New Therapeutics in C1INH Deficiency: A Review of Recent Studies and Advances
- 136 Downloads
Hereditary angioedema (HAE) is a genetic condition causing a significant burden of illness for affected individuals. Episodes of angioedema involving the skin, gastrointestinal tract, as well as the larynx and oropharynx are often unpredictable and cause significant morbidity and mortality. Isolation of the underlying protein deficiency, specifically the serine protease C1 inhibitor, and further description of its role in multiple physiologic cascades has led to the development of several specific therapies for HAE. This report provides a brief overview of HAE but focuses primarily on reviewing recently published clinical studies of therapeutics developed for medical management of the condition.
KeywordsHereditary angioedema C1INH deficiency Ecallantide Icatibant C1 inhibitor protein Bradykinin Kallikrein Clinical studies Treatment Therapeutics
Dr. Riedl has received grant support from Dyax Corp., CSL Behring, Shire, Pharming Group, and ViroPharma; has served on scientific advisory boards for Dyax Corp., CSL Behring, Shire, and ViroPharma; and has received payment for the development of continuing medical education presentations from the Robert Michael Educational Institute and Medscape.
Dr. Parikh reported no potential conflicts of interest relevant to this article.
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 3.• Kaplan AP, Joseph K. The bradykinin-forming cascade and its role in hereditary angioedema. Ann Allergy Asthma Immunol 2010;104:193–204. This is an authoritative, up-to-date review of hereditary angioedema pathophysiology with a focus on bradykinin as the primary mediator of symptoms. PubMedCrossRefGoogle Scholar
- 15.• Lumry WR, Castaldo AJ, Vernon MK, et al. The humanistic burden of hereditary angioedema: impact on health-related quality of life, productivity, and depression. Allergy Asthma Proc. 2010;31:407–14. Little quantitative research has examined the burden of illness associated with HAE. This publication provides unique insight into the effect of C1INH deficiency on individuals. PubMedCrossRefGoogle Scholar
- 19.Longhurst HJ, Bork K (2006) Hereditary angioedema: causes, manifestations, and treatment. Br J Hosp Med (Lond) 67:654–657Google Scholar
- 27.Androgens. In: Brunton LL, Lazo JS, Parker KL: Goodman and Gilman’s The Pharmacological Basis of Therapeutics. 11th edition. McGraw-Hill, 2005.Google Scholar
- 30.•• Craig TJ, Levy RJ, Wasserman RL, et al. Efficacy of human C1 esterase inhibitor concentrate compared with placebo in acute hereditary angioedema attacks. J Allergy Clin Immunol 2009;124:801–8. This was a recent rigorous phase 3 study that demonstrated important dose-related efficacy for pasteurized C1INH therapy in treating HAE attacks. PubMedCrossRefGoogle Scholar
- 31.•• Zuraw BL, Busse PJ, White M, et al. Nanofiltered C1 inhibitor concentrate for treatment of hereditary angioedema. N Engl J Med 2010;363:513–22. This was a recent paper reporting pivotal outcomes data from phase 3 studies of nanofiltered C1INH for both acute and long-term prophylactic treatment of HAE. PubMedCrossRefGoogle Scholar
- 32.•• Zuraw B, Cicardi M, Levy R, et al. Recombinant human C1-inhibitor for the treatment of acute angioedema attacks in patients with hereditary angioedema. J Allergy Clin Immunol 2010;126:821–7. This article reported pivotal phase 3 study results for the efficacy and safety of rhC1INH in treating HAE attacks. PubMedCrossRefGoogle Scholar
- 34.•• Cicardi M, Banerji A, Bracho F, et al. Icatibant, a new bradykinin-receptor antagonist, in hereditary angioedema. N Engl J Med 2010; 363:532–41. This article reported the pivotal study data from two controlled phase 3 studies (FAST-1 and FAST-2) investigating the efficacy and safety of icatibant in treating HAE attacks. PubMedCrossRefGoogle Scholar
- 36.• Bowen T, Cicardi M, Farkas H, et al. 2010 international consensus algorithm for the diagnosis, therapy and management of hereditary angioedema. Allergy Asthma Clin Immunol. 2010;6:24. This is a recent expert consensus document incorporating new HAE therapeutics into the management approach. Additional international, evidence-based consensus documents are in development. PubMedCrossRefGoogle Scholar
- 37.• Longhurst HJ, Farkas H, Craig T, et al. HAE international home therapy consensus document. Allergy Asthma Clin Immunol. 2010;6:22 This article provides important data and expert opinion regarding the benefits and potential risks of patient self-administered therapy in managing HAE. PubMedCrossRefGoogle Scholar
- 40.Lumry W, Li HH, Levy RJ, et al. Results from FAST-3: a phase 3, randomized, double-blind, placebo-controlled, multicenter study of subcutaneous icatibant in subjects with acute attacks of hereditary angioedema [oral abstract]. Presented at the American Academy of Asthma, Allergy, and Immunology, San Francisco, CA. March 18–22, 2011.Google Scholar