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Supplements New Horizons in the Diagnosis and Treatment of Hereditary Angioedema: Overcoming Barriers to Management and Improving Patient Outcomes
Severity of Hereditary Angioedema, Prevalence, and Diagnostic Considerations
Jonathan A. Bernstein, MD
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Current and Emerging Therapies to Prevent Hereditary Angioedema Attacks
William R. Lumry, MD
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Current and Emerging Therapies to Prevent Hereditary Angioedema Attacks

William R. Lumry, MD
Hereditary angioedema (HAE) is a rare genetic disease defined by recurrent attacks of edema, causing a substantial burden for patients, with morbidity, mortality, and reduced quality of life. This burden is increased by delayed diagnosis, inappropriate treatment, and suboptimal follow-up and patient education. Several novel therapeutics have recently been approved or are currently under evaluation for prevention of HAE attacks.
Am J Manag Care. 2018;24:-S0
Prior to 2008, treatment options for hereditary angioedema (HAE) in the United States were severely lacking or associated with significant adverse effects (AEs)1; however, 6 effective medications have now been FDA approved, with additional agents currently undergoing clinical trials. These therapies act on different targets within the contact/kinin system (CKS) to reduce bradykinin production or its effects, decrease angioedema, and improve outcomes in patients with HAE.2

Current Treatment Options for HAE

Bradykinin, the primary mediator of swelling in HAE, is produced by cleavage of high-molecular weight (HMW) kininogen by plasma kallikrein. Kallikrein is formed through activation of prekallikrein by factor XIIa.3 Once bradykinin is generated, it binds to bradykinin receptors on vascular endothelial cells; this binding leads to vasodilation and increase in vascular permeability, resulting in localized swelling known as angioedema.3,4 Control of this process relies on inhibition of key steps by complement component 1 esterase inhibitor (C1-INH), but in patients with HAE, adequate functional C1-INH is lacking.3,5 Without a correctly functioning inhibitory mechanism, the CKS produces excess bradykinin, resulting in angioedema.3 In addition to working within the CKS, C1-INH inhibits C1 esterase in the classic complement pathway, plasmin in the fibrinolytic system, and factor XIa in the intrinsic coagulation system.6 Four agents/classes (shown in green in Figure 12,6,7) target steps in the CKS to block key components of the CKS, decreasing the amount of bradykinin or its effect on the vasculature and thereby reducing vascular leak that causes the swelling.2

Recommendations for Treatment and Prevention of Swelling Attacks

Therapy for HAE can be generally divided into 2 approaches, acute (or “on-demand”) treatment of attacks and prevention of attacks, which is broken down into short-term prophylaxis (STP) and long-term prophylaxis (LTP).7 While every patient with HAE should have access to on-demand therapy for acute attacks, not all patients require prophylaxis.7 The 2017 revision and update to the international World Allergy Organization (WAO)/European Academy of Allergy and Clinical Immunology (EAACI) guideline for the management of HAE provides evidence-based recommendations for both of these approaches.7 The medications’ FDA-approved indications (acute treatment or prophylaxis of HAE), availability as home therapy, pediatric age groups, and routes of administration (these may differ in other countries) are provided in Table 1,8,9 followed by summaries of the new guideline recommendations.

C1-INH: Plasma-derived and Recombinant Formulations

Supplementation for the lacking or dysfunctional C1-INH protein is accomplished with human plasma-derived protein (Berinert, Cinryze, Haegarda) or recombinant purified protein (Ruconest). C1-INH replacement can be used for either treatment or prevention of attacks.7 Human plasma-derived C1-INH (pdC1-INH) is purified from human plasma through processes of cryoprecipitation, adsorption, precipitation, purification, pasteurization, and nanofiltration. Recombinant C1-INH (rhC1-INH) is extracted from the milk of transgenic rabbits using a 3-step chromatography purification process.7 Both types of C1-INH are effective and safe for treatment of HAE swelling attacks.7 Although derived from human plasma, pdC1-INH has not been associated with the transmission of hepatitis B or C, or human immunodeficiency virus.10-12 Because rhC1-INH is derived from rabbit milk, transmission of human viruses is not a concern; however, rhC1-INH is contraindicated in any patient with known or suspected allergies to rabbits or rabbit-derived products.13 Both agents have identical mechanisms of action but distinct serum half-lives; pdC1-INH has a half-life of over 30 hours, whereas the half-life of rhC1-INH is approximately 3 hours.7 Despite the shorter half-life, a recent study found that treatment with rhC1-INH demonstrated a sustained response of at least 72 hours in 93% of patients with HAE who were treated for an acute attack.14 C1-INH is given intravenously (IV) using weight-based dosing for on-demand treatment of swelling attacks at either a fixed-dose IV or weight-based dose subcutaneously (SC) for prevention of attacks.

Dosing and administration of pdC1-INH, based on the results of their corresponding clinical trials, is as follows: For adults and adolescents: 20 international units (IU)/kg IV for Berinert15; 2500 units (maximum: 100 IU/kg) IV every 3 days for Cinryze16; 60 IU/kg SC every 3 days for Haegarda.17 For children: 12 years: 20 IU/kg IV for Berinert15; 2500 units (maximum: 100 units/kg) IV every 3 days for Cinryze16; safety and efficacy of Haegarda has not been established. Six to 11 years: 20 IU/kg IV for Berinert15; 1000 IU IV every 3 days for Cinryze16; safety and efficacy of Haegarda have not been established. One to 5 years: 20 IU/kg IV for Berinert; safety and efficacy of Cinryze and Haegarda have not been established. Recommended dose of rhC1-INH (Ruconest) for acute attack in both adults and adolescents is 50 IU/kg with a maximum of 4200 IU is to be administered as a slow IV injection over approximately 5 minutes.13


In 2017, the pdC1-INH agent (Haegarda) was approved by the FDA for prophylaxis of HAE in adolescent and adult patients. This is the second agent approved for HAE prophylaxis and the first C1-INH for SC administration.18 This agent is a concentrated form of pdC1-INH (Berinert). This agent was evaluated in the COMPACT phase 3 trial involving 90 patients (12 years of age or older) who had presented with 4 or more attacks in a consecutive 2-month period within 3 months before screening. In this international, multicenter, double-blind, randomized, placebo-controlled, crossover trial, patients were randomized to 1 of 4 treatment groups that self-administered twice-weekly SC C1-INH 40 or 60 IU/kg followed by placebo for 16 weeks each, or vice versa.19 The primary efficacy end point of the study was reduction of the time-normalized number of HAE attacks. The secondary end points included the responder rate and the number of rescue medication uses. Both doses compared with placebo reduced the rate of attacks of HAE. The treatment response (50% reduction in attacks) occurred in 90% of patients receiving the 60-IU/kg dose and in 76% receiving the 40-IU/kg dose. The need for rescue medication was decreased with treatment compared with placebo. The median reduction in the attack rate relative to placebo was 89% with 40 IU and 95% with 60 IU in patients being treated during the two 16-week clinical trial periods.19 Although mild, AEs did not differ from placebo. The most common AEs experienced by patients included injection-site reaction, hypersensitivity reaction (pruritus, rash, urticaria), nasopharyngitis, and dizziness.17,19

FDA approval of pdC1-INH (Berinert) in 2009 was based on the IMPACT 1 study, a placebo-controlled, double-blind, prospective, multinational, randomized, parallel-group, dose-finding, 3-arm clinical study.15,20 The 124 adult and pediatric participants enrolled were experiencing acute, moderate to severe attacks of laryngeal, abdominal, or facial HAE. Patients were randomized to receive a single 10 unit/kg body weight dose of pdC1-INH (Berinert), a single 20 unit/kg dose of pdC1-INH (Berinert), or a single dose of placebo by slow IV infusion (recommended to be given at a rate of approximately 4 mL per minute) within 5 hours of an attack.20 If the attack did not improve, the participants were given an extra 10 IU/kg body weight, placebo, or 20 IU/kg body weight, respectively, at 4 hours. pdC1-INH (Berinert) relieved symptoms from an established attack significantly sooner than placebo. Participants treated with 20 units/kg of pdC1-INH (Berinert) experienced a significant reduction in time to onset of relief from symptoms of an attack as compared with placebo (median of 50 minutes for pdC1-INH [Berinert] 20 units/kg body weight, as compared with >4 hours for placebo). The time to onset of relief from symptoms of an HAE attack for participants in the 10 unit/kg dose of pdC1-INH (Berinert) was statistically insignificant compared with participants in the placebo group.20 The efficacy of pdC1-INH (Berinert) 20 units/kg was confirmed by observing the reduction in intensity of HAE symptoms at an earlier time compared with placebo,20 rendering pdC1-INH (Berinert) as an on-demand treatment of acute abdominal, facial, or laryngeal attacks of HAE in adult and pediatric patients. Potential AEs associated with the use of pdC1-INH (Berinert) include nausea, risk of anaphylaxis (rare), thrombotic events, and viral transmission (theoretical).15

Approval of pdC1-INH (Cinryze) as a therapy for preventing HAE attacks was evaluated in the CHANGE trial, a 24-week, multicenter, double-blind, placebo-controlled, crossover study. The FDA approved this medication in 2008 for routine prophylaxis of HAE in adult and adolescent patients.16 The primary efficacy outcome was the total number of angioedema episodes in each treatment period in adults and adolescents. An attack of HAE was defined as swelling in any location on the patient’s body following a report of no swelling on the previous day.21 Patients received blinded pdC1-INH (Cinryze) 1000 units IV twice weekly for 12 weeks at the study site and then crossed over to receive twice-weekly IV infusions of placebo for 12 weeks at the study site, or vice versa. The primary end point was the number of attacks of angioedema per period. The number of attacks was reduced significantly with the treatment group, and both the severity and duration of attacks were also reduced.21 Estimated median time to the onset of symptom relief was 2 hours in the treatment group, as compared with more than 4 hours in the placebo group. There is a concern for clotting and infection with the use of pdC1-INH (Cinryze) for prophylaxis via indwelling venous ports.21 Patients can be taught to self-administer the pdC1-INH (Cinryze) IV dose by their healthcare provider. Common AEs presenting in clinical trials were headache, nausea, rash, hypersensitivity, and vomiting.16


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