset: In the Phase 3 KONFIDENT trial, it began relieving symptoms faster than placebo (median time to the start of relief about 1.3 hours), and many attacks resolved within 24 hours.
• How used: Taken as soon as an attack begins; a second dose may be taken if symptoms persist (per the label).
• Significance: Removes the burden of carrying and using injections for acute attacks — especially valuable for needle-averse patients and for treating attacks early, anywhere. Laryngeal (throat) attacks remain an emergency — seek immediate care regardless of on-demand therapy.

FDA-APPROVED Icatibant is a synthetic peptide that blocks the bradykinin B2 receptor, directly preventing bradykinin from causing swelling. It is self-administered as a subcutaneous injection in the abdomen.

• Dose: 30 mg subcutaneous injection, self-administered
• Onset: Symptom relief typically begins within 30 minutes to 2 hours
• Repeat dosing: May be repeated after 6 hours if needed; maximum 3 doses in 24 hours
• Advantages: Self-injectable, does not require refrigeration after first opening, generic available in some markets
• Side effects: Injection site reactions (redness, swelling, pain at the injection site) in most patients; generally mild

FDA-APPROVED Berinert is a plasma-derived C1-INH concentrate that replaces the missing or dysfunctional protein. It is given as an intravenous infusion.

• Dose: 20 IU/kg intravenous, administered slowly
• Onset: Symptom relief typically within 30–60 minutes
• Advantages: Well-established safety profile; can be self-administered after training
• Considerations: Requires IV access; plasma-derived product (screened for viral safety)

FDA-APPROVED Ruconest (conestat alfa) is a recombinant human C1-INH produced in transgenic rabbits. It provides the same replacement function as plasma-derived C1-INH but without the theoretical risk of blood-borne pathogens.

• Dose: 50 IU/kg IV (max 4,200 IU), up to 2 doses within 24 hours
• Contraindication: Known or suspected rabbit allergy
• Advantage: Not derived from human plasma

FDA-APPROVED Ecallantide is a recombinant protein that directly inhibits plasma kallikrein, preventing bradykinin generation. It is effective but has important safety considerations.

• Dose: 30 mg subcutaneous (3 injections of 10 mg each)
• Critical limitation: Must be administered by a healthcare provider (not self-administered) due to a 3–4% risk of anaphylaxis. Patients must be observed for at least 1 hour after injection.
• Availability: FDA-approved but available in the US only; not approved in Europe or Japan

Every HAE patient should have a written emergency action plan that includes:

• Your HAE type and diagnosis
• Your prescribed on-demand treatment and how to administer it
• Your treating allergist/immunologist’s contact information
• A statement that antihistamines, epinephrine, and corticosteroids do not treat HAE
• The HAEA Emergency Hotline number: 1-866-798-5598

The US Hereditary Angioedema Association (HAEA) provides free emergency ID cards and downloadable action plans at haea.org.

• Which on-demand treatment is best for me?
• Can I self-administer my on-demand treatment at home?
• How many doses of on-demand treatment should I keep at home?
• Should I carry on-demand treatment when I travel?
• What should I do if I have a laryngeal attack?
• Does my local emergency department stock HAE-specific treatments?
• Have I been trained on self-injection technique?
• Should I treat mild attacks or only severe ones? (Answer: treat all attacks.)

FDA-APPROVED Lanadelumab is a monoclonal antibody that targets plasma kallikrein, the enzyme that generates excess bradykinin in HAE.

In the long-term open-label extension (HELP OLE), lanadelumab maintained high efficacy with many patients remaining attack-free for extended periods.

FDA-APPROVED Garadacimab (brand name: Andembry) targets Factor XIIa, blocking the kallikrein-kinin cascade at its upstream trigger. This is a novel mechanism distinct from other HAE therapies.

• Trial: VANGUARD (NCT04656418)
• Dose: Monthly subcutaneous injection
• FDA approval: June 16, 2025 (adults and pediatric patients ≥12 years)
• Advantage: Monthly dosing; upstream mechanism blocks cascade activation
• EMA status: Approved February 13, 2025

FDA-APPROVED Haegarda is a plasma-derived C1-INH concentrate administered subcutaneously for routine prophylaxis, replacing the deficient protein directly.

• Dose: 60 IU/kg SC twice weekly
• Attack reduction: ~95% reduction in median attack rate (COMPACT trial)
• Administration: Self-administered subcutaneous injection after training
• Advantage: Directly replaces the deficient protein; well-established safety profile
• Consideration: Twice-weekly injections; injection volume can be significant

FDA-APPROVED Cinryze is a plasma-derived C1-INH concentrate administered intravenously for routine prophylaxis.

• Dose: 1,000 IU IV every 3–4 days
• Advantage: Long track record of safety and efficacy
• Consideration: Requires IV access; less convenient than subcutaneous options
• Note: Largely supplanted by subcutaneous Haegarda and newer therapies, but remains an option

FDA-APPROVED Berotralstat is an oral plasma kallikrein inhibitor and was the first oral prophylactic therapy approved for HAE.

Honest assessment: Berotralstat’s 44% attack reduction is lower than the ~87–95% achieved with injectable options (lanadelumab, Haegarda). Some patients and physicians consider it less effective. However, the convenience of a daily pill and the avoidance of injections make it a preferred choice for some patients, particularly those with moderate attack frequency. It can also be used in combination with injectable prophylaxis for patients who need additional attack reduction.

FDA-APPROVED Donidalorsen (brand name: Dawnzera, from Ionis) was FDA-approved in August 2025 for the prevention of HAE attacks in patients aged 12 and older. It is the first RNA-targeted therapy for HAE — an antisense oligonucleotide that lowers production of prekallikrein, reducing the bradykinin that drives attacks.

• Trial: OASIS-HAE (Phase 3) — reduced monthly attacks by ~81% versus placebo over 24 weeks.
• Mechanism: Antisense oligonucleotide targeting prekallikrein messenger RNA (a new class for HAE).
• How it is given: Subcutaneous injection once every 4 weeks (or every 8 weeks for some patients) — a self-administered autoinjector.
• Significance: Offers a less-frequent dosing option and an entirely new mechanism for long-term prophylaxis.

INVESTIGATIONAL Deucrictibant is an oral bradykinin B2-receptor antagonist in Phase 3 development for both on-demand and prophylactic use. It is not yet FDA-approved.

• Mechanism: Oral bradykinin B2-receptor antagonist (the same target class as injectable icatibant, but taken as a pill).
• Status: Phase 3 trials ongoing (not FDA-approved).
• Potential advantage: An oral option that blocks bradykinin at the receptor.

• Dental procedures — even routine cleanings can trigger facial or laryngeal attacks
• Surgery — particularly procedures involving intubation or manipulation of the upper airway
• Medical procedures — endoscopy, bronchoscopy, or any procedure that may cause trauma to mucous membranes

Preferred approach: C1-INH concentrate (Berinert or Cinryze) administered 1–6 hours before the procedure. On-demand treatment must also be available during and after the procedure in case of breakthrough.

Alternative: Fresh frozen plasma (FFP) can be used where C1-INH concentrates are not available, but it is a less precise option and carries a small risk of paradoxically worsening attacks (though this is rare).

• Am I having enough attacks to benefit from long-term prophylaxis?
• Which prophylactic option is best for my situation — injectable or oral?
• How effective is each option at reducing my attacks?
• What are the side effects and drug interactions?
• Can I switch between prophylactic options if one doesn’t work well enough?
• Should I still keep on-demand treatment available while on prophylaxis?
• I have a dental/surgical procedure coming up — do I need short-term prophylaxis?
• Are there any clinical trials for new prophylactic therapies I might be eligible for?

• Icatibant (Firazyr): Pre-filled syringe, subcutaneous, self-administered after training
• Berinert (IV C1-INH): Can be self-administered after IV access training; some patients use butterfly needles at home
• Haegarda (SC C1-INH): Subcutaneous self-injection after training
• Lanadelumab (Takhzyro): Pre-filled syringe or autoinjector, subcutaneous, self-administered

Training: All patients should receive formal self-administration training from their HAE specialist or a certified nurse educator. This typically involves 1–2 supervised sessions before independent use.

• Always carry at least two doses of on-demand treatment when traveling
• Carry a physician’s letter explaining your condition, medications, and the need to carry injectable drugs
• Research hospitals at your destination that stock HAE-specific treatments
• For international travel, contact the HAEA or local HAE patient organization at your destination
• Medications requiring refrigeration should be transported with ice packs in an insulated bag
• Never check medications in airline luggage — always carry in your cabin bag

• WAO/EAACI: World Allergy Organization / European Academy of Allergy and Clinical Immunology — publishes the primary international HAE guidelines (Maurer et al., Allergy 2022)
• HAWK: Hereditary Angioedema Working Group — international consensus documents (Cicardi et al.)
• US HAEA: US Hereditary Angioedema Association — Medical Advisory Board recommendations
• HAEi: HAE International — global patient advocacy network covering 98+ countries
• RITA-ERN: European Reference Network for Rare Immunological Diseases
• ACAAI: American College of Allergy, Asthma & Immunology — Practice Parameter on Angioedema

• C1-INH concentrate availability varies by country depending on plasma fractionation capacity. Some countries still rely on fresh frozen plasma for acute attacks.
• HAE with normal C1-INH is predominantly recognized and studied in Europe, where genetic testing for relevant variants is more widely available.
• Diagnostic delay remains a major global problem, averaging 8–13 years in many countries and longer in low-resource settings.
• Androgens (danazol) are still used in some low-resource settings but have been removed from first-line in all major guidelines due to significant side effects.

DE-ADOPTED AS FIRST-LINE Attenuated androgens (danazol, stanozolol) were the only prophylactic option available for HAE for decades. They work by increasing C1-INH production. However, they have significant side effects that have led all major guidelines to remove them from first-line therapy:

• Hepatotoxicity, including risk of hepatocellular adenoma and hepatocellular carcinoma with long-term use
• Virilization in women (deepened voice, hirsutism, acne, menstrual irregularities)
• Weight gain, mood changes, lipid abnormalities
• Contraindicated in pregnancy and children
• Growth effects in children

Danazol may still be used in some patients where targeted therapies are unavailable or unaffordable, but at the lowest effective dose with regular liver monitoring. All major guidelines (WAO/EAACI, HAEA, HAWK) recommend targeted therapies over androgens.

SUPERSEDED Before C1-INH concentrates became available, fresh frozen plasma (FFP) was used to treat acute HAE attacks because it contains C1-INH. However, FFP also contains substrates of the contact activation system (prekallikrein, Factor XII, kininogen), which can theoretically worsen attacks. Modern HAE-specific therapies have largely replaced FFP, though it remains an option where C1-INH concentrates are unavailable.

INEFFECTIVE FOR HAE These standard treatments for allergic angioedema do not work for HAE because HAE is driven by bradykinin, not histamine. Unfortunately, many HAE patients receive these treatments repeatedly before being correctly diagnosed, contributing to the long diagnostic delay. If a patient has angioedema that does not respond to antihistamines, epinephrine, and corticosteroids, HAE should be considered in the differential diagnosis.

• Avoid estrogen. Estrogen-containing contraceptives (the combined pill, patch, ring) and estrogen-based hormone replacement therapy can worsen HAE. Progestin-only or non-hormonal methods are generally preferred — discuss with your specialist.
• ACE inhibitors (a class of blood-pressure medicine) should also be avoided in HAE; an ARB is usually a safer alternative if blood-pressure treatment is needed.

• Attack frequency is unpredictable in pregnancy — some people improve, others worsen, often in the later trimesters or around delivery.
• Plasma-derived C1-INH is the mainstay for both treating attacks and prevention during pregnancy and while breastfeeding.
• The newer agents (lanadelumab, berotralstat, garadacimab, donidalorsen, sebetralstat, icatibant, ecallantide) have limited pregnancy safety data and are generally not first-choice — decisions are individualized with your team.
• Have an on-demand plan for labor and delivery; C1-INH is commonly given around delivery if needed.

• Which HAE treatments are safest for me during pregnancy and breastfeeding?
• What birth-control options are safe given that estrogen can worsen HAE?
• Should my prophylaxis change if I am planning to conceive?
• What is the plan for treating attacks during labor and delivery?

• Learn the prodromal symptoms. Many HAE patients experience warning signs before swelling starts: tingling, tightness, a rash-like pattern (erythema marginatum), fatigue, or mood changes. Recognizing these can enable earlier treatment.
• Track triggers. Stress, infections, menstruation, physical trauma, and certain medications can trigger attacks. Helping the patient maintain an attack diary can identify patterns.
• Watch for abdominal attacks. Abdominal HAE attacks cause severe pain, nausea, and vomiting and can mimic a surgical abdomen. Knowing that this is an HAE pattern can prevent unnecessary surgery.

• Learn how to administer the patient’s on-demand treatment. Whether it is a subcutaneous injection (icatibant) or an IV infusion (Berinert), caregivers should receive the same training as the patient.
• Know where medications are stored. Keep on-demand treatments accessible, not locked away. Check expiration dates regularly.
• During a laryngeal attack: Administer on-demand treatment immediately, call 911, and stay with the patient. Bring the emergency action plan and medication information to the emergency department.

• Schools: Work with the school nurse to ensure on-demand treatment is available and that staff know what to do during an attack. A 504 plan or IEP may be appropriate for children with HAE.
• Workplaces: Help the patient communicate their needs to their employer, including the need to carry medication and the potential for unpredictable absences during severe attacks.
• Travel: Assist with travel preparation: physician letters, medication transport, and identifying local medical resources at the destination.

• The unpredictability of attacks creates chronic anxiety. Many HAE patients live with the fear of when the next attack will happen, particularly laryngeal attacks. This is a real psychological burden.
• Connect with the HAE community. The HAEA offers peer support programs and patient events that reduce isolation.
• Consider professional support. Psychologists experienced in chronic illness management can help with anxiety, depression, and coping strategies.
• Caregiver burnout applies to HAE too. The unpredictable nature of attacks means caregivers must be always prepared. Take breaks, accept help, and maintain your own health.

• “hereditary angioedema treatment 2026”
• “lanadelumab Takhzyro HAE HELP trial”
• “berotralstat Orladeyo HAE APeX-2”
• “garadacimab Factor XIIa HAE”
• “HAE prophylaxis oral therapy”
• “icatibant Firazyr HAE acute treatment”
• “C1 inhibitor concentrate HAE”

• “donidalorsen Dawnzera HAE OASIS-HAE”
• “sebetralstat Ekterly HAE KONFIDENT oral on-demand”
• “deucrictibant HAE”
• “NTLA-2002 gene editing hereditary angioedema”
• “BMN 331 AAV gene therapy HAE”
• “STAR-0215 anti-kallikrein HAE”
• “HAE clinical trials 2026”