Current Allergy and Asthma Reports

, Volume 11, Issue 4, pp 300–308 | Cite as

New Therapeutics in C1INH Deficiency: A Review of Recent Studies and Advances



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.


Hereditary 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

  1. 1.
    Bork K, Meng G, Staubach P et al (2006) Hereditary angioedema: new findings concerning symptoms, affected organs, and course. Am J Med 119:267–274PubMedCrossRefGoogle Scholar
  2. 2.
    Ghebrehiwet B, Randazzo BP, Dunn JT et al (1983) Mechanisms of activation of the classical pathway of complement by Hageman factor fragment. J Clin Invest 71:1450–1456PubMedCrossRefGoogle Scholar
  3. 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
  4. 4.
    Joseph K, Tholanikunnel B, Kaplan A (2002) Heat shock protein 90 catalyzes activation of the prekallikrein-kininogen complex in the absence of factor XII. Proc Natl Acad Sci U S A 99:896–900PubMedCrossRefGoogle Scholar
  5. 5.
    Joseph K, Shibayama Y, Ghebrehiwet B et al (2001) Factor XII-dependent contact activation on endothelial cells and binding proteins gC1qR and cytokeratin 1. Thromb Haemost 85:119–124PubMedGoogle Scholar
  6. 6.
    Gompels M, Lock R, Abinun M et al (2005) C1 inhibitor deficiency: consensus document. Clin Exp Immunol 139:379–394PubMedCrossRefGoogle Scholar
  7. 7.
    Cugno M, Zanichelli A, Foieni F et al (2009) C1-inhibitor deficiency and angioedema: molecular mechanisms and clinical progress. Trends Mol Med 15:69–78PubMedCrossRefGoogle Scholar
  8. 8.
    Pappalardo E, Caccia S, Suffritti C et al (2008) Mutation screening of C1 inhibitor gene in 108 unrelated families with hereditary angioedema: functional and structural correlates. Mol Immunol 25:3536–3544CrossRefGoogle Scholar
  9. 9.
    Rosen FS, Pensky J, Donaldson V et al (1965) Hereditary angioneurotic edema: two genetic variants. Science 148:957–958PubMedCrossRefGoogle Scholar
  10. 10.
    Prada AE, Zahedi K, Davis AE 3rd (1998) Regulation of C1 inhibitor synthesis. Immunobiology 199:377–388PubMedGoogle Scholar
  11. 11.
    Agostoni A, Cicardi M (1992) Hereditary and acquired C1-inhibitor deficiency: biological and clinical characteristics in 235 pa. Medicine 71:206–215PubMedCrossRefGoogle Scholar
  12. 12.
    Bork K, Wulff K, Hardt J et al (2009) Hereditary angioedema caused by missense mutations in the factor XII gene: clinical features, trigger factors, and therapy. J Allergy Clin Immunol 124:129–134PubMedCrossRefGoogle Scholar
  13. 13.
    Nzeako U, Frigas E, Tremaine W (2001) Hereditary angioedema: a broad review for clinicians. Arch Intern Med 161:2417–2429PubMedCrossRefGoogle Scholar
  14. 14.
    Bork K, Barnstedt S (2003) Laryngeal edema and death from asphyxiation after tooth extraction in four patients with hereditary angioedema. J Am Dent Assoc 134:1088–1094PubMedGoogle Scholar
  15. 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
  16. 16.
    Bracho FA (2005) Hereditary angioedema. Curr Opin Hematol 12:493–498PubMedCrossRefGoogle Scholar
  17. 17.
    Bork K, Staubach P, Eckardt AJ et al (2006) Symptoms, course, and complications of abdominal attacks in hereditary angioedema due to C1 inhibitor deficiency. Am J Gastroenterol 101:619–627PubMedCrossRefGoogle Scholar
  18. 18.
    Agostoni A, Aygoren-Pursun E, Binkley KE et al (2004) Hereditary and acquired angioedema: problems and progress: proceedings of the third C1 esterase inhibitor deficiency workshop and beyond. J Allergy Clin Immunol 114:S51–S131PubMedCrossRefGoogle Scholar
  19. 19.
    Longhurst HJ, Bork K (2006) Hereditary angioedema: causes, manifestations, and treatment. Br J Hosp Med (Lond) 67:654–657Google Scholar
  20. 20.
    Frank MM, Sergent JS, Kane MA et al (1972) Epsilon aminocaproic acid therapy of hereditary angioneurotic edema. A double-blind study. N Engl J Med 286:808–812PubMedCrossRefGoogle Scholar
  21. 21.
    Agostoni A, Marasini B, Cicardi M et al (1978) Hepatic function and fibrinolysis in patients with hereditary angioedema undergoing long-term treatment with tranexamic acid. Allergy 33:216–221PubMedCrossRefGoogle Scholar
  22. 22.
    Gelfand JA, Sherins RJ, Alling DW et al (1976) Treatment of hereditary angioedema with danazol. Reversal of clinical and biochemical abnormalities. N Engl J Med 295:1444–1448PubMedCrossRefGoogle Scholar
  23. 23.
    Pitts JS, Donaldson VH, Forristal J et al (1978) Remissions induced in hereditary angioneurotic edema with an attenuated androgen (danazol): correlation between concentrations of C1-inhibitor and the fourth and second components of complement. J Lab Clin Med 92:501–507PubMedGoogle Scholar
  24. 24.
    Agostoni A, Cicardi M, Martignoni GC et al (1980) Danazol and stanozolol in long-term prophylactic treatment of hereditary angioedema. J Allergy Clin Immunol 65:75–9PubMedCrossRefGoogle Scholar
  25. 25.
    Bork K, Bygum A, Hardt J (2008) Benefits and risks of danazol in hereditary angioedema: a long-term survey of 118 patients. Ann Allergy Asthma Immunol 100:153–161PubMedCrossRefGoogle Scholar
  26. 26.
    Craig TJ (2008) Appraisal of danazol prophylaxis for hereditary angioedema. Allergy Asthma Proc 29:225–231PubMedCrossRefGoogle Scholar
  27. 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
  28. 28.
    Bowen T, Brosz J, Brosz K et al (2010) Management of hereditary angioedema: 2010 Canadian approach. Allergy Asthma Clin Immunol 6:20PubMedCrossRefGoogle Scholar
  29. 29.
    Zuraw B (2010) HAE therapies: past, present, and future. Allergy Asthma Clin Immunol 6:23PubMedCrossRefGoogle Scholar
  30. 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. 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. 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
  33. 33.
    •• Cicardi M, Levy RJ, McNeil DL, et al. Ecallantide for the treatment of acute attacks in hereditary angioedema. N Engl J Med 2010;363:523–31. This article reported initial phase 3 study data on the efficacy and safety of ecallantide in treating HAE attacks. PubMedCrossRefGoogle Scholar
  34. 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
  35. 35.
    Price DD, Finniss DG, Benedetti F (2008) A comprehensive review of the placebo effect: recent advances and current thought. Annu Rev Psychol 59:565–590PubMedCrossRefGoogle Scholar
  36. 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. 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
  38. 38.
    Longhurst HJ, Carr S, Khair K (2007) C1-inhibitor concentrate home therapy for hereditary angioedema: a viable, effective treatment option. Clin Exp Immunol 147:11–17PubMedGoogle Scholar
  39. 39.
    Levy RJ, Lumry WR, McNeil DL et al (2010) EDEMA4: a phase 3, double-blind study of subcutaneous ecallantide treatment for acute attacks of hereditary angioedema. Ann Allergy Asthma Immunol 104:523–529PubMedCrossRefGoogle Scholar
  40. 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

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Clinical Immunology and Allergy, Department of MedicineUCLA David Geffen School of MedicineLos AngelesUSA

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