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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
Participating Faculty

Current and Emerging Therapies to Prevent Hereditary Angioedema Attacks

William R. Lumry, MD
The approval of rhC1-INH by the FDA in 2014 was based on the results of a randomized, double-blind, placebo-controlled, phase 3 trial (RCT) including an open-label extension (OLE). The pivotal RCT and OLE studies analyzed the results from 44 participants who experienced 170 HAE attacks.22 RhC1-INH is the only recombinant C1-INH treatment option approved for treatment of acute angioedema attacks in both adult and adolescent patients with HAE. This was a 2-part phase 3 clinical trial of rhC1-INH that evaluated the safety and efficacy in treatment of acute attacks of HAE. Studies enrolled 75 patients with HAE, with results demonstrating rhC1-INH to be a safe and effective option to treat patients experiencing acute HAE attacks. The study evaluated the safety and efficacy of rhC1-INH in 2 treatment arms. Participants in the double-blind phase 1 study were randomized to receive 100 IU/kg of rhC1-INH or saline solution in a 1:1 ratio once.13 Results from this study showed significant reduction in median time to beginning of symptom relief. Common AEs presenting in participants included headache, nausea, diarrhea, and risk of anaphylaxis.13

Ecallantide: Kallikrein Inhibitor

Ecallantide is an SC administered fixed-dose potent and selective inhibitor of plasma kallikrein that is FDA approved for the treatment of attacks of HAE in patients 12 years or older.23 As shown in Figure 1, ecallantide’s action on plasma kallikrein prevents cleavage of HMW kininogen, which produces bradykinin and blocks the positive feedback loop that activates factor XII, leading to less kallikrein production.23 During a multicenter, randomized, double-blind, placebo-controlled trial and phase 3 trials, EDEMA-3 and EDEMA-4, ecallantide was found to be effective in treating HAE attack, showing clinically and statistically significant improvements at 4 hours compared with placebo in scores of mean-symptom complex severity and treatment outcome score.24 Dosing may be repeated once within 24 hours if this initial dose is not effective. The most common AEs associated with ecallantide were headache, nausea, diarrhea, pyrexia, injection-site reactions, and nasopharyngitis.23 Hypersensitivity reactions, including anaphylaxis, occurred in 3% to 4% of ecallantide-treated patients in the clinical trials. Therefore, administration of the drug must be performed by a healthcare professional at home or in a healthcare setting with appropriate support to manage an anaphylactic reaction should one occur.23

Icatibant: Bradykinin 2-Receptor Antagonist

Icatibant is an SC administered fixed-dose synthetic peptide that prevents binding of bradykinin to the bradykinin type 2 (B2) receptor through specific and selective competitive antagonism (see Figure 12,6,7).25 This effectively prevents bradykinin from binding to these receptors and initiating the vascular leak resulting in angioedema. Icatibant received FDA approval in 2011 for the treatment of swelling attacks of HAE in adults 18 years and older.25 The phase 3 FAST-3 trial evaluated the efficacy and safety of a single SC injection of 30 mg icatibant administered to adults with type I or II HAE within 6 hours of an attack.26 Compared with those receiving placebo, patients receiving icatibant for cutaneous or abdominal attacks had significantly reduced median times to 50% or more reduction in symptom severity (2.0 vs 19.8 hours; P < .001), onset of primary symptom relief (1.5 vs 18.5 hours; P < .001), or almost complete symptom relief (8.0 vs 36.0 hours; P = .012), and time to initial symptom relief (0.8 vs 3.5 hours; P < .001).26 During clinical trials, 97% of patients reported transient injection-site reactions, including localized swelling, itching, burning, and redness when using icatibant. Less frequent AEs included pyrexia, transaminase increase, dizziness, and rash.25 In contrast to ecallantide, icatibant may be self-administered SC by patients upon recognition of an attack.25 If the first injection is not sufficient, additional injections may be administered at intervals of no less than 6 hours, with no more than 3 injections within a 24-hour period.25

Attenuated Androgens

Attenuated androgens, such as danazol, have been used since 1976 to prevent HAE attacks.6,7 Androgens cannot be administered as-needed for an attack because they require several days to become effective.8 Androgens are believed to increase the level of C1-INH in a dose-dependent fashion, probably by inducing production in hepatocytes; however, the exact mechanism of action is unknown. These agents are effective in patients with HAE; however, numerous dose-dependent AEs occur in nearly all patients, including virilization, weight gain, diminished libido, hirsutism, headache, myalgia, depression, hepatotoxicity, hypercholesterolemia, and acne.6,7 Androgens are contraindicated during pregnancy, in prepubertal children or adolescents, and patients with hepatic disease, breast cancer, and prostate cancer.7,26 Furthermore, androgens interact with many other drugs, such as statins, and long-term use requires semiannual blood and urine tests, along with an annual ultrasound of the liver.7


Although it is not well understood how the coagulation system plays a role in bradykinin elevation, C1-INH acts on plasmin, which is capable of activating factor XII in the CKS.27 Therefore, antifibrinolytics, such as epsilon aminocaproic acid and tranexamic acid, have been historically used as preventive treatment of HAE. However, these agents are not FDA approved and not recommended for long-term prophylaxis in HAE-C1-INH deficiency due to inferior efficacy compared with other options.7 These agents are usually reserved for patients for whom other treatments are contraindicated or if other therapies are not available.7

Treatment Strategies

Treatment typically focuses on 3 objectives when treating a patient with HAE experiencing an attack: pharmacotherapy, airway management (if required), and supportive therapy (if required).1 Early treatment of an attack has been associated with better outcomes, including shorter time to resolution of symptoms and shorter duration of attack, regardless of location or severity.7,28 Laryngeal angioedema with resulting asphyxiation is responsible for substantial mortality in HAE.7,20 A study by Bork et al evaluated mortality in patients with HAE and found that 33% of patient deaths were due to laryngeal angioedema.27 Patients who are experiencing an attack involving their airway should use their on-demand therapy if readily available and then proceed to the closest emergency medical facility.

Because self-administration improves time to treatment, all patients should be considered for home therapy and self-administration training with on-demand therapy.7 When an attack occurs, WAO/EAACI clinical guidelines recommend IV C1-INH, SC ecallantide, or icatibant for acute treatment.7 As noted above, self-administration with ecallantide is not recommended.23

STP should be provided to patients if circumstances such as a medical or dental procedure is likely to trigger an attack. Patients who anticipate facing particularly stressful situations may be considered for STP. Procedures associated with mechanical interventions to the upper aerodigestive tract, such as endotracheal intubation, bronchoscopy, or esophagogastroduodenoscopy, may lead to swelling near the site of intervention.7 The WAO/EAACI guideline recommends that all patients undergoing any medical, surgical, or dental procedure involving any mechanical impact to the upper aerodigestive tract receive C1-INH as preprocedural prophylaxis as close as possible to the start of the procedure. Dosage has yet to be fully established.7 Androgens (eg, danazol 200 mg thrice daily) given 5 days before and 2 days after the procedure are recommended as an alternative to C1-INH, and although the guideline acknowledges the use of tranexamic acid in the past for STP, most panel experts recommended against this use.7

LTP should be considered in patients when HAE is particularly burdensome.7 Successful treatment requires a high degree of compliance, so LTP therapy must be individualized based on disease activity, frequency of attacks, patient’s quality of life, availability of healthcare resources, failure to achieve adequate control through use of on-demand treatments, and patient preference.7 The WAO/EAACI guideline recommends C1-INH currently available in both IV and SC formulations as first-line therapy for LTP if available. Patients may experience breakthrough attacks while receiving LTP, so on-demand therapy should be provided for all patients regardless of using preventive therapy. Patients should be evaluated annually for changes in response to therapy and/or treatment modifications required.7

A key factor that should be considered when prescribing therapy for HAE is route of administration. Whether acute or prophylactic treatment, route of administration can affect patient satisfaction with treatment, which ultimately impacts compliance. A survey by Riedl et al sought to evaluate satisfaction with IV C1-INH products among patients with HAE.29 Of 47 patients, 34 (72%) reported administering C1-INH through peripheral veins, and 19 (40%) were currently or had previously used a central venous port for administration. Of patients administering C1-INH through a peripheral vein, 62% reported having difficulty finding a usable vein or getting the infusion to work properly, and 47% of patients with ports reported problems, such as occlusion, thrombosis, and infection associated with their port.29 Although the WAO/EAACI guideline does not recommend any particular route of administration, it acknowledges the improved convenience with SC administration,7 which may play a role in compliance. To this point, a recent study by Jose et al found that 50% of patients with HAE prefer a noninvasive route of administration, including oral (24%), SC (18%), or non-IV route (8%).30 Table 2 provides a summary of guideline recommendations for acute treatment and prophylaxis with available HAE medications.7

New and Emerging Treatments

Pediatric Developments

RhC1-INH is currently undergoing a phase 2, multicenter, open-label study (NCT01359969) to evaluate the agent’s safety, immunogenicity, and pharmacology in patients aged 2 to 13 years experiencing an acute attack. Preliminary results from this trial were announced in October 2017.31 After 20 children were treated for 73 attacks, the median time to onset of relief was 60 minutes (95% CI, 60-63 minutes) and to minimal symptoms was 122 minutes (95% CI, 120-126 minutes).31 In addition to demonstrating efficacy at resolving attacks, rhC1-INH was safe and well tolerated. No patients withdrew from the study for AEs, and no serious AEs, hypersensitivity reactions, or neutralizing antibodies were reported.31

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