Therapeutic Advances in Hereditary Angioedema: A Focus on Present and Future Options

Abstract

Hereditary angioedema (HAE) is a rare genetic disorder characterized by unpredictable and potentially life-threatening episodes of swelling, driven primarily by excessive bradykinin production. These episodes commonly involve the skin, gastrointestinal tract, and upper airway, significantly impacting patients’ quality of life. Recent advances in understanding the underlying pathophysiology of HAE have transformed clinical care, enabling the development of highly targeted treatments that disrupt critical steps within the kallikrein–kinin pathway. Current on-demand therapies rapidly relieve acute symptoms, while contemporary prophylactic strategies have substantially reduced attack frequency and improved patient autonomy and health-related quality of life. Emerging therapies—including novel oral agents, monoclonal antibodies, RNA therapies, and pioneering gene editing approaches—continue to evolve, aiming to simplify treatment and further personalize care. These innovative treatments collectively strive to address remaining unmet needs, ensuring broader accessibility, convenience, and long-term sustainability of care for individuals living with HAE. This narrative review highlights the progression of therapeutic options in HAE, summarizing current advances and exploring future strategies toward personalized and patient-centered care.

Key Summary Points

Hereditary angioedema (HAE) is a rare, potentially life-threatening disease characterized by recurrent swelling attacks due to excessive bradykinin production.

Advances in disease pathophysiology have led to targeted therapies that block key steps in the kallikrein–kinin cascade, improving symptom control and reducing attack frequency.

Approved treatment options now include injectable and oral agents for both on-demand use and long-term prophylaxis, allowing for individualized, patient-centered care.

Emerging therapies—including gene editing, RNA-based agents, and long-acting monoclonal antibodies—aim to simplify treatment, reduce burden, and address remaining unmet needs.

Disparities in access to treatment remain a global challenge, underscoring the need for equitable care, policy reform, and living clinical guidelines.

Introduction

Hereditary angioedema (HAE) is a rare, potentially life-threatening disorder marked by recurrent episodes of painful, non-pruritic and non-pitting swelling, commonly affecting the skin, gastrointestinal tract, or upper airway [1–3]. Unlike allergic angioedema, HAE attacks occur without urticaria and respond poorly to conventional allergy treatments [1–3]. The majority of HAE cases result from pathogenic variants in the SERPING1 gene, leading to either reduced levels (HAE type I) or impaired function (HAE type II) of C1 esterase inhibitor (C1-INH)—a critical regulator of the complement and kallikrein–kinin pathways. Deficient or dysfunctional C1-INH leads to uncontrolled activation of the contact system, resulting in excess bradykinin generation, vasodilation, and increased vascular permeability [4–9]. A less common but increasingly recognized subtype, HAE with normal C1-INH (HAE-nC1INH), features normal C1-INH levels and function, and is associated with mutations in factor XII (F12), plasminogen (PLG), angiopoietin 1 (ANGPT1), kininogen 1 (KNG1), myoferlin (MYOF), and heparan sulfate-glucosamine 3-O-sulfotransferase 6 gene (HS3ST6). Although a subset of cases remain genetically unexplained, emerging variants in carboxypeptidase N (CPN1) and DAB2 interacting protein (DAB2IP) have also been proposed as potential contributors to HAE-nC1INH, though their pathogenic roles are yet to be confirmed [7, 10–19]. Regardless of the underlying genetic basis, all HAE subtypes are characterized by resultant increased vascular permeability.

Patients with HAE experience significant physical, psychological, and social challenges. Diagnostic delays—particularly in cases of HAE-nC1INH—are common and frequently result in misdiagnosis, unnecessary medical interventions, and delayed initiation of effective care [20–22]. Even with advances in diagnosis and treatment, many patients continue to experience breakthrough attacks, treatment-related adverse events, and therapeutic fatigue, underscoring unmet clinical needs [2, 23]. Attacks can be unpredictable, severely painful, disfiguring, and occasionally fatal, profoundly impacting health-related quality of life, emotional well-being, and social functioning [23–25].

Management of HAE relies on two primary therapeutic pillars: (1) on-demand treatment, aimed at rapidly controlling acute attacks to minimize morbidity and mortality; and (2) prophylaxis, intended to prevent attacks and reduce the overall burden of disease. Prophylactic strategies also include short-term prophylaxis, which is used to prevent attacks triggered by procedures known or suspected to precipitate angioedema episodes (e.g., surgery, dental interventions). Decisions are typically individualized on the basis of patient history and prior attack patterns. Long-term prophylaxis is aimed at reducing the frequency and severity of attacks and improving overall quality of life. Contemporary therapeutic approaches encompass bradykinin receptor antagonists, C1-INH replacement, kallikrein inhibitors, and innovative investigational modalities such as antisense oligonucleotides, gene editing strategies, and RNA-based therapeutics. The continued evolution of these targeted therapies offers increasing opportunities to address previously unmet patient needs through more personalized care. This narrative review summarizes the current and rapidly evolving therapeutic landscape for HAE, highlighting recent advances, emerging treatments, and future directions toward individualized, patient-centered management. This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Pathophysiology Driven Therapeutic Targets in HAE

Translating an enhanced understanding of HAE pathophysiology into clinical practice has allowed the development of treatments that precisely target key molecular checkpoints, significantly improving therapeutic efficacy and patient outcomes. The pathogenesis of HAE stems from dysregulation of the contact (kallikrein–kinin) system, a proteolytic cascade that generates the vasoactive peptide bradykinin. In classic forms (types I and II HAE), deficiency or dysfunction of C1-INH—a serine protease inhibitor that regulates activated factor XII (FXIIa) and plasma kallikrein—leads to unchecked cleavage of high molecular weight kininogen (HK) and excessive bradykinin production [1, 2, 7, 9]. Bradykinin binds to bradykinin B₂ receptors on endothelial cells, disrupting tight junctions and increasing vascular permeability—the central pathophysiologic mechanism underlying angioedema in HAE [1, 7, 9, 26]. In cases of HAE-nC1INH, mutations in genes such as F12, PLG, or ANGPT1 lower the threshold for bradykinin generation or compromise endothelial integrity [7, 11, 27–29]. Notably, plasmin—a fibrinolytic enzyme—can also activate FXII, linking the fibrinolytic and contact systems and providing an additional amplification loop for bradykinin production. This mechanism is particularly relevant in certain HAE-nC1INH subtypes (e.g., HAE-PLG or HAE-FXII), where gain-of-function mutations may enhance susceptibility to FXII activation by plasmin. This mechanism underpins the therapeutic efficacy of antifibrinolytic agents in these HAE subtypes [28, 30].

This common convergence on bradykinin supports a rational, pathway-directed therapeutic approach, targeting distinct checkpoints within the cascade. Current and emerging therapeutic strategies include restoring C1-INH levels; inhibiting upstream activators, such as FXII or kallikrein activity; directly inhibiting plasma kallikrein activity; blocking the bradykinin B₂ receptors; and utilizing innovative modalities, such as RNA interference or gene editing, to modulate expression and prevent pathological activation of key enzymes in the pathway. Figure 1 provides a detailed overview of these mechanistic targets, illustrating critical interactions within the kallikrein–kinin system and associated therapeutic interventions.

Fig. 1.

Pathophysiology and therapeutic targets in hereditary angioedema. Created in BioRender. Publishing licenced obtained. Uminski K (2025) https://BioRender.com/hbazqgy. B2 receptor, bradykinin B₂ receptor; HK, high molecular weight kininogen FXII, factor 12; FXIIa, activated factor XII; pdC1-INH, plasma-derived C1 esterase inhibitor; rC1-INH, recombinant C1 esterase inhibitor. General figure concept inspired by Veronez CL et al. The Expanding Spectrum of Mutations in Hereditary Angioedema. J Allergy Clin Immunol Pract. 2021 Jun;9(6):2229–2234. https://doi.org/10.1016/j.jaip.2021.03.008

Approved Therapies in Hereditary Angioedema

Optimal treatment selection involves a patient-specific approach that considers multiple factors including attack severity, frequency, known triggers, comorbidities, concurrent medications, and age or reproductive status. Equally important are patient preferences regarding route of administration, treatment setting, dosing schedule, and integration into daily life. The evolution of therapeutic delivery—from intravenous to subcutaneous and oral formulations—has empowered patients, facilitating greater self-management, autonomy, and treatment ownership under the oversight of their care team [31, 32]. Shared decision-making remains central in promoting adherence and optimizing long-term outcomes. Current guidelines advocate universal access to effective on-demand therapy and individualized prophylactic strategies based on disease burden, risk profile, and patient-specific preferences and circumstances [31, 33–35].

The following sections review therapies approved for acute treatment and long-term prophylaxis. For each agent, we outline its mechanism of action, key clinical trial evidence, population-specific considerations, and safety profile to guide informed and tailored therapy decisions. A summary of all approved agents, their indications, mechanisms of action, routes of administration, dosing, and select cautions or adverse events is provided in Table 1.

Table 1.

Currently approved therapies for hereditary angioedema

Therapy	Mechanism	Route	Dose	Key safety/cautions
On-demand treatment
Ecallantide (Kalbitor®)	Plasma kallikrein inhibitor	SC injection	30 mg	3–4% anaphylaxis risk—administer under medical supervision
Icatibant (Firazyr®)	Bradykinin B2 receptor antagonist	SC injection	Adults: 30 mg Adolescents and children 2–17 years and < 65 kg: dose adjusted based on body weight	Injection-site pain/erythema
Plasma-derived C1 esterase inhibitor (pdC1-INH; Berinert®, Cinryze®)	Human C1-INH replacement	IV infusion	Berinert®: 20 IU/kg Cinryze®: Adults and adolescents ≥ 12 years: 1000 IU Children 2–11 years: > 25 kg: 1000 IU 10–25 kg: 500 IU	Rare thrombosis at very high doses; infusion reactions
Recombinant human C1 esterase inhibitor (rhC1-INH; conestat alfa, Ruconest®)	Recombinant C1-INH (rabbit)	IV infusion	Body weight: < 84 kg: 50 IU/kg ≥ 84 kg: 4200 IU	Contraindicated with rabbit allergy; mild hypersensitivity
Sebetralstat (Ekterly®)	Plasma kallikrein—small-molecule inhibitor	Oral	600 mg (2 × 300 mg tablets)	Mild headache and gastrointestinal symptoms
Long-term prophylaxis
Berotralstat (Orladeyo®)	Plasma kallikrein—small-molecule inhibitor	Oral	150 mg capsule once-daily	Nausea, abdominal pain; CYP2D6 interactions
Donidalorsen (Dawnzera®)	Antisense oligonucleotide targeting hepatic prekallikrein mRNA	SC	80 mg every 4 weeks (every 8 weeks in select patients)	Mild injection-site reactions, headache, nasopharyngitis
Garadacimab-gxii (Andembry®)	Anti-FXIIa monoclonal antibody	SC	Loading dose: 2 × 200 mg; maintenance dose: 200 mg monthly, starting 1 month after loading dose	Mild URTI, headache; no thrombotic signal
Intravenous plasma-derived C1 esterase inhibitor (pdC1-INH; Cinryze®)	Human C1-INH replacement	IV	≥ 12 years: 1000 IU every 3–4 days 6–11 years: 500 IU every 3–4 days	Venous-access complications with chronic IV use
Subcutaneous plasma-derived C1 esterase inhibitor (pdC1-INH; Haegarda®)	Human C1-INH replacement	SC	60 IU/kg twice-weekly (every 3–4 days)	Mild injection-site reactions
Lanadelumab-flyo (Takhzyro®)	Anti-kallikrein monoclonal antibody	SC	≥ 12 years: 300 mg every 2 weeks ≥ 2 to < 12 years: dose adjusted	Injection-site pain, mild ↑ALT

ALT alanine aminotransferase, CAD coronary artery disease, C1-INH C1 esterase inhibitor, CV cardiovascular, CYP2D6 cytochrome P450 2D6, EACA epsilon-aminocaproic acid, FXIIa activated factor XII, GI gastrointestinal, IV intravenous, mRNA messenger ribonucleic acid, pd plasma-derived, PO oral, q every, rh recombinant human, SC subcutaneous, URTI upper respiratory tract infection, y years

On-Demand Treatment for Attacks

Ecallentide (Kalbitor®) is a selective plasma kallikrein inhibitor mainly available in the USA for on-demand treatment of HAE attacks in patients ≥ 12 years. It is administered subcutaneously as three 10 mg injections (total dose 30 mg) [36]. Two pivotal phase 3 trials (EDEMA3 and EDEMA4; n = 168) demonstrated that a single dose led to significant symptom improvement at 4 h compared with placebo, as measured by the Treatment Outcome Score and Mean Symptom Complex Severity scores [37, 38]. Efficacy was noted across multiple attack sites, including abdominal, peripheral, and laryngeal regions, with onset of symptom relief noted within 2 h and sustained for up to 24 h. Approximately 5% of patients may experience hypersensitivity reactions, with about half of these meeting criteria for anaphylaxis. As such, ecallantide must be administered by a healthcare provider in a setting equipped for management of anaphylaxis [37, 38].

Icatibant (Firazyr®) is a selective bradykinin B₂ receptor antagonist approved for on-demand treatment of acute HAE attacks. In adults, the recommended dose is a single 30 mg subcutaneous injection. In children aged ≥ 2 years, the recommended dose is a single 10–25 mg subcutaneous injection based on body weight. In the FAST-3 trial, icatibant significantly reduced median time to 50% symptom improvement compared to placebo (2.0 vs. 19.8 h; < 0.001) [39]. Observational and registry data also suggest that early self-administration is associated with faster symptom resolution and shorter overall attack duration. Approximately 88–97% of attacks resolve with a single dose; repeat dosing (≥ 6 h apart, maximum 3 doses/day) is seldom required [40–43]. Icatibant is generally well tolerated. The most common adverse effect is mild, transient injection-site reaction, reported in 90% of patients [39, 44]. Regulatory approval for pediatric use varies by region. In the USA, icatibant is approved only for adults aged ≥ 18 years, while in the European Union, Canada, Australia, and Japan, it is approved for patients aged ≥ 2 years, with weight-based pediatric dosing.

Plasma-derived C1 esterase inhibitor (pdC1-INH; Berinert®, Cinryze®) is a human plasma-derived replacement therapy that restores regulation of the kallikrein–bradykinin pathway by replenishing functional C1-INH levels, thereby reducing bradykinin production and facilitating rapid symptom resolution [45–47]. It has been shown to effectively treat attacks in adults and children with HAE due to C1INH deficiency. Two intravenous formulations are approved: Berinert® and Cinryze®. Berinert® is administered at a weight-based dose of 20 IU/kg. In a pivotal randomized trial (n = 125) Berinert® reduced median time to symptom relief (0.5 vs 1.5 h, p = 0.0025), and time to complete resolution (4.9 h vs 7.8 h, p = 0.0237) compared with placebo [48]. Cinryze®, typically dosed at 1000 IU, demonstrated efficacy in a randomized trial (n = 68) significantly shortening the median time to symptom relief compared to placebo (2 vs. > 4 h, p = 0.02 [49]. Both products are supported by guidelines and expert consensus as first-line acute therapies during pregnancy and lactation [2, 33, 34]. Safety is well established, with no documented transmission of infectious agents due to viral inactivation and purification processes. Thromboembolic events are rare and typically associated with supratherapeutic dosing or pre-existing risk factors [45, 50–52]. pdC1INH (Berinert®) is approved in Australia, Canada, Europe, Japan, and the USA for the treatment of attacks in pediatric and adult patients with HAE. pdC1INH (Cinryze®) is approved in Europe for acute treatment in patients aged ≥ 2 years.

Recombinant human C1 esterase inhibitor (rhC1-INH; conestat alfa, Ruconest®) is the only non-plasma-derived C1-INH approved for the on-demand treatment of HAE attacks. The recommended dose is 50 IU/kg intravenously (maximum 4200 IU). A second identical dose may be given ≥ 4 h later if symptoms persist (maximum two doses in 24 h) [53, 54]. In a pooled analysis of two trials, rhC1-INH reduced the median time to onset of symptom relief compared to placebo (66–122 min vs. 495 min; p < 0.001) [54, 55]. Produced in transgenic rabbit milk, rhC1-INH avoids theoretical risks of viral transmission associated with plasma-derived products. Although manufacturing and purification processes reduce rabbit protein content to very low levels, its use is contraindicated in individuals with a known or suspected rabbit allergy due to potential for an anaphylactic reaction. The manufacturing process includes multiple validated viral inactivation and clearance steps (such as chromatography, solvent/detergent treatment, and nanofiltration), which effectively reduce the risk of pathogen transmission to negligible levels. It is approved for use in patients aged ≥ 2 years in Europe and in patients ≥ 12 years in the USA.

Sebetralstat (Ekterly®) is an oral plasma kallikrein inhibitor approved in the USA for on-demand treatment of HAE attacks in patients aged ≥ 12 years with HAE due to C1-INH deficiency. It is the first oral on-demand treatment for HAE, offering a non-injectable alternative for acute therapy. In the phase 3 KONFIDENT trial (n = 110), single 300 mg and 600 mg doses of sebetralstat significantly reduced the median time to onset of symptom relief compared to placebo (1.61 and 1.79 h vs. 6.72 h, respectively; p < 0.001 and p = 0.001). More attacks fully resolved within 24 h with sebetralstat compared to placebo (42.5% and 49.5% vs. 27.4%) [56]. Efficacy was consistent across subgroups, including age, sex, body weight, attack location, baseline severity, and prophylaxis status [56]. Sebetralstat is generally well tolerated with most adverse events being mild, such as headache and gastrointestinal symptoms. No serious drug-related events or treatment discontinuations have been reported. Ongoing studies include the KONFIDENT-S open-label extension trial (NCT05505916), which evaluates long-term safety and efficacy in adolescents and adults, and the KONFIDENT-KID pediatric trial (NCT06467084), currently enrolling children aged 2–11 years to investigate safety, pharmacokinetics, and efficacy in this pediatric cohort.

Frozen plasma (FP) is a fallback treatment for HAE attacks when other recommended therapies (ecallantide, icatibant, pd-C1-INH, rC1-INH, or sebetralstat) are unavailable or inaccessible. FP provides functional C1 esterase inhibitor and may lead to attack resolution in some cases. However, it also contains contact-system substrates (prekallikrein, factor XII, and HK) that can theoretically amplify bradykinin generation and, in rare cases, paradoxically worsen symptoms. Current guidelines recommend reserving FP for emergency situations when other recommended therapies are inaccessible, emphasizing close clinical monitoring, shared decision-making, and preparedness for potential paradoxical symptom worsening—particularly critical in cases involving airway compromise [2, 57].

Treatment for Long-Term Prophylaxis

Berotralstat (Orladeyo®) is the first once-daily oral plasma kallikrein inhibitor approved for long-term prophylaxis. The recommended dose is 150 mg orally once daily. A lower dose of 110 mg once daily may be considered for patients with hepatic impairment, persistent gastrointestinal adverse effects, or those receiving P-glycoprotein (P-gp) or breast cancer resistance protein (BCRP) inhibitors. This reduced dose is approved in certain jurisdictions, including Japan and the USA. In the phase 3 APeX-2 trial (n = 120), berotralstat 150 mg daily significantly reduced mean monthly HAE attack rate compared to placebo (1.31 vs. 2.35 attacks/month; p < 0.001) [58]. A greater proportion of patients receiving berotralstat achieved ≥ 50% and ≥ 70% reduction in attack frequency [59]. On-demand therapy use was also reduced, and Angioedema Quality of Life (AE-QoL) scored improved beyond the minimally clinically important difference [60, 61]. Berotralstat is generally well tolerated. The most commonly reported adverse events were mild gastrointestinal symptoms. These were typically self-limited [59, 60]. No serious drug-related adverse events or hepatotoxicity signals have been reported. As a CYP2D6 substrate and weak inhibitor, berotralstat may interact with CYP2D6 modulators. Data are limited in individuals with severe hepatic impairment, and use during pregnancy, lactation, or in children under 12 years of age is not currently supported by clinical evidence. Interim results from the phase 3 APeX-P trial in 29 children aged 2 to < 12 years showed pharmacokinetics consistent with adults. HAE attack rate during the standard-of-care period was 0.96 (0–5.0) attacks per 4-week period [62]. Following initiation of berotralstat, the median (range) HAE attack rate for each 4-week period from day 1 to week 48 was 0 (week 4, 0–4.0; week 48, 0–1.7) [62]. Full trial results will be essential to confirm these early findings and to guide future regulatory approvals in pediatric populations.

Donidalorsen (Dawnzera®) is a subcutaneous antisense oligonucleotide approved for long-term prophylaxis in HAE due to C1 inhibitor deficiency. It suppresses hepatic prekallikrein production by targeting prekallikrein mRNA. The recommended dose is 80 mg subcutaneously every 4 weeks, with the option of extending to every 8 weeks in selected patients. In the phase 3 OASIS-HAE trial donidalorsen 80 mg every 4 weeks reduced mean monthly attacks by 81% vs. placebo (0.44 vs. 2.26 attacks/month; p < 0.001), with a 90% median reduction from baseline [63]. Quality-of-life and symptom control scores significantly improved [63, 64]. A less frequent 8-week regimen showed a 55% reduction [63]. Phase 2 data showed a 90% reduction in attack rate, with 92% of patients attack-free during weeks 5–17, and sustained efficacy confirmed over 2 years (96% reduction) in an open-label extension [65]. Adverse events were mild (e.g., injection-site reactions, headache, nasopharyngitis); no serious safety concerns were reported. It is approved in the USA for use in adults and adolescents aged ≥ 12 years. Ongoing studies include OASISplus (NCT05392114), a long-term extension evaluating sustained safety and efficacy.

Garadacimab-gxii (Andembry®) is a subcutaneous monoclonal antibody that targets activated factor XIIa (FXIIa), for long-term prophylaxis in HAE due to C1 inhibitor deficiency [66]. It is approved in the USA, Canada, Europe, Japan, and Australia for use in adults and adolescents aged ≥ 12 years. In the phase 3 VANGUARD trial (n = 64), monthly 200 mg dosing reduced mean monthly attack rates by 87% vs. placebo (0.27 vs. 2.01 attacks/month; p < 0.0001), with 62% of patients remaining attack-free over 6 months [67]. Adverse events were generally mild (e.g., nasopharyngitis, headache), with no thrombotic or bleeding signals observed [67]. An ongoing open-label extension trial (NCT04739059) has reported a 95% reduction in attack rates from baseline and sustained tolerability over a median treatment duration of 13.8 months [68]. Currently, no clinical data are available on the safety of garadacimab during pregnancy or lactation.

Intravenous plasma-derived C1 esterase inhibitor (pdC1-INH; Cinryze®) restores physiologic C1-INH activity to prevent HAE attacks. Cinryze is administered intravenously for routine long-term prophylaxis at a standard dose of 1000 units every 3–4 days, with dose adjustments (e.g., up to 2000 units of 80 IU/kg) considered on the basis of clinical response and regional regulatory guidelines. The pivotal randomized crossover trial (n = 22) demonstrated a significant reduction in attack frequency (6.26 vs. 12.73 attacks per 12-week period; p < 0.001), alongside clinically meaningful reductions in days with swelling (66%), attack severity and duration [69]. Long-term open-label studies confirm sustained efficacy, approximately 50% overall reduction in attacks, and improved quality of life. Cinryze is generally well tolerated; however, long-term intravenous administration may be associated with venous access complications, including chronic injury, venous stenosis, and risk of bloodstream infections—particularly in patients requiring central venous access [70–72]. Cinryze is approved from age ≥ 6 years in the USA and ≥ 12 years in Canada, and is considered safe for use during pregnancy and lactation on the basis of cumulative registry and observational data. Berinert®, though licensed for on-demand use, has been used off-label for long-term prophylaxis—particularly prior to the availability of lanadelumab and subcutaneous pdC1-INH—with supportive evidence from clinical experience and retrospective studies.

Subcutaneous plasma-derived C1 esterase inhibitor (pdC1-INH; Haegarda®) restores physiologic C1-INH activity, to prevent HAE attacks. Haegarda is specifically approved for routine long-term prophylaxis and is administered as 60 IU/kg subcutaneously twice weekly. The pivotal COMPACT trial, Haegarda resulted in a 95% reduction in attack rate compared to placebo, with 40% of patients remaining completely attack-free. Long-term extension and real-world studies confirm sustained efficacy (≥ 30 months; 99% days attack-free), reduced rescue medication use, and improved quality of life [73–76]. Mild injection-site reactions are the primary adverse effects. Haegarda is approved for use in patients aged ≥ 6 years in the USA, and ≥ 12 years in Canada. It is considered safe for use during pregnancy and lactation, supported by post-marketing and registry data [77].

Lanadelumab-flyo (Takhzyro®) is a fully human monoclonal antibody that selectively inhibits plasma kallikrein to prevent HAE attacks in patients with C1-INH deficiency. In the phase 3 HELP trial (n = 125), lanadelumab 300 mg subcutaneously every 2 weeks reduced attack rates by 97.2% vs. placebo, with up to 77% of patients remaining attack-free [78]. Additional benefits included reduced on-demand therapy, fewer laryngeal attacks, and improved quality of life. Onset was rapid (within 2 weeks) and sustained over 26 weeks [78]. Long-term open-label data (mean treatment duration 29.6 months) confirmed durable efficacy, with 37.3% of patients remaining attack-free over the full study period and 81.6% completing ≥ 30 months of treatment [79]. Lanadelumab is generally well tolerated; the most common adverse events are mild injection-site reactions, headache, and viral upper respiratory tract infections [78, 79]. Lanadelumab is approved for patients aged ≥ 12 years in Canada and ≥ 2 years in the USA and EU. Safety data during pregnancy and lactation remain limited; use is not currently recommended in these populations.

Alternative and Legacy Prophylactic Therapies

Attenuated androgens [e.g., danazol (Cyclomen®) and stanozolol (Winstrol®)] are oral agents that induce hepatic C1-INH synthesis [80], increase C1-INH mRNA expression in peripheral mononuclear cells [68], and enhance bradykinin catabolism via aminopeptidase P [81]. A systematic review of 63 studies has confirmed that attenuated androgens are effective for long-term prophylaxis [82]. Placebo-controlled trials have shown that these treatments can reduce attack rates from over 90% with placebo to as low as 2% with danazol [82]. However, their long-term use is limited by dose- and duration-related adverse effects, including weight gain, virilization, menstrual irregularities, mood changes, dyslipidemia, hepatotoxicity (e.g., cholestasis, hepatic adenomas or carcinomas), and increased cardiovascular risk [82]. Androgens are contraindicated in children, during pregnancy or lactation, and in individuals with liver disease, breast or prostate cancer. Guidelines recommend reserving androgens as second- or third-line options, used at the lowest effective dose, with regular monitoring [33–35].

Antifibrinolytic agents, such as tranexamic acid (TXA; Cyklokapron®) and epsilon-aminocaproic acid (EACA; Amicar®), have been used as second-line options for prophylaxis in HAE, particularly when targeted therapies are unavailable or contraindicated. These agents work by inhibition of fibrinolysis by blocking the conversion of plasminogen to plasmin. This reduces plasmin-mediated activation of the contact system, which in turn decreases bradykinin generation [1]. Although less effective than modern targeted therapies, antifibrinolytics can reduce attack frequency in select patients, with about 60% showing benefit [83]. These agents are generally well tolerated, with side effects limited to mild gastrointestinal discomfort or myalgias, and they carry a relatively low thromboembolic risk.

Investigational and Emerging Therapies

A diverse array of novel agents is in clinical development, aiming to improve convenience, reduce treatment burden, and introduce new mechanisms of action. These include CRISPR/Cas9-based gene editing therapies (lonvoguran-ziclumeran; in development for long-term prophylaxis), short interfering RNAs targeting hepatic protein synthesis (ADX-324; in development for long-term prophylaxis), subcutaneous monoclonal antibodies against plasma kallikrein (navenibart; in development for long-term prophylaxis), and oral bradykinin B₂ receptor antagonists (deucrictibant; in development for both on-demand and long-term prophylaxis). Table 2 provides an overview of these emerging therapies, summarizing their targets, planned indications, route of administration, and current phase of development. The following section reviews each agent in more detail, highlighting key clinical trial data, safety profiles, and anticipated roles in future HAE care.

Table 2.

Emerging and investigational therapies in HAE

Candidate	Target	Intended use	Route	Most advanced stage
Lonvoguran-ziclumeran (NTLA-2002)	KLKB1 gene inactivation—CRISPR/Cas9	Prophylaxis	IV single dose	Phase 3 pivotal (HAELO)
ADX-324	GalNAc3-conjugated siRNA targeting hepatic prekallikrein mRNA	Prophylaxis	SC	Phase 3 (STOP-HAE)
Navenibart (STAR-0215)	Plasma kallikrein—long-acting mAb	Prophylaxis	SC q3–6mo	Phase 2/3 (ALPHA-STAR/ALPHA-ORBIT)
Deucrictibant (PHVS416/022121)	Bradykinin B2 receptor antagonists	On-demand ± prophylaxis	Oral	Phase 3 (RAPIDe-3/CHAPTER-3)

CRISPR/Cas9 clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9, F12 coagulation factor XII gene, FDA US Food and drug administration, HAE hereditary angioedema, IV intravenous, KLKB1 plasma kallikrein gene, mAb monoclonal antibody, mRNA messenger RNA, SC subcutaneous, siRNA short interfering RNA

Gene Editing

Lonvoguran-ziclumeran (NTLA-2002) is a one-time, in vivo CRISPR/Cas9 gene editing therapy delivered via lipid nanoparticles, designed to inactivate the KLKB1 gene—encoding plasma kallikrein—to provide durable prophylaxis in HAE type I/II [84, 85]. In a phase 1/2 dose-escalation trial, single doses (25, 50, or 75 mg) achieved dose-dependent reductions in plasma kallikrein (− 67% to − 95%) and reduced mean monthly attack rates by 75–97% over 16 weeks, with 40–73% of patients remaining attack-free [85]; no serious safety signals were reported [85]. Interim follow-up (median 20 months) demonstrated a 98% mean reduction in attacks and sustained tolerability. A pivotal phase 3 trial, HAELO (NCT06634420), has begun dosing adults (≥ 18 years) with type I/II HAE, randomizing 2:1 to lonvoguran-ziclumeran (50 mg) or placebo, with crossover at week 28.

RNA-Based Therapeutics

ADX-324 is a short interfering RNA (siRNA) in development for long-term prophylaxis in HAE type I/II. It selectively targets hepatic prekallikrein mRNA to reduce prekallikrein production. A first-in-human phase 1/2a trial (NCT05691361; ADX-324-101) is ongoing, involving subcutaneous single ascending doses in healthy volunteers followed by an open-label expansion cohort in patients with HAE. The phase 3 STOP-HAE trial (NCT06960213) is now recruiting and will assess efficacy, safety, pharmacokinetics, pharmacodynamics, and health-related quality of life across two dosing regimens compared with placebo.

Monoclonal Antibodies

Navenibart (STAR-0215) is a long-acting monoclonal antibody that inhibits plasma kallikrein, currently under investigation for long-term prophylaxis of HAE due to C1 inhibitor deficiency or dysfunction (types I and II). In a phase 1a study involving healthy adults, single subcutaneous doses up to 1200 mg were well tolerated, with no serious adverse events and only mild injection-site reactions. Navenibart demonstrated up to 85% inhibition of plasma kallikrein activity (P < 0.001) and exhibited a mean half-life of 82–106 days at doses ≥ 300 mg, supporting the feasibility of subcutaneous administration every 3 to 6 months [86]. The ongoing phase 1b/2 ALPHA-STAR trial (NCT05695248) is evaluating the safety, pharmacokinetics, and preliminary efficacy of navenibart in patients with HAE. Additionally, the phase 3 ALPHA-ORBIT trial (NCT05695248), a global, randomized, placebo-controlled study, is enrolling approximately 145 adults with HAE to assess the safety and efficacy of navenibart administered every 3 or 6 months. The primary endpoint of the trial is the time-normalized monthly attack rate at 6 months, and the key secondary endpoint is the percentage of patients who are attack-free at 6 months.

Small-Molecule Inhibitors

Deucrictibant (PHVS416) is a novel oral bradykinin B₂ receptor antagonist under investigation for both on-demand and long-term prophylactic treatment of HAE due to C1 inhibitor deficiency (types I and II). It is being investigated in two formulations: an immediate-release liquid-filled capsule (PHVS416) for on-demand therapy, and an extended-release tablet (PHVS719) for long-term prophylaxis. In the phase 2 RAPIDe-1 trial (PHVS416), single doses of 10, 20, or 30 mg significantly accelerated symptom relief during acute attacks, with a median time to ≥ 30% symptom reduction of 2.1–2.7 h versus 8.0 h with placebo (p < 0.0001) [87]. Approximately 87% of attacks achieved complete resolution within 24 h. Deucrictibant was well tolerated, with no serious adverse events reported. In the CHAPTER-1 trial (PHVS719), daily oral deucrictibant at 20 mg and 40 mg reduced monthly attack rates by 79.3% and 84.5%, respectively, compared to placebo [88]. Ongoing phase 3 trials (RAPIDe-3 [NCT06343779] and CHAPTER-3 [NCT06669754]) and an open-label extension study (CHAPTER-4 [NCT06679881]) are further evaluating its safety and efficacy for both on-demand and prophylactic use.

Discussion

HAE has traversed a remarkable therapeutic trajectory, shifting from hospital-based plasma infusions for on-demand treatment, to self-administered prophylactic and on-demand regimens. Modern therapies not only markedly lower HAE attack frequency but also prioritize patient-centered convenience, enabling self-administration without reliance on specialized storage or clinical settings. These developments align with the 2021 Delphi consensus, which designates “complete disease control and normalisation of quality of life” as the paramount therapeutic aim [31]. Notwithstanding these strides, salient gaps remain. Clinical trials predominantly enroll adults with C1-INH deficiency (type I and II HAE), leaving pediatric, geriatric, comorbid, pregnant, lactating, and normal-C1-INH populations underrepresented. HAE-nC1INH represents a particularly challenging and increasingly recognized subgroup, characterized by heterogeneity in underlying genetic variants and a lack of validated biomarkers to support diagnosis and treatment selection. Despite the rapid growth of the therapeutic pipeline for HAE with C1-INH deficiency, HAE-nC1INH patients are frequently excluded from interventional studies, creating a substantial evidence gap. As a result, treatment decisions in this population often rely on extrapolation from C1-INH-deficient cohorts, off-label prescribing, and accumulating data from observational registries and real-world practice. This reliance underscores the urgent need for prospective, controlled studies to define optimal management strategies and ensure equitable access to effective therapies across the full spectrum of HAE subtypes. Furthermore, despite advancements in convenience with modern therapies, barriers such as high cost, regulatory latency, and limited access—particularly in underserved populations—contribute to persistent treatment gaps. These realities highlight the need for interventions that are not only convenient and effective but also broadly accessible, equitable, and adaptable to the diverse circumstances of patients living with HAE.

Emerging therapeutics are being rationally designed to address persistent gaps in HAE management, including treatment burden. Oral agents such as deucrictibant offer needle-free administration for both prophylactic and on-demand use. RNA-based therapies—including antisense oligonucleotides like donidalorsen and siRNAs like ADX-324, target hepatic protein synthesis and enable extended dosing intervals. First-in-human CRISPR/Cas9 gene editing with NTLA 2002 introduces the possibility of a durable, potentially one-time intervention by silencing KLKB1. Together, these innovations represent a shift from reactive symptom management to mechanism-based, individualized prophylaxis that aligns with patient preferences and evolving standards of care.

Guideline frameworks must evolve commensurately. While existing Canadian (2019) [34] and US HAEA (2020) [35] and WAO/EAACI (2021) [33] statements endorse universal access to on-demand therapy, individualized prophylaxis, and even aim for disease normalization, they do not reflect several recently approved or late-phase therapies for which high-quality evidence now exists. Although some degree of lag is inevitable, more agile approaches are needed to minimize the delay between regulatory approval and incorporation into clinical recommendations. Adopting a living-guideline model—updated iteratively as pivotal evidence accrues—will be essential to translate rapid scientific progress into harmonized clinical practice. It is important to note that from the time of manuscript preparation to publication, there may be substantial changes in the regulatory approval status of novel therapies across different jurisdictions. As such, this review reflects the status at the time of writing, while recognizing that new approvals may further reshape the therapeutic landscape.

While this review summarizes key trial data and therapeutic advances, treatment selection in clinical practice must be individualized. Decisions between on-demand and prophylactic therapies, as well as between specific agents within these categories, depend on factors such as drug availability, regulatory approval and reimbursement status, patient comorbidities, and personal preferences. Shared decision-making between patients and clinicians remains central to optimizing outcomes and aligning therapy with patient values and circumstances. Equity remains a central concern in the evolving therapeutic landscape of HAE. The same structural barriers that once delayed access to C1-INH therapies—such as disparities in healthcare infrastructure, reimbursement policies, and diagnostic capacity—now risk further entrenching inequities as high-cost biologics and advanced genomic technologies become available. Without deliberate efforts to ensure affordability, access, and availability, the benefits of innovation may remain out of reach for many. Addressing pricing, reimbursement, and distribution challenges—supported by robust post-marketing registries and global collaboration—will be essential to ensure that treatment access is driven by clinical need rather than geography or socioeconomic status [89–91]. In sum, the field stands at a pivotal moment: if emerging therapies fulfill their clinical promise and guideline frameworks adapt with sufficient agility, HAE could transition from an unpredictable and burdensome disease to one that is controllable—and potentially curable—for all individuals living with the condition.

Author Contributions

Kelsey Uminski prepared the first draft of the manuscript. Dawn Goodyear and Stephen Betschel contributed to the manuscript through critical input and both substantive and editorial revisions. All authors read and approved the final version.

Funding

No funding or sponsorship was received for this study or publication of this article.

Data Availability

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Declarations

Conflict of Interest

Kelsey Uminski has received educational grants from CSL Behring, Roche and Novo Nordisk, research funding from Bayer and Novo Nordisk, consultancy fees from Bayer, Biocryst Pharmaceuticals, Novo Nordisk, Roche, Sanofi and Takeda, speaker fees from Bayer, CSL Behring, Pfizer, Roche, Sanofi, and Takeda, and travel support from Novo Nordisk, Octapharma, Roche,and Sanofi. Dawn Goodyear reports advisory boards and consultancy from Alexion, BioCryst, CSL Behring, Medison, Pfizer, Octapharma, Sanofi, Sobi, Roche and Takeda; research funding from Takeda. Stephen Betschel has participated in advisory board or equivalent for Astria, Biocryst Pharmaceuticals, CSL Behring, Ionis, Kalvista, Pharvaris, Sanofi and Takeda, received grants or honoraria from Biocryst Pharmaceuticals, CSL Behring, Kalvista and Takeda, and participating or participated in a clinical trial with Takeda.

Ethical Approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.