Current and Prospective Targets of Pharmacologic Treatment of Hereditary Angioedema Types 1 and 2

Abstract

Hereditary angioedema (HAE) is a rare disease that causes episodic attacks of subcutaneous and submucosal edema, which can be painful, incapacitating, and potentially fatal. These attacks are mediated by excessive bradykinin production, as a result of uncontrolled activation of the plasma kallikrein/kinin system, which is caused by a C1 esterase inhibitor deficiency or dysfunction in HAE types 1 and 2, respectively. For many years, treatment options were limited to therapies with substantial adverse effects, insufficient efficacy, or difficult routes of administration. Increased insights in the pathophysiology of HAE have paved the way for the development of new therapies with fewer side effects. In the last two decades, several targeted novel therapeutic strategies for HAE have been developed, for both long-term prophylaxis and on demand treatment of acute attacks. This article reviews the advances in the development of more effective and convenient treatment options for HAE and their anticipated effects on morbidity, mortality, and quality of life. The emergence of these improved treatment options will presumably change current HAE guidelines, but adherence to these recommendations may become restricted by high treatment costs. It will therefore be essential to determine the indications and identify the patients that will benefit most from these newest treatment generations. Ultimately, current preclinical research into gene therapies may eventually lead the way towards curative treatment options for HAE. In conclusion, an increasing shift towards the use of highly effective long-term prophylaxis is anticipated, which should drastically abate the burden on patients with hereditary angioedema.

Treatment of hereditary angioedema: When the goal is having a normal life

“…Administration of lanadelumab by subcutaneous injection has led to rapid and sustained reduction in attack rates and marked improvement in the health-related quality of life of patients with HAE-C1-INH 12 years of age and older, with a favorable safety profile. 1,4,5 Injection site pain was reported by up to 42% of patients treated with lanadelumab, and no serious adverse events were reported within the 26-week study period. A recent US guideline with compelling evidence for management of HAE recommends that LTP treatment of HAE-C1-INH include first-line medications (intravenous C1-INH, subcutaneous C1-INH, or lanadelumab).…”

“…Knowledge of the pathogenesis of HAE has allowed for the development of highly effective, safe, and innovative therapies for HAE in recent years. 1,4,5 Targeted approved treatments for HAE include C1-INH replacement using plasma-derived or recombinant C1-INH by the intravenous or subcutaneous routes, which are effective for both prevention and treatment of attacks according to the respective indications, and the bradykinin B2 receptor antagonist icatibant, which is widely used for on-demand treatment with the convenience of approved indication for subcutaneous selfadministration. 1 Kallikrein has also been considered as a therapeutic target for HAE because of its pivotal role in bradykinin production.…”

“…The use of antisense methods for targeting plasma prekallikrein expression at the mRNA level has recently been reported. 4 An antisense oligonucleotide (IONIS-PKK-Rx or PKK-Rx) and also a ligand-conjugated antisense oligonucleotide designed for receptor-mediated delivery to liver hepatocytes (PKK-LRx) were administered to 2 patients with recalcitrant angioedema in a compassionate-use pilot study. An effective reduction in attack rate was achieved in the 2 patients by subcutaneous injections of both PKK-Rx and PKK-LRx for 12 and 30 weeks, respectively.…”

“…This reduction was accompanied by a substantial decrease in prekallikrein activity, and no serious adverse events were reported. 4 An investigational CRISPR/ Cas9-based therapy (NTLA-2020) that is designed to knock out the KLKB1 gene and has been formulated in lipid nanoparticle platform technology is being developed for the treatment of HAE. A single administration of NTLA-2002 in mice bearing the human KLKB1 gene and nonhuman primates resulted in robust gene editing and sustained reductions in both total kallikrein protein level and activity in ongoing preclinical studies (data reported by Jessica Seitzer [abstract presented at the 2021 AAAAI Virtual Annual Meeting]).…”

“…A single administration of NTLA-2002 in mice bearing the human KLKB1 gene and nonhuman primates resulted in robust gene editing and sustained reductions in both total kallikrein protein level and activity in ongoing preclinical studies (data reported by Jessica Seitzer [abstract presented at the 2021 AAAAI Virtual Annual Meeting]). Novel therapeutic targets for HAE, including the human mAb garadacimab against FXIIa, which is currently under phase II clinical evaluation for the prophylactic treatment of HAE (ClinicalTrials.gov identifier NCT03712228), have recently been reviewed by Fijen et al 4 and Caballero. 5 Although there have been tremendous advances in the therapy for patients with HAE and more are to come, challenges remain.…”