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.

Fig. 1

Schematic representation of the pathways inhibited by C1 esterase inhibitor (C1-INH). C1-INH inhibits proteases in the complement, contact activation and fibrinolytic pathways. In hereditary angioedema, uninhibited activation of the contact pathway because of deficiency in functional C1-INH results in unregulated cleavage of high molecular weight kininogen by kallikrein, leading to generation of excessive free bradykinin, which is a potent vasoactive peptide. Proteolytic activities are indicated with green arrows, and steps inhibited by C1-INH are shown by red bars. From Zuraw [1]. © 2008 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society [1]

Fig. 2

Simulation of peak recombinant human C1 esterase inhibitor (rhC1-INH) concentrations for levels of the proposed dosing regimen (50 U/kg for up to 84 kg body weight and a fixed dose of 4200 U for patients with body weight >84 kg). The 25th and 75th percentiles with the median values are represented as boxes; ends of whiskers represent 1.5 times the interquartile ranges (from the 25th and 75th quartiles). Any observations beyond 1.5 times the interquartile ranges are indicated as open circles, and the dashed line represents the lower limit of normal C1-INH (0.7 U/mL). Reprinted from Farrell et al. © 2013 The British Pharmacological Society [32]

Fig. 3

Kaplan–Meier plot of time to onset of symptom relief based on Treatment Effect Questionnaire results. In this phase 3, randomized, double-blind, placebo-controlled study, patients with an acute attack of hereditary angioedema were treated with recombinant human C1 esterase inhibitor (rhC1-INH) (50 U/kg for patients weighing <84 kg and 4200 U for patients weighing ≥84 kg). The censor flags indicate time points at which data were censored: patients who did not achieve the beginning of persistent symptom relief during the 24-h assessment period were censored at the last assessment time point (i.e. excluded from further efficacy analyses). Patients who received prohibited medications or open-label rescue rhC1-1NH before perceiving persistent symptom relief were censored at the last time point at which the Treatment Effect Questionnaire score was assessed before these medications were administered. Patients who did not experience minimal symptoms during the assessment period also were censored at the last assessment time point. Reprinted from Riedl [39], Copyright 2014, with permission from American College of Allergy, Asthma & Immunology