Breakthroughs in hereditary angioedema management: a systematic review of approved drugs and those under research

Abstract

Hereditary angioedema (HAE) is a rare genetic disorder, characterized by recurrent and unexpected potentially life-threatening mucosal swelling. The impairment underlying HAE could be a defect in C1-inhibitor activity, or in its serum concentration. Patients affected by HAE should be treated with on-demand or prophylactic drugs. Lifelong C1-inhibitor supplementation is sometimes required. In this review, we review the currently approved drugs for HAE due to C1-inhibitor defect and to describe those under research. In particular, we focused on the mechanisms of action, routes of administration, and efficacy of these therapies. A systematic review of the literature was performed using the PubMed database for original articles and clinical trials of HAE treatments from 2005 to 2019. The approved HAE treatments can minimize the risk of death, but they are not effective in complete healing from the disease. The new gene therapies seem to provide promising opportunities for the treatment of hereditary angioedema. However, there are still many unmet needs, including efficacy, route, and timing of administration.

Clinical characteristics and burden of illness in patients with hereditary angioedema: findings from a multinational patient survey

“…At the time of this study, treatments for HAE included on-demand medications to treat attacks after onset (such as icatibant, C1-INH inhibitor [Berinert® and Cinryze®], and ecallantide), and long- or short-term prophylactic therapy to prevent attacks (such as Cinryze®, androgens, and antifibrinolytics) [ 9 ]. However, despite improvements in the available HAE therapies, unmet needs remained; treatments require frequent dosing or intravenous administration, have limited efficacy, or are associated with poor tolerability [ 10 ].…”

Sugar Matters: Improving In Vivo Clearance Rate of Highly Glycosylated Recombinant Plasma Proteins for Therapeutic Use

“…Decades ago, substitution of pC1-INH turned out to be effective in patients suffering from HAE [ 9 , 14 , 18 ]. HAE is characterized by recurrent episodes of severe swelling, which can result in life-threatening situations [ 5 , 19 ]. C1-INH administration on demand and as prophylaxis reduced the severity and the frequency of attacks, respectively [ 20 ].…”

“…HAE is a rare disease, caused by partial C1-INH deficiency and characterized by recurrent episodes of severe swelling of, for instance, the face, genitals and gastrointestinal tract. Swelling of the upper airways may occasionally result in asphyxia [ 5 ]. One of the treatments for HAE in previous decades was the administration of plasma-derived C1-INH (pdC1-INH); more recently, recombinant C1-INH (rC1-INH, produced in transgenic rabbits) is used [ 5 ].…”

“…Swelling of the upper airways may occasionally result in asphyxia [ 5 ]. One of the treatments for HAE in previous decades was the administration of plasma-derived C1-INH (pdC1-INH); more recently, recombinant C1-INH (rC1-INH, produced in transgenic rabbits) is used [ 5 ]. C1-INH is heavily glycosylated, containing at least six N -linked and 26 O -linked glycosylation sites, and is considered to be one of the most heavily glycosylated proteins in human plasma [ 6 ].…”

In Vitro Modeling of Bradykinin-Mediated Angioedema States

“…The only FDA-approved clinical use of a BK receptor ligand is that of icatibant, an injectable peptide antagonist of the B 2 receptor, to abort attacks of HAE-C1-INH. C1-INH replenishment and various strategies to inhibit plasma kallikrein, FXII or fibrinolysis have also been or are being developed [ 27 ]. An orally bioavailable small molecule antagonist of the BK B 2 receptor is also at an early stage of development [ 28 ].…”