Treatment of Hereditary Angioedema

Abstract

Hereditary angioedema due to C1-esterase inhibitor deficiency (C1-INH-HAE) is a rare autosomal dominant disease. In the last decade, new drugs and new indications for old drugs have played a role in the management of C1-INH-HAE. This review examines current therapy for C1-INH-HAE and provides a brief summary of drugs that are under development. Increased knowledge of the pathophysiology of C1-INH-HAE has been crucial for advances in the field, with inhibition of the kallikrein-kinin system (plasma kallikrein, activated factor XII) as a key area in the discovery of new drugs, some of which are already marketed for treatment of C1-INH-HAE. Pharmacological treatment is based on 3 pillars: treatment of acute angioedema attacks (on-demand treatment), short-term (preprocedure) prophylaxis, and long-term prophylaxis. The 4 drugs that are currently available for the treatment of acute angioedema attacks (purified plasma-derived human C1 esterase inhibitor concentrate, icatibant acetate, ecallantide, recombinant human C1 esterase inhibitor) are all authorized for self-administration, except ecallantide. Purified plasma-derived human C1 esterase inhibitor concentrate is the treatment of choice for short-term prophylaxis. Tranexamic acid, danazol, intravenous and subcutaneous nanofiltered purified plasma-derived human C1 esterase inhibitor concentrate, and lanadelumab can be used for long-term prophylaxis. New drugs are being investigated, mainly as long-term prophylaxis, and are aimed at blocking the kallikrein-kinin system by means of antiprekallikrein, antikallikrein, and anti–activated FXII action.

Specific Targeting of Plasma Kallikrein for Treatment of Hereditary Angioedema: A Revolutionary Decade

“…Two kallikrein inhibitors were approved in the past 3 years and several new kallikrein inhibitors were assessed in clinical trials. 49…”

“…One newly approved molecule and several pipeline molecules targeting plasma kallikrein are under development for the acute treatment and long-term prophylaxis of HAE. 49 Many of these new therapies are administered orally. 49 In the 2017 US FDA Patient-Focused Drug Development meeting of 162 patients with HAE, the administration route was the most frequently chosen factor driving treatment preference, in which oral medications were preferred over subcutaneous ones.…”

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.…”

“…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. For recently available kallikrein inhibitors, efficacy in real-life conditions outside clinical trials and long-term safety are important issues to explore.…”