Treatment of Hereditary Angioedema: Current Perspectives

Abstract

Hereditary angioedema (HAE) is a rare familial disease characterized by recurrent self-limiting episodes of soft tissue swelling affecting different parts of the body. Acute HAE attacks range from benign, but disfiguring skin edema, to painful abdominal, and even life-threatening laryngeal attacks. The disease is caused by an aberrant C1 esterase inhibitor (C1-INH), which regulates complement, fibrinolytic, and contact pathways. Elevated serum level of bradykinin as a result of contact pathway activation is thought to be the major mediator of pain and edema formation in HAE. Current therapy of acute HAE attacks is limited and mainly offers symptom control. In the United States only fresh frozen plasma provides some reconstitution of C1-INH, but the efficacy and safety of this treatment is controversial. In some European countries two human derived C1-INH concentrates have been used successfully. Prophylactic therapy for patients with frequent HAE attacks is confined to attenuated androgens and in some countries anti-fibrinolytics and C1-INH are also used. To satisfy the unmet needs, investigation of one recombinant C1-INH, two drugs working on bradykinin pathway and two human derived C1-INH concentrates are underway. This review article also discusses some recent patents related to the filed.

Enzymatic pathways in the pathogenesis of hereditary angioedema: The role of C1 inhibitor therapy

“…41 A diagnosis of HAE should be suspected in cases in which there is a history of recurrent attacks of peripheral angioedema (nonpruritic, nonpitting) and/or abdominal pain in the absence of urticaria. The swelling can be seen affecting many parts of the body, most commonly the extremities, face, or genitalia.…”

“…The 2 main areas for development are C1INH replacement therapy directed against the fundamental defect in HAE, and agents directed downstream at the contact (bradykinin-forming) system. The rationale for the various approaches is described here; a thorough review of the clinical evidence for the various agents is outside the scope of this article, but the reader is referred to Krassilnikova et al, 41 Frank, 49 and Bernstein 50 for more detailed reviews.…”

“…(Non-US guidelines have, in fact, been recommending use of plasma-derived C1INH for routine and procedural prophylaxis as well as treatment of acute attacks for some time. 16,51 ) Data from initial clinical studies with these agents are reviewed elsewhere, 41,49,50 and a recent study of Cinryze use for acute therapy or prophylaxis has just been published. 52 …”

Hereditary angioedema: Diagnosis and management–a perspective for the dermatologist

“…A recombinant transgenic C1 INH is also under investigation for treatment of HAE attacks. 34,35 There has been the development of other targeted therapies for acute treatment of HAE attacks, 34,35 which act specifically at points in the contact (kallikrein-kinin) system (Fig 2) downstream of the sites of action of C1 INH. Kalbitor (ecallantide) inhibits kallikrein and prevents subsequent bradykinin generation.…”

“…Icatibant, a bradykinin B(2) receptor antagonist, is also under investigation for treatment of HAE. 34,35 Conclusions HAE is a relatively uncommon disorder that many physicians may rarely, if ever, encounter, but it should be recognized as an important and potentially life-threatening condition. Significant progress has been made since the first description of a hereditary form of AE in the late 1800s, and our understanding of the underlying pathology has led, in recent years, to more specific and better-tolerated treatments.…”