Proof-of-concept study of icatibant (JE 049), a bradykinin B2 receptor antagonist in treatment of hereditary angioedema

Abstract

Background/Aims Bradykinin (BK) is considered to be a key mediator in acute attacks of hereditary angioedema (HAE) due to C1 inhibitor (C1-INH) deficiency. During acute HAE attacks, increased BK plasma levels are detectable. The highly specific BK B2 receptor antagonist Icatibant leads to reduction of fluid extravasation in C1-INH knockout mice. The efficacy and safety of Icatibant in the treatment of acute HAE attacks have been assessed in this study. Methods In the open-label study 20 acute HAE attacks (10 cutaneous, 3 abdominal, 7 combined) in 15 hospitalized patients were treated with Icatibant as follows (n=4 each group): a) 0.4mg/kg body weight (BW) over 2hr i.v.; b) 0.4mg/kg BW over 0.5hr i.v.; c) 0.8mg/kg BW over 0.5hr i.v.; d) 30mg s.c.; and e) 45mg s.c. Evaluation was performed by questionnaires and visual analogue scales. Treatment efficacy was compared to similar, untreated attacks reported previously by the same patients. Results Treatment with Icatibant shortened the time to onset of symptom resolution (median time between treatment start and symptom resolution as reported by the patient: 1.5, 1.4, 1.1, 0.5, and 0.6hr respectively, untreated: 48 and 24hr for groups 1 and 2). Upon treatment, duration of the attacks was considerably shorter than that of previous attacks. Icatibant was well tolerated. Conclusions Icatibant has shown to alleviate symptoms of acute cutaneous, abdominal or combined attacks of HAE, thus confirming the key role of BK in this disease. Clinical Pharmacology & Therapeutics (2005) 77, P14–P14; doi: 10.1016/j.clpt.2004.11.055