Overview 

Hereditary angioedema (HAE) is a rare genetic disorder caused by mutations in the SERPING1 gene that result in a deficiency in the level or function of C1-esterase inhibitor (C1-INH).¹ HAE is characterized by debilitating, painful, and sometimes fatal swelling episodes. These attacks can occur in the subcutaneous and/or mucosal tissue, often affecting the face, extremities, lips, abdomen, genitalia, and less commonly, the airway. HAE affects approximately 1 in 50,000 people.¹ As an autosomal dominant condition, it often affects multiple individuals in the same family and carries a high disease- and treatment-related burden. Patients often live in fear of the unpredictable and potentially fatal attacks. Treatment for HAE first became available in the 1960s with attenuated androgens and antifibrinolytics. However, androgens are associated with significant side effects and antifibrinolytics are minimally effective in many patients. In 1979, the first C1 INH replacement therapy became available in Germany to treat attacks, followed by other HAE-specific medications for on-demand or preventative treatment of HAE symptoms.

Historically patients learned to self-administer intravenous plasma-derived C1-INH concentrates every 3 to 4 days to prevent attacks. In recent years, newer treatment options have become available to help reduce the treatment burden, offer multiple routes of administration, facilitate rapid use of rescue medication, improve the durability of prophylaxis, and normalize life for affected individuals.

Pathophysiology

C1-INH is a shared regulator of the complement and contact systems. When it is deficient or dysfunctional, both systems destabilize and set off a series of enzymatic reactions. Overactivation of the complement system results in reduced C4 levels, a feature that can be used diagnostically to screen for C1-INH deficiency but is not mechanistically responsible for angioedema symptoms. Overstimulation of the contact system results in increased Factor XII and plasma kallikrein activity leading to excessive production of bradykinin. Bradykinin, acting through the bradykinin B2-receptor, causes the localized vasodilation, vascular leak, and clinical swelling seen in HAE due to C1-INH deficiency (Type I) or dysfunction (Type II).^2,3 Patients with HAE Type I and II typically have functional C1-INH (fC1-INH) levels substantially less than 50% of normal.¹ Clinical studies have suggested protection from HAE attacks when fC1-INH levels are increased to >40% by exogenous administration, though clinical variability exists.⁴

HAE with normal C1-inhibitor levels (HAE-nC1-INH) is a rarer type of HAE that has been more recently described. These patients present with normal C4 and C1-INH level/function, making it more challenging to diagnose.^5,6 Several genetic variants of HAE-nC1-INH have been described, though in some patients no monogenic cause has been identified. The pathophysiology of HAE-Factor XII (FXII) and HAE-Plasminogen (PLG) has been elucidated, while the pathophysiology of other forms of HAE-nC1-INH is less understood. Current evidence convincingly shows HAE-FXII and HAE-PLG are due to dysregulated bradykinin production or signaling, though the latter is not dependent on the FXII-kallikrein pathway.⁷ Other forms of HAE-nC1-INH may be bradykinin-mediated or involve additional mediators affecting vascular permeability.

Symptomology and Disease Burden

Angioedema can be mast-cell mediated or bradykinin-mediated.⁸ Mast-cell mediated angioedema is due to the release of mast cell mediators (histamines, leukotrienes, prostaglandins, etc). It generally has a quick onset, is often associated with urticaria, swelling, and itching, and responds acutely to antihistamines and epinephrine. In contrast, HAE is bradykinin-mediated, with a relatively slow progression and slow resolution of symptoms. It is not associated with urticaria during the swelling event and does not respond to antihistamines, epinephrine, or corticosteroids. It is worth noting that since urticaria is common in the general population, approximately 15% of patients with HAE may experience hives unrelated to their HAE symptoms at some point in their lifetime.

All 3 types of HAE display similar symptomology.⁷ The clinical presentation of HAE is highly variable with regard to attack frequency, attack severity, and anatomical sites of swelling. This clinical variability is evident in a single individual tracking symptoms over time and also between individuals with HAE, even within families who harbor the same causative mutation.⁹ No simple relationship exists between disease severity and C1-INH level.

HAE attacks are characterized by recurrent episodes of self-limiting subcutaneous, mucosal, intestinal, and/or laryngeal non-pitting edema.¹⁰ While attacks can affect any part of the body, they most frequently strike the face and extremities.⁷ Episodes typically resolve on their own in 2 to 5 days but are painful, debilitating, and potentially life-threatening during this time.^7,10 Attacks involving the extremities are most common and affect 96% of patients with HAE.¹¹ Extremity swelling is functionally disabling and impacts a patient’s ability to use their hands and feet. Abdominal attacks are also quite common, affecting 93%.¹¹ The intestinal swelling creates a functional bowel obstruction resulting in abdominal distention, cramping, nausea, vomiting, extreme pain, and occasionally diarrhea as symptoms resolve. Severe attacks with intravascular fluid loss into the bowel may cause hypovolemia and hypotension. Patients presenting with HAE abdominal attacks are often misdiagnosed, and historically underwent unnecessary appendectomies, or exploratory laparotomies to investigate the nature of the bowel obstruction. Approximately 50% to 70% of patients will have a laryngeal attack at some point in their lifetime.⁹ These can lead to fatal asphyxiation if unrecognized and untreated with historical mortality rates of 30% to 40% in undiagnosed patients with HAE. A fatal laryngeal attack can sometimes be the first attack encountered by an undiagnosed individual.⁴ Because of the mortality risk, all family members of a patient with an established diagnosis should be evaluated for HAE.⁴

An HAE attack may be preceded by prodromal symptoms. The most well-recognized HAE prodrome is erythema marginatium (Figure 1) which presents as a flat, non-pruritic, unraised rash, typically on the extremities or the trunk. This can also be seen in some infectious diseases. Patients may describe it as red wheals or a mite rash. In HAE, erythema marginatium is often a reliable indicator that an attack is forthcoming within a few hours. Other prodromal features are nonspecific and include fatigue, aggression, depression, thirst, and exhaustion.¹²

Figure 1. Erythema Marginatium

Triggers for HAE attacks may include surgical or dental procedures, infections, trauma, hormonal changes (puberty, menstruation, pregnancy, birth control, menopause), medications (specifically exogenous estrogens and ACE-inhibitors), stress, strong emotions (including excitement and happiness), sports, exercise, and repetitive motions. However, often attacks occur without any clear trigger, highlighting the difficult unpredictability of symptoms. Patients may forgo routine preventative care, such as Pap Smears and mammograms, necessary medical treatment, or dental procedures due to fear of triggering an attack.¹³

Diagnosis

Clinical manifestations of the disease are often absent in infancy, typically appearing in childhood or adolescence, and then increasing during puberty. An earlier age of symptoms onset is often associated with a more severe disease course.¹⁰ It is important for clinicians to conduct appropriate work-up to differentiate HAE from other types of angioedema due to key differences in morbidity, mortality, and effective treatment plans. Important questions regarding a person's clinical history and experience with angioedema attacks can help guide clinical investigations (Table 1).⁷

Features that may confound or exclude an HAE diagnosis should be ruled out, such as the presence of urticaria or ACE-inhibitor associated angioedema.

International guidelines recommend testing for antigenic C4, antigenic C1-INH, and fC1 INH in all patients in whom HAE is suspected (Table 2).^14,15 Antigenic C4 levels are generally always low in both Type I and Type II HAE but, in a small subset of patients, may normalize during asymptomatic periods. Alone, C4 is 80% sensitive for detecting HAE.⁷ Patients with Type I HAE will demonstrate low C1-INH and fC1-INH levels; patients with Type II HAE will have normal or elevated C1-INH coupled with low fC1-INH levels.¹²

HAE with normal C1-INH levels is often a clinical diagnosis and can be more challenging. C4, C1-INH, and fC1-INH levels will all typically be normal. Clinicians depend heavily on a patient’s clinical presentation, personal history, family history/presence of genetic mutations, and lack of response to antihistamines, epinephrine, corticosteroids, and a trial of omalizumab for preventative treatment.⁷ Genetic testing should be conducted in patients exhibiting characteristic HAE symptoms and history, but have a normal laboratory work-up as identification of an HAE-nC1INH genetic variant helps confirm the diagnosis.¹²

Impact on Quality of Life

Attack frequency correlates with levels of anxiety and depression, as well as decreases in general health status, daily functioning, and health-related quality of life (QoL) in patients with HAE.¹⁵ The prospect of a sudden laryngeal attack with fatal consequences looms over nearly all patients living with HAE, and is described as the most feared complication of the disease.¹¹ Disfigurement caused by facial swelling has been described by children as young as kindergarteners as producing a “monster” effect, negatively impacting their self-image, social interactions, and ability to participate in school and activities.¹¹ The unpredictability of the disease is a common source of anxiety for patients. Adults report excessive absences due to attacks, feeling unreliable at work, and difficulty maintaining employment; while children and adolescents report not being able to live up to their full potential, missing school, sports, games, holidays, play dates, and even being barred from participation in athletics due to potential liability concerns.¹¹

Treatment

The goal of HAE therapy is to attain control over the disease and normalize a patient's life. This is done by a combination of strategies: stopping attacks before they occur and when they do occur, treating them immediately.

Historically, attenuated androgens were used to prevent HAE symptoms. This is effective for some patients but is associated with numerous potentially serious adverse side effects, particularly for women.¹⁶ The mechanism by which androgens prevent HAE attacks is not well-established but may involve increasing C1-INH levels and increasing kinin degradation. However, with the further elucidation of the underlying pathophysiology of HAE, treatment advances became possible. In 2008, human plasma-derived C1 esterase inhibitor was FDA-approved for the treatment of HAE — a transformative milestone.^11,13 In the subsequent years, over a half dozen other agents have been approved for the prevention or treatment of HAE attacks, with more under investigation.

Three treatment strategies exist for HAE: on-demand therapy, long-term prophylaxis, and short-term prophylaxis.¹⁷ On-demand therapy is used to immediately treat and resolve symptoms of an active attack at the time of symptom onset. Long-term prophylactic treatment is taken regularly to reduce the overall frequency and severity of attacks. Short-term prophylaxis is administered prior to an expected triggering event (such as, before a medical procedure) to reduce the likelihood of an attack. These agents function to inhibit or regulate various stages of the contact system to reduce bradykinin production (Table 3).

On-demand Therapy

On-demand agents are rapidly bioavailable, fast-acting rescue medications designed to target different stages within the pathways leading to bradykinin overproduction and HAE symptoms. Depending on the site of involvement, an acute attack can be disabling, severely painful, and even fatal. Administering on-demand therapy can shorten the duration, reduce the severity, and lessen the impact of an HAE attack.¹⁵

Five agents are available for on-demand therapy (Table 4). While treatment is mandatory for attacks involving the upper airways, all HAE attacks are eligible for on-demand therapy. The earlier an attack is treated, the more quickly it will resolve¹⁵ Underscoring the importance of patient education and training on self-administration with on-demand medication. All licensed on-demand HAE medications can be self-administered, except for ecallantide, which must be administered by a healthcare provider due to the risk of anaphylaxis (Table 4). Sebetralstat is the most recently FDA-approved on-demand therapy and the only oral on-demand agent available.¹⁸ Oral dosing is anticipated to remove barriers to use of rescue medication, allowing patients to administer treatment earlier than with an injectable medication due to ease of use, portability, and removal of pain and anxiety associated with parenteral dosing.¹⁹ A long-term open-label extension study demonstrated no incidences of dysphagia with sebetralstat when used to treat laryngeal or abdominal attacks.²⁰

All patients with HAE should have on-demand therapy available to treat an attack. Patients should be provided with education on when and how to treat HAE attacks, including appropriate training on self-administration of medication (Table 5). Patients should carry 2 doses of on-demand medication given the occasional need for a second dose to adequately treat symptoms. Patients should be encouraged to recognize and treat attacks as early as possible. Airway attacks are unique given the potentially life-threatening nature. Patients should treat any airway symptoms as early as possible and emergency department evaluation is recommended for monitoring to ensure no further intervention is required beyond administration of the effective HAE rescue medication.

Long-Term Prophylaxis

The goal of long-term prophylaxis (LTP) is to reduce the frequency and severity of HAE attacks. Six LTP agents are FDA-approved for the treatment of HAE (Table 6). LTP should be discussed with every patient and management plans should be individualized through shared decision making. Numerous factors are important when considering LTP treatment, including attack frequency and severity, use of on-demand medication, quality of life, treatment accessibility, failure to maintain control with on-demand therapy alone, and patient preference. ^20,21 Patients on LTP should be regularly assessed for safety, effectiveness, adherence, treatment burden, and quality-of-life impact. Because these conditions change frequently, providers should re-evaluate LTP in patients at every visit. All patients on LTP should also have on-demand therapy available, as breakthrough attacks may still occur.

International guidelines recommend plasma-derived (pd) C1-esterase inhibitor (IV or SC every 4 days), lanadelumab (SC every 2 to 4 weeks), or berotralstat (PO daily) as first-line agents for LTP.²⁰ Since the updated guidelines were published in January 2022, two additional agents were FDA-approved for LTP in 2025: donidalorsen and garadacimab.

Donidalorsen is a prekallikrein-directed antisense oligonucleotide, FDA-approved in 2025 for LTP in patients ≥12 years and dosed SC every 4 to 8 weeks via autoinjector. The efficacy and safety of donidalorsen were established in a Phase 3 study (N=90) that demonstrated an 81% reduction in attack rate versus placebo when administered every 4 weeks in study weeks 1 to 25. This was also accompanied by a significant improvement in quality-of-life metrics.^22,23 While head-to-head studies are lacking, switch studies evaluated outcomes when patients were transitioned from subcutaneous C1-INH, lanadelumab, or berotralstat to donidalorsen. Switched patients demonstrated improved disease control, reduced attack frequency, improved QoL, and improved treatment satisfaction.²⁴

Garadacimab is an anti-Factor XIIa monoclonal antibody approved in 2025 for LTP in patients ≥12 years. Garadacimab is dosed monthly with a subcutaneous autoinjector. The Phase 3 VANGUARD study evaluated its safety and efficacy in 161 patients with HAE. Garadacimab reduced attack frequency by 95% versus baseline run-in and 60% of patients became attack-free.²⁵ This was coupled with an improvement in health-related QoL, work-related productivity, treatment satisfaction, and disease control.²⁶

In the absence of updated guidelines and head-to-head studies, selecting the appropriate LTP medication is determined by shared decision making, longitudinal follow-up  evaluation, and treatment individualization. The effectiveness of LTP is contingent upon proper medication dosing adherence that can be impeded by a variety of factors, including access to treatment, dosing frequency, side effects, and comfort/skill with treatment administration. Treatment selection is also influenced by a number of patient factors, including attack frequency, rapidity of attack progression, history of laryngeal attacks, patient access to medical care, history of frequent hospitalization, treatment complications, and quality of life. Treatment-related factors, such as efficacy, safety, cost, route of administration, and patient preference/tolerability should also be considered.  

Quality of Life Assessment Tools

Quality of life and disease assessment tools tend to be underutilized by healthcare providers but can provide an objective means to track QoL and disease activity over time, allowing clinicians to adjust therapy as needed.

The HAE-QoL is a broad, comprehensive QoL assessment tool with domains for physical functioning, role functioning, bodily pain, general health, vitality, social functioning, emotional role, mental health, and health transition.²⁷ The US HAEA QoL is a tool specific to the United States that was developed by the HAE Association (HAEA) to evaluate challenges specific to the United States, such as unique aspects of the US healthcare system, including access to care and medications within its framework. The 41-item tool addresses items related to school, work, social activities, family life, physical activities, access to treatment, treatment affordability, coverage issues, and treatment burden.²⁸

The HAE Activity Score is a disease assessment tool that measures disease severity and provides clinicians with a snapshot of a patient's disease control.²⁹ Its primary focus is to measure the frequency and severity of attacks and the impact on daily activities. Tool items ask about number of attacks, emergency room visits, psychological/psychiatric treatment, absenteeism, general health, and impairment in everyday activities due to pain.

Because treatment individualization is an ongoing process in HAE, tracking QoL and disease severity are helpful in assessing if a change is needed in the patient’s current management plan. QoL tools can help objectively measure and track these changes over time, however open conversations with patients regularly provide important qualitative information in understanding how and if the patient’s needs are being met. Questions developed by an international consensus meeting to guide discussions include: ¹

• Are there any activities that you avoid because of your HAE?
• How often do you experience HAE attacks?
• How would you describe the severity of your HAE attacks?
• How often does HAE cause you to miss work, school, or activities at home?
• How often do you have to use acute rescue medication for each HAE attack and do you feel that you respond well?
• What is the average time from attack onset to treatment administration? Time to initial symptom relief? Time to complete resolution of symptoms?
• Have you had any changes in life status that may affect the activity of your HAE?
• How often do you experience fear/anxiety/depression associated with your HAE?
• Have you had any difficulties accessing or administering your acute or prophylactic HAE treatment?
• To what extent has HAE interfered with your social life, family, relationships, or physical activities?
• How often have you had to visit the hospital for an HAE attack?
• Have you made any lifestyle modifications to avoid triggers?

Considerations in Children

According to the 2023 European Academy of Allergy and Clinical Immunology (EAACI) Congress, one of the greatest unmet needs in HAE is disease recognition and management in young children.³⁰ Treatment is also particularly challenging due to more limited approved treatment options (Figure 2).³⁰ This emphasizes the need for accurate early diagnosis, provision of on-demand therapy, and education regarding primary attack prevention.¹⁵ Attacks in children are often triggered by infections, strenuous physical activity, accidental trauma, and strong emotional responses. Identifying triggers can help families take measures to avoid them, such as receiving routine vaccinations.

Figure 2. Age-based Indications for HAE Prevention and On-demand Therapy

Symptom onset in children generally occurs at age ≥4 years old and often worsens during puberty.³⁰ Data from a long-term Hungarian study (from years 1986 to 2018) of 70 pediatric patients with HAE Type I and II help illustrate the course of HAE and its treatment throughout childhood and adolescence. The study calculated a mean age of onset of 7.5 years, with no differences between boys and girls.³¹ A total of 3,009 attacks were reported. Attack frequency increased with age (Figure 3), with most attacks involving the subcutaneous tissue (Figure 4).

Figure 3. Attack Distribution in Hungarian Children (N=70) with HAE Types I and II by Age (1986-2018)

Figure 4. Attack Location in Hungarian Children (N=70) with HAE Types I and II by Age (1986-2018)

Children and adolescents are typically treated in the same way as adults, however, disease management for children under 12 years of age is more challenging due to more limited approved treatment options.²⁰ International guidelines recommend that all patients, including children, have access to on-demand therapy once they are diagnosed, even if they have not yet had an attack.^15,30 Human plasma-derived C1 esterase inhibitor is available for intravenous on-demand use for this population, although data is limited in children under age 6.^20,32

The option to place children under 6 years of age on LTP is a case-by-case decision and should take into consideration the needs of each individual child. Not every child will need LTP. For those who do, lanadelumab is the only LTP FDA-approved in children as young as 2 years of age. The safety and efficacy of lanadelumab in this population was established in the Phase 3 SPRING trial (N=21) that demonstrated a 94.8% reduction in attack frequency from baseline, allowed 16 children to become attack-free, and improved HR QoL metrics.³³ Human plasma-derived C1 esterase inhibitor is also available for children under 12 years. Two formulations are available for LTP as IV or SC injections with indications for children aged 6 years and above. International guidelines also recommend icatibant for on-demand treatment of HAE attacks in children under 12 years, though this is considered off-label use in the United States (FDA-approved for 18 and older).

By age 12 years, most treatment options available for adults are also indicated in children or used off-label in children.

Case Studies

The past decade has introduced treatment options that have changed the way HAE is managed. The introduction of lower-burden treatment options, longer acting injectables, and oral agents now allows for greater levels of treatment personalization (Table 6). This reinforces guideline recommendations to regularly review treatment plans for patients. Schedules change, hormones change, people move, and lifestyles change — all of which may necessitate a change in the management plan. The following cases highlight some of the challenges patients may face and how providers can help navigate them.

Case 1: Jenna’s Nausea

Jenna is a 32-year-old woman with HAE who struggles with frequent abdominal attacks. She is currently taking pdC1-INH, which she is supposed to take subcutaneously every 4 days for LTP. However, she often gets nauseous and develops a headache whenever she takes her medication. She also has a busy schedule between work and family life which has caused her to delay, avoid, or forget taking her medication altogether. This has resulted in increased attack frequency, and she now struggles with unpredictable attacks every few weeks which has disrupted her work and social life and become a significant source of stress and anxiety for her. She feels debilitated by nausea when she takes the medicine and debilitated by HAE when she forgoes it.

Disease and QoL assessment tools are important for tracking how both HAE symptoms and prescribed medication are impacting patients, including recognizing when a change is warranted. Guidelines recommend LTP treatment be reviewed regularly to ascertain if the prescribed agent is still appropriate for the patient. For Jenna, injecting a medication that gives her debilitating nausea every 4 days is not motivating her to adhere to her therapy. It is important to discuss with Jenna her specific goals of treatment and what changes may be helpful in getting her back on track. Two main factors are affecting her treatment plan: intolerance of the medication and reduced adherence. If side effects were managed by antiemetics, analgesics, or dose adjustments, would dosing every 4 days continue to serve as a barrier to her adherence? Is she willing to juggle more medication to manage her side effects or will this further increase her treatment burden? Is she open to trying something different?

Additionally, it would be important to ask about her on-demand medication use considering the frequency of her attacks. Is she treating her attacks? Does she have sufficient on-demand therapy? Is the on-demand therapy working well for her? A candid conversation will help shape a more personalized treatment plan for Jenna.

Case 2: Chase’s Hesitations

Chase is a 25-year-old man with HAE who has had 4 emergency department (ED) visits in the past 6 months due to repeated HAE attacks, including 2 with laryngeal involvement. He carries sebetralstat for on-demand use, but delays taking it because he’s not sure if he should be taking it during a laryngeal attack. He often minimizes the severity of his attack and waits to see if the symptoms will dissipate on their own, and he worries that he may unnecessarily administer rescue medication and then not have his medicine when he “really” needs it. This delay in treatment administration allows his symptoms to worsen and he ends up in the ED with severe and dangerous symptoms. He finds it challenging to recognize when an attack is developing.

Chase is on a convenient oral medication for on-demand therapy, yet he is anxious about taking it during a laryngeal attack. Chase should be educated and reassured of the safety of taking sebetralstat orally even during a laryngeal or abdominal attack. If oral administration during a laryngeal attack continues to be an ongoing source of anxiety for him and impedes life-saving administration, would he be open to and prefer a subcutaneous injection instead? Would he benefit from potentially having 2 different on-demand medications available?

Symptom identification is also a challenge for Chase. He could benefit from keeping a symptom journal to help identify any early or prodromal symptoms for his attacks. This could facilitate faster recognition and earlier treatment, thereby avoiding greater severity. Important educational points to review include better outcomes with earlier administration and the fact that some attacks may require a second dose of on-demand medication. Reliable access to medication doses and refills must be addressed with health plans and payors as restricted access leads to “rationing” by patients and untreated HAE attacks; the concept of saving medication until it is “really” needed leads to high morbidity and considerable mortality risk in these scenarios.

If access to medication is limited, it is important to investigate the reasons for this. Is his copay too high? Would he benefit from an on-demand medication that may be available at a lower cost, for example, a generic?

Finally, Chase seems to be a good candidate for LTP. His frequent attacks and difficulty with effectively using on-demand medication should initiate a conversation about preventative treatment options.

Case 3: Aviva’s Isolation

Aviva is a 40-year-old woman in rural Alabama. Her nearest allergist is 4 hours away. In her local area, she struggles to find a provider knowledgeable about HAE and travels long distances for medical consultations and treatment. This has increased her treatment gaps, attack rate, and severity. She feels isolated and unsupported.

Aviva is facing a challenge many people with chronic rare diseases face, particularly if they live far away from a major academic center. From a systemic perspective, numerous challenges exist, and solutions require multiple collaborative efforts. Specialists should aim to coordinate care with local primary care providers and advanced practitioners to expand reach into rural geographies and provide expertise in the management of patients through collaborative care models. Primary care providers can make efforts to actively connect their patients with HAE to allergists/immunologists for specialized care services. Telehealth provides opportunities for patients and specialists to connect for follow-up and minimize the number of in-clinic appointments for traveling patients when medically appropriate. Follow-up visits can also be coordinated with local primary care providers.

From Aviva’s perspective, placing her on medication that can be self-administered should be a priority. She is also likely a good candidate for LTP with a dosing schedule she can adhere to and an on-demand medication that can be easily self-administered. Social and emotional support can be extremely difficult to find when a patient is struggling with a rare disease. HAE is genetic. Does she have relatives who also struggle with HAE? Has her immediate family been evaluated for HAE? She can be invited to connect with patients via online communities and patient-advocacy groups. It may also help emotionally to connect with others locally who may have a different type of angioedema or another rare disease.

While it is important for all patients to be their own advocates, it is even more important for those who are distant from specialized healthcare services. However, patients often do not know how to find an appropriate specialist or best navigate a complex healthcare system. When specialized providers meet patients from distant geographies, either in clinic or via telehealth education, particularly on what is available for treatment and what they should expect out of treatment, should be a priority. This will help patients recognize if their treatment plan is meeting their needs or requires adjustment based on a number of factors, including safety, tolerability, effectiveness, comfort, and even convenience.

Emerging Therapies

The HAE treatment armamentarium has grown considerably over the past few years. Recently approved medication allow for greater independence and a lower treatment burden. However, gaps remain. Emerging therapies are aimed at making HAE treatment more tolerable and less burdensome while maintaining high levels of efficacy, all with the goal of normalizing life for patients.

Oral Deucrictibant: On-demand and LTP

Deucrictibant is an oral bradykinin B₂ receptor inhibitor being developed as an extended release tablet for LTP and an immediate-release capsule for on-demand use. The safety and efficacy of deucrictibant were evaluated in the CHAPTER-1 (LTP) and RAPIDe-2 (On demand) extension trials.³⁴

CHAPTER-1 was a 2-part Phase 2 double-blind, placebo-controlled trial that randomized 30 patients to deucrictibant XR release tables (20 mg/day or 40 mg/day) or placebo for 12 weeks for LTP. Participants completing the 12 weeks then entered into an open-label extension trial of deucrictibant (40 mg/day). Results demonstrated a 93.1% durable reduction in attack rate study period (≥1.5 years), a durable reduction in attack severity, and a 92.6% reduction in on-demand treatment utilization.

The RAPIDe-1, RAPIDe-2A, and RAPIDe-3 were dosing finding studies exploring the safety and efficacy of deucrictibant IR capsules as on-demand therapy (10 mg, 20 mg, 30 mg); the 20 mg capsule dose was chosen for further evaluation in the long-term, open label RAPIDe-2 trial.³³ Results demonstrated good tolerance across all assessed doses; time to onset of symptom relief (rated feeling at least “a little better”) was a median 1.1 hours, substantial symptom relief (rated feeling at least “better”) was a median 2.5 hours, attack severity was reduced by 2.8 hours (median), and complete attack resolution was observed by a median 10.6 hours. A single dose of deucrictibant was efficacious in achieving complete attack resolution without the need for additional rescue medication within 24 hours for 89.2% of patients. Approximately 10% required a second dose of deucrictibant.

Overall, oral bradykinin B₂ receptor antagonism with deucrictibant has shown promise in both the treatment and prevention of HAE symptoms. Deucrictibant is currently being further evaluated in the Phase 3 CHAPTER-3 and RAPIDe-3 trials.³⁵

Long-Term Prophylaxis

Subcutaneous Navenibart

Navenibart is a subcutaneously administered monoclonal antibody against plasma kallikrein being evaluated for LTP. Its long half-life and preliminary data suggests q3- and/or q6-month dosing may effectively prevent HAE attacks, making it a potentially convenient long-acting LTP.³⁶ The proof-of-concept Phase 1b/2 ALPHA-STAR trial recruited 16 adults with HAE Type 1 and 2. Interim results demonstrated an overall 92% average reduction in attack rate from baseline; this was also accompanied by a reduction in attack severity, HAE burden, and rescue medication utilization.^37,38 Results were confirmed in the interim analysis of the ongoing open-label ALPHA-SOLAR extension study.³⁹ A Phase 3 trial was recently initiated and is expecting results in 2027.

Intravenous NTLA-2002 (Gene Therapy)

NTLA-2002 (lonvoguran ziclumeran) is a gene-based therapy that utilizes CRISPER-Cas9 technology to edit KLKB1, the gene encoding kallikrein B1, and reduce the total plasma kallikrein protein level and potentially providing long-term disease control with a single dose.⁴⁰ A Phase 2 trial randomly assigned 27 adults with HAE to a single 25 mg or 50 mg dose of NTLA-2002 or placebo and evaluated the monthly attack rate out to Week 16. By Week 16, there was a 78.1% and 79.5% reduction in attack rates from baseline in the 25 mg and 50 mg groups, respectively. Forty percent of patients in the 25 mg group and 73% of patients in the 50 mg group were attack free with no additional treatment. Total plasma kallikrein protein levels dropped 55% and 86% from baseline in the 25 mg and 50 mg groups, respectively.

Based on these results, the Phase 3 multinational HAELO study was initiated in January 2025 and is currently ongoing. Sixty patients will be recruited and administered a single blinded IV infusion of the study drug or placebo, observed for 28 weeks, and then provided with the option to receive a single-blinded infusion of the opposite intervention. Upon completion of the first 28 weeks, participants will be offered entry into a long-term observation period of 76 weeks, for a total of 104 weeks.

Conclusion

Improved understanding of HAE pathophysiology has paved the way for the clinical development of advanced therapies that now offer more effective management strategies and significantly improved patient outcomes. Future research is continuing in this effort to investigate novel strategies to reduce HAE treatment burden, normalize life, and expand treatment options for special populations, particularly pediatrics. Continued collaboration among healthcare providers is essential to help expand care to underserved populations, reduce time to diagnosis, and initiate HAE treatment plans that both save and improve lives.

References

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