Shining a Light on Unmet Needs in Hereditary Angioedema Special Patient Populations

This symposium review is based on a satellite session that took place at the European Academy of Allergy and Clinical Immunology (EAACI) Hybrid Congress 2023 on 10^th June 2023, held in Hamburg, Germany

Meeting Summary

This satellite symposium took place at the European Academy of Allergy and Clinical Immunology (EAACI) Hybrid Congress 2023 in Hamburg, Germany, in June 2023. Aleena Banerji, Clinical Director at Massachusetts General Hospital, Boston, USA, chaired the symposium, and provided an overview of the evolution of long-term prophylaxis (LTP) for hereditary angioedema (HAE). Banerji also highlighted the current limitations and challenges for special patient populations with HAE. Marcus Maurer, Professor of Dermatology and Allergy, and Executive Director of the Institute of Allergology at Charité – Universitätsmedizin Berlin, Germany, and Co-Director of the Fraunhofer Site for Allergology and Immunology, Fraunhofer Institute for Translational Medicine and Pharmacology (ITMP), Berlin, Germany, evaluated the approaches and global challenges to address the unmet needs in paediatric patients with HAE, with a spotlight on advancing care for these patients. Anete Sevciovic Grumach, Physician, Professor, and Senior Researcher at the Center of Reference for Rare Diseases, Clinical Immunology, University Centre Faculty of Medicine of ABC, São Paulo, Brazil, gave an insight into the diagnostic and management challenges in HAE with normal C1 inhibitor values (HAE-nC1-INH). The speakers also facilitated a scientific exchange and clinical experience sharing through interactive expert panel discussions.

Introduction

HAE is a rare and life-threatening genetic disorder characterised by symptoms of severe, painful, recurring attacks of oedema (swelling).^1-4 HAE affects an estimated 1 in 50,000 people worldwide.² Individuals with HAE often miss out on opportunities or activities due to the uncertainty of HAE attacks.⁵ Moreover, HAE is frequently under-recognised, underdiagnosed, and undertreated.^1,6

The Evolving Long-Term Prophylaxis Landscape for Special Patient Populations

Aleena Banerji

The care of patients with HAE necessitates a comprehensive multifaceted approach.¹ Banerji emphasised that it is crucial for healthcare professionals to broaden their perspective beyond the frequency of attacks, its severity, and treatment option availability. Banerji highlighted the importance of considering other key aspects of the HAE burden, including the disease course, potential misdiagnosis, symptoms experienced, and financial costs, as well as the impact on education and employment, and overall quality of life (QoL), including symptoms of depression and anxiety.¹ Consequently, Banerji emphasised the importance of integrated care and an individualised treatment plan when deciding to use LTP. This involves taking into account individual patient needs, including their lifestyle, and personal preferences, with the ultimate aim of improving their QoL.^1,7 This also requires shared decision-making between the physician and patient, with the involvement of specialists in HAE.⁷

The International Guidelines for the Management of Hereditary Angioedema

The HAE guidelines have continuously evolved through the years, adapting to the changing treatment landscape.^7-9 According to the International World Allergy Organization (WAO) and EAACI guideline, treatment goals for HAE are to achieve total disease control and normalise patients' lives.⁷ They recommend patients are evaluated for LTP during each visit, considering disease activity, burden, and control, as well as patient preferences.⁷ Furthermore, the guideline recommends the use of plasma-derived (pd)C1 inhibitor (INH), lanadelumab, and berotralstat as first-line LTP, with androgens serving only as second-line LTP.⁷ In addition, the guideline suggests routine monitoring of disease activity, impact, and control for all patients using LTP to inform treatment dosage optimisation and outcomes.⁷ Banerji stated that regular follow-up is necessary for every patient, regardless of their LTP status.

Regarding special patient populations with HAE, including children and those who are pregnant, the guideline recommends C1-INH or icatibant for treating attacks in children under the age of 12 years, with pdC1-INH the preferred therapy during pregnancy and lactation (note: pdC1-INH should be given to females who are pregnant only if clearly indicated).⁷ It is important to note that currently, there are no approved therapies specifically for patients with HAE-nC1-INH; thus, no recommendations can be made in this regard.^7,10

The Pathophysiology of Hereditary Angioedema and Mechanisms of Action of Approved Long-Term Prophylaxis Treatments for Hereditary Angioedema C1 Inhibitor Type 1/2

To provide context for understanding the treatment options for LTP, Banerji gave an overview of the pathophysiology of HAE (Figure 1).¹¹ Bradykinin is the key mediator responsible for increased vascular permeability and the manifestation of symptoms of angioedema.¹¹ The contact system plays an important role in this process, with triggers activating Factor XII, which subsequently acts on prekallikrein to form active plasma kallikrein.¹¹ This leads to the generation of cleaved high-molecular-weight kininogen, and the subsequent generation of bradykinin, C1-INH serves as an inhibitor within this pathway (Figure 1).¹¹ Banerji explained that patients with HAE, due to C1-INH deficiency (HAE-C1-INH Type 1/2), lack inhibition of this pathway, resulting in elevated bradykinin levels and subsequent vascular permeability.

Figure 1: The pathophysiology of hereditary angioedema and the mechanism of action of current approved long-term prophylaxis for hereditary angioedema C1 esterase inhibitor Type 1/2.¹¹
Not all products are approved in certain countries/regions. Indications vary by country. Please consult local prescribing information. Access is subject to change
over time.
Adapted from Fijen et al.¹¹
B2R: bradykinin type 2 receptor; C1-INH: C1 esterase inhibitor; cHMWK: cleaved high-molecular-weight kininogen; FXIIa: activated Factor XII; HAE: hereditary angioedema; HMWK: high-molecular-weight kininogen; IV: intravenous; pdC1-INH: plasma-derived C1 esterase inhibitor; SC: subcutaneous.

Considering current LTP treatments for HAE-C1-INH Type 1/2, intravenous (IV; approved in the USA and Europe for those ≥6 years of age)^12,13 and subcutaneous (approved in the USA for those ≥6 years of age;¹⁴ specific age ranges not specified on European label)¹⁵ pdC1-INH products, approved for prophylaxis in adults, adolescents, and paediatric patients,^12-14 replace the deficient protein, inhibiting the pathway, resulting in reduced bradykinin levels (Figure 1).¹¹ Both lanadelumab, approved in the USA as prophylaxis for adults and paediatric patients (≥2 years of age),¹⁶ and approved in Europe for adults and adolescents (≥12 years of age);¹⁷ and berotralstat, approved for prophylaxis in adults and adolescents (≥12 years of age),¹⁸ inhibit active plasma kallikrein, resulting in less cleaved high-molecular-weight kininogen, and subsequently less generation of bradykinin.¹¹

When initiating LTP, a multifaceted assessment of characteristics should be considered.^9,19 This includes clinical factors, such as attack frequency and severity, overall disease burden impacting health-related QoL, patient comorbidities, disease control, and access to emergent treatments.^9,19 Additionally, treatment-specific factors, such as the benefit-to-risk profile and treatment properties (e.g., route of administration), should be taken into account.¹⁹

Banerji emphasised the importance of adopting an holistic approach to evaluating the different treatment options, and ensuring consistent follow-ups to monitor the efficacy, safety, and tolerability of LTP strategies. This is crucial for accommodating changing needs, minimising disease burden, and improving QoL.⁹

Despite the changing landscape of LTP, Banerji highlighted the ongoing unmet needs, including the limited number of LTP treatment options in many countries, particularly in comparison with Europe and the USA. There is also a need for more treatment options for paediatric populations, and further data in pregnancy, as well as in biomarkers in patients with HAE-nC1-INH who exhibit clinical symptoms of HAE-C1-INH Type 1/2.

Spotlight on Advancing Paediatric Environment

Marcus Maurer

Early diagnosis of paediatric patients with HAE is crucial. Maurer highlighted the uncertainties and burdens associated with HAE in children, along with the limited treatment and diagnostic options available. While the principles of HAE in adults apply to children, Maurer emphasised that paediatric patients are not simply small adults. Therefore, Maurer stated that disease awareness is vital, particularly among paediatricians and general practitioners. It is worth noting that about 25% of patients with HAE have new mutations, which can impact the process of rapid diagnosis.⁷

Maurer also identified the need for improved tools and education to enhance the diagnosis of paediatric patients, surpassing the existing resources available for adults. There is a requirement for better advice and training for patients, teachers, and healthcare professionals on how to manage and recognise an HAE attack.⁷ Additionally, there is a need for tools to measure disease activity, QoL, and disease management and control.⁷

Education can also play a crucial role. The course of HAE can be difficult to recognise in paediatric patients; onset typically occurs at ≥4 years of age.^20-22 Maurer stated that recognising the early symptoms of the disease is essential to react promptly, and make appropriate considerations when an HAE attack occurs. However, this is challenging in a population that regularly experiences abdominal problems.²⁰ Additionally, Maurer highlighted specific considerations for children, noting that laryngeal attacks pose a greater risk than abdominal attacks, and require immediate presentation at the hospital,²⁰ stating the risks and limitations in paediatric populations require particular care and attention. Furthermore, children undergo regular variable changes through the age ranges. Puberty, which often begins at the age of 10, can exacerbate symptoms,^20,23 posing additional problems compared with younger paediatric patients.

Guideline Recommendations for the Diagnosis of Paediatric Patients with
Hereditary Angioedema

The international guidelines underscore the importance of early diagnosis, particularly in individuals from families with HAE.^7,8,20 According to the international paediatric consensus, clinical suspicion of HAE-like symptoms at any age warrants screening, regardless of the presence or absence of family history.²⁰ The International/Canadian guideline further states that all individuals with a positive family history should be considered at risk of HAE and screened as early as possible,⁸ and that all offspring of an affected parent be tested (Figure 2).^7,20 Maurer supported this notion, stating HAE should be assumed in children from HAE-affected families. The current International WAO/EAACI guideline recommends assessing blood levels of C1-INH function, C1-INH protein, and C4 in all suspected cases.⁷ Maurer emphasised the importance of a double positive test, with the second test performed after 1 year of age to confirm HAE-C1-INH Type 1/2 diagnosis.⁷ Additionally, for symptomatic paediatric patients with negative screening, Maurer highlighted the necessity of involving specialists.

Figure 2: The diagnosis of paediatric hereditary angioedema in families with or without known hereditary angioedema.²⁰
*C1-INH functional and C4 levels are low, accompanied by a low C1-INH antigenic level in HAE Type 1. 
†Repeated after 1 year of age.
‡Angioedema with acquired C1-INH deficiency is also excluded, but HAE-nC1-INH (which is very rare in paediatric patients) is not ruled out.²⁰
Adapted from Farkas et al.²⁰
C1-INH: C1 esterase inhibitor; HAE: hereditary angioedema; HAE-nC1-INH: hereditary angioedema with normal C1 esterase inhibitor values.

Another crucial point regarding paediatric patients is that HAE attacks, as well as fear of impending attacks, can lead to emotional distress, reduced educational and vocational achievement, and impair social life.^24,25 Higher anxiety has been shown to correlate with reduced health-related QoL (r=-0.62; p≤0.01) in children with HAE (N=23), particularly in the social, emotional, and school-related domains.²⁴ Therefore, Maurer suggests that managing mental health will also improve disease outcomes.

Guideline Recommendations for the Management of Paediatric Patients with
Hereditary Angioedema

Despite current limitations in treatment options, the International/Canadian guideline recommends all paediatric patients with HAE should have access to acute treatment, even if they are symptom-free.⁸ Based on international guidelines,^7,8,20 current recommended therapies for acute treatment of HAE attacks in paediatric patients under the age of 12 years that are approved in Europe are C1-INH^13,26,27 and icatibant.²⁸ Current LTP approved for paediatric patients in Europe include pdC1-INH in those ≥6 years of age,¹³ lanadelumab for those ≥12 years of age¹⁷ (which is also approved in paediatric patients ≥2 years of age in the USA),¹⁶ and berotralstat for those ≥12 years of age.²⁹ Additionally, tranexamic acid is available for LTP.³⁰ It is important to note that not all products are approved and available in all countries for the treatment of HAE, and indications vary by country; therefore, local prescribing information should be consulted, as specific age ranges may vary.

Maurer summarised the key evidence from notable clinical studies that support the use of these treatments, indicating their safety and effectiveness for use in the paediatric population.^31-35 The Phase III IV pdC1-INH (human) study funded by Takeda (Shire; Massachusetts, USA), evaluated the safety and efficacy of IV pdC1-INH for the prevention of angioedema attacks in paediatric patients aged 6–11 years.^31,32 Patients (N=12) were randomised 1:1 for 12 weeks before switching to the alternate dose (500 or 1,000 U IV pdC1-INH, twice weekly).^31,32 No serious treatment-emergent adverse events (TEAE) or discontinuations occurred, and significantly greater reduction in the monthly normalised number of attacks was observed, with 1,000 U IV pdC1-INH (87.4% median reduction in attacks) compared with 500 U IV pdC1-INH (76.2% median reduction in attacks) relative to baseline (p=0.035).³¹

The COMPACT open-label extension study funded by CSL Behring (King of Prussia, Pennsylvania, USA), evaluated the long-term safety and efficacy of subcutaneous pdC1-INH in patients ≥6 years of age.³³ Patients were randomised to 40 IU/kg or 60 IU/kg, twice weekly for 52 weeks (with an additional extension period of ≤88 weeks in the USA; 140 weeks total), with follow-up at 2 weeks.³³ For paediatric patients ≤17 years of age (n=10), no serious TEAEs or discontinuations occurred, and 100% of those patients were classified as responders, with ≥50% reduction in HAE attacks compared with pre-study period.³³ Similarly, 100% of paediatric patients experienced <1 HAE attack per 4-week period during treatment.³³

The Phase III open-label SPRING study, funded by Takeda (Shire), evaluated the safety, pharmacokinetics, and pharmacodynamics of lanadelumab in paediatric patients aged 2– <12 years.^34,35 Those aged 2–<6 years received 150 mg every 4 weeks for 52 weeks; and those aged 6–<12 years received 150 mg every 2 weeks for 26 weeks, with the option to continue with 150 mg every 2 weeks, or switch to every 4 weeks, if attack free for 26 consecutive weeks, for a total of 52 weeks, with follow-up at 2 or 4 weeks.^34,35 Overall, 17 patients (81.0%) reported at least one TEAE, no event was reported as an adverse event of special interest, and no serious TEAEs, deaths, or discontinuations occurred.³⁵ The overall HAE attack rate was reduced by approximately 95% compared with baseline in patients treated with lanadelumab.³⁵

In summary, diagnosing and managing paediatric patients with HAE is important so that they can potentially lead a normal life. Undiagnosed patients face challenges that bring uncertainty and apprehension, while diagnosed asymptomatic patients still require appropriate treatment options. In paediatric patients, there is an unmet need for acute and prophylactic therapies, including oral and/or subcutaneous options. Access to both new and existing therapy options is essential for paediatric patients with HAE.

Interactive Expert Panel Discussion: Addressing the Needs of Paediatric Patients with Hereditary Angioedema

The panel discussion focused on the diagnosis and treatment of paediatric patients with HAE. Banerji asked whether proactive conversations should be initiated for family planning. Maurer noted that most patients initiate conversations early when intending to start a family. They express concerns about managing their HAE during pregnancy, consider options of support, and assess their ability to care for children with HAE. The importance of early diagnosis, including umbilical blood screening, was emphasised, along with the significance of following clinical advice, and having a well-defined action plan.

Grumach provided an alternative viewpoint, suggesting some families may be hesitant and anxious to undergo HAE testing, due to the emotional difficulty of the possibility of their children being affected. Maurer, however, pointed towards a shift in perspective among patients and parents, with fewer concerns about having children due to the availability of modern LTP that enables a more normal life, and better disease management.

Focusing on younger children (<10 years of age), Banerji highlighted HAE symptoms typically begin around puberty. Banerji enquired about the frequency of attacks, and the use of LTP in these patients. Maurer explained that HAE is highly unpredictable in adults, and even more so in children. Some children may require LTP for symptom management, while others may not. This depends on patient, parent, and caregiver vigilance, as well as the availability of clinical advice. Grumach added that children can experience moderate-to-severe disease and severe attacks, necessitating the use of LTP in such cases. Maurer emphasised the importance of implementing an early action plan to support their development, and reduce the burden on QoL.

Regarding very young children, the panel noted that options are currently limited. Prophylaxis with C1-INH is recommended, although IV administration twice-weekly is a challenge for young children. The panel expressed the need for alternatives, such as longer acting injectables or oral therapies.

Diagnostic and Management Challenges in Hereditary Angioedema with Normal C1
Inhibitor Values

Anete Sevciovic Grumach

To date, six genetic mutations have been identified in HAE-nC1-INH; mutations in the HAE-FXII, HAE-ANGPT1, HAE-HS3ST6, HAE-KNG1, HAE-MYOF, and HAE-PLG genes.^7,36 Additionally, there are cases where the genetic mutations causing HAE-nC1-INH are currently unknown.^7,36 Grumach highlighted that patients with HAE-nC1-INH require the right diagnosis and appropriate management. A current challenge is the lack of a specific biochemical test or confirmatory biomarker for HAE-nC1-INH. A differential diagnosis of HAE-nC1-INH has been developed, requiring the review of clinical features, laboratory tests and treatment response (Figure 3).³⁷ This includes identifying a patient’s history of recurrent wheals/hives, and the use of certain medications, for example, angiotensin-converting enzyme inhibitors, non-steroidal anti-inflammatory drugs, and hormones, which can cause recurrent drug-induced or drug-triggered angioedema.³⁷ If biochemical markers indicate a low level of C1-INH and/or function, the most likely diagnosis is HAE-C1-INH Type 1/2 or acquired angioedema with C1-INH deficiency.³⁷ Patients with longstanding recurrent angioedema that responds to high-dose antihistamines and/or omalizumab may most likely have mast cell-mediated angioedema.³⁷ If they do not respond, mutations associated with HAE-nC1-INH should be tested for, and family history should be ascertained.

Figure 3: Overview of the differential diagnosis of hereditary angioedema HAE with normal C1 esterase inhibitor C1-INH values.³⁷
Adapted from Buttgereit et al.³⁷
AAE: acquired angioedema; ACE-I: angiotensin-converting enzyme inhibitor; C1-INH: C1 esterase inhibitor; HAE: hereditary angioedema; HAE-nC1-INH: hereditary angioedema with normal C1 esterase inhibitor values; NSAID: non-steroidal anti-inflammatory drug.

Key clinical features of HAE-nC1-INH diagnosis are recurrent angioedema affecting more than one organ,³⁸ absence of wheals,³⁸ hormonal influence (e.g., clinical symptoms provoked by oral contraceptives, hormonal replacement therapy, or pregnancy),^38,39 and positive family history of angioedema,⁸ with normal levels of C4 and C1-INH.⁸ In accordance with the International WAO/EAACI guideline, patients suspected to have HAE with normal C1-INH levels and function should be assessed for known genetic mutations underlying HAE-nC1-INH.⁷

Real-World Evidence of the Assessments Used by Physicians to Inform the Diagnosis of Hereditary Angioedema with Normal C1 Inhibitor

The approximate prevalence of HAE-nC1-INH is 0.37 per 100,000 persons in the USA.⁴⁰ A review of USA physician diagnosis of HAE-nC1-INH highlighted variability in the assessments used, where most used quantitative biochemical tests of C1-INH function and recorded family history of angioedema.⁴⁰ Many considered responses to medications, such as corticosteroids and antihistamines, with only a small number using genetic testing.⁴⁰

Grumach identified the importance of genetic testing if the patient’s family history is unknown. A study assessing gene mutations associated with HAE in patients with normal C1-INH and no family history of angioedema (N=132), found 12.1% (n=16132) were heterozygous for one of the known HAE-nC1-INH specific gene mutations (HAE-FXII, HAE-PLG). The remaining 87.9% (n=116/132) had angioedema without a known mutations.⁴¹ Triggers of angioedema by angiotensin-converting enzyme inhibitors and oestrogens varied, with oestrogen being a 100% trigger factor for HAE-FXII.⁴¹ Based on these findings, patients with longstanding recurrent angioedema not responding to antihistamines or omalizumab, and without a family history of angioedema, should be investigated for mutations linked with HAE-nC1-INH.^37,41 Grumach also added that for HAE-FXII, penetrance is gender specific, with 4.0% (n=1/25) in males and 86.1% (n=68/79) in females.³⁹

Management of Attacks in Patients with Hereditary Angioedema with Normal C1 Inhibitor

Grumach summarised a study funded by Takeda (Shire) that investigated the use of icatibant as an on-demand treatment for HAE-nC1-INH (N=42) in Brazil.⁴² The study demonstrated that patients with HAE-nC1-INH had shorter median (range) for all treatment-related time-to-event outcomes compared with patients with HAE-C1-INH Type 1/2.⁴² Time from first administration to complete resolution was 1.0 (0.0–88.0) hours for HAE-nC1-INH compared with 5.5 (0.0–96.0) hours for HAE-C1-INH Type 1/2; and total attack duration was 7.0 (0.3–99.0) hours compared with 18.5 (0.1–100.0) hours, respectively.⁴² The mean (standard deviation) time from HAE attack onset to resolution was significantly shorter in HAE-nC1-INH (9.8 [18.7] hours) compared with HAE-C1-INH Type 1/2 (19.6 [24.0] hours; p=0.0174).⁴²

In addition, Grumach highlighted several ongoing clinical studies that included patients with HAE-nC1-INH.^43-45 The only known clinical trial focusing on patients with normal C1-INH is the CASPIAN Study, a Phase III, multicentre, randomised, placebo-controlled, double-blind study (funded by Takeda [Shire]), evaluating the efficacy and safety of lanadelumab for prevention against acute attacks of non-histaminergic angioedema with normal C1-INH in patients aged ≥12 years.⁴³ A Phase II, double-blind, placebo-controlled study (funded by CSL Behring) investigating the efficacy and safety of garadacimab in the prevention of HAE attacks, included up to 10 participants with HAE-FXII/PLG enrolled for open-label treatment.⁴⁴ Finally, a Phase II, randomised, double-blind, placebo-controlled study (funded by Ionis Pharmaceuticals [Carlsbad, California, USA]), assessing the clinical efficacy, safety, and tolerability of donidalorsen in patients with HAE, included three participants with HAE-nC1-INH enrolled in the open-label Part B of the study.⁴⁵ Of note, no head-to-head trials have been performed, and therefore no direct comparisons can be drawn.

In summary, although rare, the true prevalence of HAE-nC1-INH remains unclear, with difficulties in diagnosis, and a lack of a specific biochemical test or confirmatory biomarker. The pathological mechanisms of HAE-nC1-INH are not fully understood, with several unknown genetic mutations.⁴⁶ Therefore, adopting a personalised approach to HAE-nC1-INH management is essential to help address the current unmet needs that still exist.⁴⁶

Interactive Expert Panel Discussion: Exploring HAE-nC1-INH and the Diagnostic Challenges

Banerji enquired about the panel’s opinion regarding the symptoms or treatment responses that are indicative of bradykinin-mediated angioedema compared with histamine-mediated angioedema, especially in the instance where genetic testing is inaccessible. Grumach emphasised the importance of conducting differential diagnosis and testing for mast cell-mediated responses, as well as exploring other treatment responses to ascertain if patients have HAE-nC1-INH. Grumach stressed that obtaining an accurate diagnosis is crucial for achieving favourable treatment outcomes. Maurer added that angioedema presents challenges and nuances, particularly in regard to treatment availability, as accessibility and reimbursement of effective treatment options vary across countries. Furthermore, genetic testing may not always be feasible to confirm the presence of known HAE-nC1-INH mutations. The panel agreed that physicians need access to treatment options and genetic mutation testing to effectively implement the differential diagnosis algorithm. The panel also acknowledged the high degree of misdiagnosis, and indicated the necessity of using high-dose antihistamines and omalizumab for patients with recurrent angioedema, specifically those with a histaminergic profile. Banerji also enquired about the available support for individuals experiencing recurrent angioedema, despite normal laboratory test results. Maurer highlighted the importance of educating healthcare professionals regarding the complexity of angioedema, and increased awareness of the condition. Maurer recommended the sharing of clinical practice, case studies, treatment approaches, and prognosis to facilitate continuous learning, particularly in light of unknown genetic variants. Current guidelines for HAE-nC1-INH are limited, and Maurer identified the need for incorporating regular updates and recommendations. Finally, it was mentioned that laryngeal and abdominal angioedema can manifest with various symptoms and potential causes, reinforcing the need for considering a wide range of differential diagnoses, and confirming HAE before considering treatment options.

Conclusion

The symposium session provided insights into the evolution of LTP for HAE management, and highlighted the ongoing unmet needs. These needs include limited LTP treatment options in many countries, particularly for paediatric patients and those with HAE-nC1-INH. There is a need to improve HAE disease awareness and provide education, comprehensive personalised care, tools, and establish biomarkers to enable early diagnosis, and improve outcomes and QoL for those with HAE.

VV-MEDMAT-86870 | August 2023