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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 pdC1-INH agent (Cinryze), approved for prophylaxis of HAE attacks in adolescents and adults, recently received FDA approval for prophylaxis in children aged 6 to 11 years.9,32 Interim results from a phase 3 trial published in mid-2017 reported a mean difference in the number of monthly angioedema attacks between the baseline and treatment period of –1.89 (SD, 1.31) with the 500-unit dose and –1.89 (SD, 1.11) with the 1000-unit dose, which were reductions of –84.8% and –88.1%, respectively.33 No serious AEs or discontinuations occurred during the study.26 In June 2018, the FDA approved the supplemental Biologics License Application (sBLA) to expand the indication for pdC1-INH (Cinryze) to include children 6 years and older.32 Currently, this is the only C1-INH prophylaxis option for children younger than 12 years.34

In addition to expanded pediatric indications for C1-INH formulations, icatibant is undergoing evaluation for treatment of swelling attacks in children and adolescents.35 In March 2018, a phase 3 trial of icatibant was completed, evaluating its use for HAE attacks in children and adolescents aged 2 through 17 years. Results published in late 2017 reported a median time to onset of symptom relief of 1.0 hour.35 Additionally, more than 70% of patients experienced symptom relief by 1.1 hours and more than 90% by 2.0 hours.36 Of 32 patients in the safety population, 9 (28.1%) experienced 32 treatment-emergent AEs, including gastrointestinal (GI) symptoms and injection-site reactions.35 Most injection-site reactions resolved within 6 hours post-dose.35 Although no announcement has been made regarding FDA approval of an expanded indication, the European Commission approved a label extension to use icatibant in adolescents and children 2 years and older in October 2017.36

Other Developments

RhC1-INH for Prophylaxis

RhC1-INH (Ruconest), the only FDA-approved rhC1-INH, is currently indicated for treatment of acute attacks in patients with HAE.13 A double-blind, placebo-controlled, international phase 2 trial (NCT02247739) was recently completed, evaluating the use of rhC1-INH for prophylaxis in patients with HAE.37 Over 4 weeks, the mean number of attacks was reduced by 72.1% and 44.4% in patients who received the rhC1-INH twice and once weekly, respectively.37 AEs were reported in 45% (13/29), 34% (10/29), and 29% (8/28) of patients in once-weekly, twice-weekly, and placebo groups, respectively, with headache (twice-weekly group) and nasopharyngitis (once-weekly group) being most common.37 FDA acceptance to review the manufacturer’s sBLA for rhC1-INH was announced in January 2018 with an action date of September 21, 2018.

New SC Formulation

Currently, SHP616 is another pdC1-INH being evaluated for SC administration in HAE prophylaxis. In the phase 3 SAHARA trial, which used a fixed dosage of C1-INH 2000 IU SC, SHP616 demonstrated a significant and clinically meaningful median HAE attack rate reduction of 79% from day 0, or 85% from day 15 (steady state achievement) in the active compared to the placebo treatment phase of the crossover study. Seventy-eight percent of patients experienced a 50% or greater reduction in their HAE attack rate, with 38% of patients remaining attack-free during treatment with SHP616. No treatment-related serious AEs or deaths were reported in this study. The most commonly noted AEs were injection-site reactions, viral upper respiratory tract infection, upper respiratory tract infection, and headache.9

In addition to the expanded indications and improvements on known therapeutics reviewed above, several novel therapies are currently undergoing development for acute treatment or prophylaxis of HAE.2 The mechanisms of action of these new agents are shown in purple in Figure 2,2,6,7 with agent information and recent clinical trial data summarized below.

Kallikrein Inhibitors

Lanadelumab, a fully human monoclonal antibody selective inhibitor of plasma kallikrein, which is administered SC, is undergoing development for HAE prophylaxis in patients 12 years and older.38,39 In February 2018, a press release announced the FDA accepted the BLA for lanadelumab, along with granting priority review.33 During the pivotal phase 3 HELP trial, administration of lanadelumab every 2 weeks resulted in an 87% reduction in mean frequency of attacks, with no treatment-related serious AEs or deaths reported.39 The most common AEs that emerged during treatment were attacks of angioedema, injection-site pain, and headache. An FDA decision date is set for August 2018.39

Similar to lanadelumab, BCX7353 works by inhibiting plasma kallikrein; this agent is administered orally.40 BCX7353 is currently undergoing development for on-demand treatment and prophylaxis of HAE attacks in patients 18 years and older with HAE.41 In the phase 2 APeX-1 prophylaxis trial, significant reductions in attacks were seen in 3 of 4 dose groups compared with placebo during weeks 2 to 4 of treatment (62.5 mg: –7%, P = .715; 125 mg: –73%, P < .001; 250 mg: –46%, P = .006; and 350 mg: –58%, P < .001).35 After positive results from the APeX-1 trial, the phase 3 APeX-2 trial started in early 2018, with top-line results expected in the first half of 2019.40 A phase 2 trial investigating oral use of a liquid formulation of BCX7353 for on-demand treatment of attacks (ZENITH) began in Europe in early 2018.

Antisense Targeting Prekallikrein

As shown in Figure 2, PKKRx reduces bradykinin by reducing prekallikrein production through an antisense mechanism. With lower amounts of prekallikrein, less plasma kallikrein can be generated and less bradykinin liberated.36 Although still in early development, a phase 1 trial of healthy volunteers showed a 95% reduction in prekallikrein levels, with a well-tolerated safety profile.2

Preclinical Agents

In addition to the agents already covered, several novel therapeutics are undergoing preclinical studies, as shown in dark blue in Figure 2, including 2 RNA interference drugs affecting factor XII production, ALN-F12 and ARC-F12; a monoclonal antibody antifactor XIIa, CSL 312; and gene therapy.2 While still very early in the clinical trial process, these agents may provide new approaches to reducing production of bradykinin and thereby preventing HAE attacks.

Individualizing Therapy and Patient Education

The clinical, economic, and quality-of-life burden to patients with HAE is substantial. The disease course of HAE is unpredictable, painful, and potentially life-threatening. Treatment plans must be individualized in partnership among the patient, family, and physician in order to achieve optimal outcomes.7,37 According to the Hereditary Angioedema Association Medical Advisory Board and WAO/EAACI guidelines, individualized treatment plans should address preventive measures, home care, and self-administration. An emergency plan with clear instructions and medications to use should be included for, if, and when an acute attack occurs. An HAE identification card, with instructions for managing an attack, along with on-demand medication, should always be carried.7,37

In addition to individualizing therapy, healthcare providers must recognize the importance of patient education to successful outcomes in HAE treatment. Proper education about avoiding potential attack triggers, recognition and early treatment of attacks, and self-administration of medications is critical to improving outcomes in these patients.

The Icatibant Outcome Survey is an observational study to evaluate the safety and efficacy of icatibant use in patients with HAE in real-world settings.21,38 An analysis of survey data compared outcomes of 652 attacks across 170 patients who either self-administered icatibant or received administration from a healthcare provider.21 As expected, the median time to administer icatibant was significantly shorter in patients who self-administered compared with those who received their care in a healthcare facility (1.5 vs 2.4 hours; P = .016). Earlier treatment time was significantly associated with a median shorter time to resolution of attack (2.5 vs 5.0 hours; P = .032) and attack duration (3.0 vs 14.0 hours; P < .0001); these data indicate the ability to self-administer at the earliest symptoms of an attack can significantly improve outcomes among patients with HAE.21 The WAO/EAACI guideline recommends that all patients be taught to self-administer the medication at home whenever possible.7 Table 3 provides a list of teaching objectives for patients who will treat their HAE in a home environment.39


HAE is a rare but debilitating and potentially life-threatening disease. There are currently 7 agents approved by the FDA to treat and/or prevent swelling attacks. These options for on-demand treatment and LTP have substantially improved the burden of disease and health-related quality of life in patients with HAE. The burden of treatment has also been decreased with the development of agents administered SC and requiring less-frequent dosing. As more patients opt to use prophylaxis alongside on-demand therapy, morbidity, mortality, and quality of life should further improve. Healthcare providers must prioritize patient–physician discussion of treatment options and strategies based on individualized patient factors, along with regular follow-up to monitor and adjust the plan as needed. Patient education is important for the proper and timely use of these life-altering and potentially life-saving agents.

Author affiliation: Clinical Professor of Internal Medicine, Allergy/Immunology Division, University of Texas Southwestern Medical School, private practice, Dallas, TX.
Funding source: This activity is supported by educational grants from CSL Behring and Shire.
Author disclosure: Dr Lumry reports the following relevant financial relationships with commercial interests: GRANT/RESEARCH SUPPORT: Hereditary Angioedema Association, BioCryst, CSL Behring, Circassia, Shire; CONSULTANT: Adverum, BioCryst, CSL Behring, Shire; SPEAKERS BUREAU: CSL Behring, Shire.
Authorship information: Acquisition of data; concept and design; drafting of the manuscript; critical revision of the manuscript for important intellectual content; provision of study materials or patients.
Address correspondence to:
Dr Lumry gratefully acknowledges Rachel L. Brown, PharmD, MPH, for her contributions to the development of this article. 
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