Recombinant Human C1 Esterase Inhibitor in the Management of Hereditary Angioedema

Abstract

Hereditary angioedema (HAE), a rare autosomal dominant genetic disorder, is caused by a deficiency in functional C1 esterase inhibitor (C1-INH). This potentially life-threatening condition manifests as recurrent attacks of subcutaneous and submucosal swelling of the skin, gastrointestinal tract and larynx. The management of HAE includes treatment of acute episodes, short-term prophylaxis in preparation for exposure to known triggers and long-term prophylaxis to decrease the incidence and severity of HAE attacks. Four products are approved in the USA for the treatment of acute attacks of HAE, including one human plasma-derived C1-INH therapy, a recombinant human C1-INH product (rhC1-INH), a plasma kallikrein inhibitor and a bradykinin B2 receptor antagonist. In addition, one human plasma-derived C1-INH therapy and danazol are approved for prophylaxis of HAE attacks. rhC1-INH, extracted from the milk of transgenic rabbits, is a glycoprotein of 478 amino acids with an identical amino acid sequence to the endogenous human C1-INH protein. Population pharmacokinetic analysis of rhC1-INH supports an intravenous dosing strategy of 50 U/kg (maximum 4200 U). The safety and efficacy of rhC1-INH in the treatment of acute attacks in patients with HAE were demonstrated in three randomized, double-blind, placebo-controlled studies and two open-label extension studies. In a pilot prophylaxis study, weekly administration of rhC1-INH 50 U/kg for 8 weeks reduced the incidence of HAE attacks and was well tolerated. Administration of rhC1-INH has not been associated with the development of anti-drug antibodies or antibodies to anti-host-related impurities.

The international WAO/EAACI guideline for the management of hereditary angioedema—The 2017 revision and update

“…Safety data from controlled and uncontrolled studies with rhC1‐INH support a favorable safety profile. Transmission of human viruses is not a concern …”

Recombinant human plasma phospholipid transfer protein (PLTP) to prevent bacterial growth and to treat sepsis

“…Importantly, PLTP is a complex glycosylated protein, with six distinct N-glycosylation sites which are essential for normal activity 12 , 13 . In earlier studies, transgenic rabbits successfully produced recombinant human proteins 14 – 17 , some of which are currently under investigation in human therapeutics (alpha-glucosidase 18 , C1-esterase inhibitor 19 ). The production of recombinant proteins by rabbits offers a number of advantages: easy generation of transgenic founders and offspring, high fertility, post-translational modifications close to what occurs in humans, insensitivity to prion diseases, and a low risk of transmission of severe diseases to humans.…”

The Use of Plasma-Derived Complement C1-Esterase Inhibitor Concentrate (Berinert®) in the Treatment of Angiotensin Converting Enzyme-Inhibitor Related Angioedema

“…Accumulation of bradykinin is responsible for angioedema episodes in HAE and AAE as well as in ACEi-AE. Drugs interfering with the pathway leading to increased levels of bradykinin are well documented in the treatment of HAE and AAE [ 21 , 22 ]. However, in ACEi-AE of the head and neck only one study has described the effect of a bradykinin B2 receptor antagonist (icatibant) compared to traditional treatment with glucocorticoids and antihistamines.…”