Background: In randomized, controlled, double-blind, multicenter phase 3 studies, one icatibant injection was efficacious and generally well tolerated in patients with a single hereditary angioedema (HAE) attack. Here, the efficacy and safety of icatibant for multiple HAE attacks was evaluated across the controlled and open-label extension phases of the For Angioedema Subcutaneous Treatment (FAST)-3 study (NCT00912093). Methods: In the controlled phase, adults with HAE type I or II were randomized (1:1) to receive a single subcutaneous injection of icatibant 30 mg or placebo within 6 h of an attack becoming mild (laryngeal) or moderate (cutaneous/abdominal). Open-label icatibant was administered for severe laryngeal symptoms. In the open-label extension phase, patients could receive up to three icatibant injections per attack. Efficacy and safety were analyzed for the first five icatibant-treated attacks at any location (prospective analysis) and laryngeal attacks (post hoc analysis) across both phases. Efficacy outcomes were based on patient-reported symptom severity (visual analog scale). Results: In groups of patients with one to five icatibant-treated attacks at any location (n = 88), the median times to onset of symptom relief, onset of primary symptom relief and almost complete symptom relief were 1.9-2.1, 1.5-2.0 and 3.5-19.7 h, respectively. The same outcomes for laryngeal attacks (n = 25) were 1.0-2.0, 1.0-2.0 and 1.5-8.1 h, respectively. The most frequently reported adverse events were a worsening or recurrence of HAE attack, headache and nasopharyngitis. Two serious adverse events (arrhythmia and noncardiac chest pain) were considered to be related to icatibant. Conclusions: Icatibant was efficacious and generally well tolerated across multiple HAE attacks, including laryngeal attacks.

Keywords:
FAST-3, Hereditary angioedema, Icatibant, Laryngeal, Open-label extension, Abdominal, Acute treatment, C1-inhibitor deficiency, Cutaneous
1.
Bork K, Staubach P, Eckardt AJ, Hardt J: Symptoms, course, and complications of abdominal attacks in hereditary angioedema due to C1 inhibitor deficiency. Am J Gastroenterol 2006;101:619-627.
2.
Bork K, Siedlecki K, Bosch S, Schopf RE, Kreuz W: Asphyxiation by laryngeal edema in patients with hereditary angioedema. Mayo Clin Proc 2000;75:349-354.
3.
Bork K, Hardt J, Witzke G: Fatal laryngeal attacks and mortality in hereditary angioedema due to C1-INH deficiency. J Allergy Clin Immunol 2012;130:692-697.
4.
Cicardi M, Bergamaschini L, Cugno M, Beretta A, Zingale LC, Colombo M, Agostoni A: Pathogenetic and clinical aspects of C1 inhibitor deficiency. Immunobiology 1998;199:366-376.
5.
Cugno M, Nussberger J, Cicardi M, Agostoni A: Bradykinin and the pathophysiology of angioedema. Int Immunopharmacol 2003;3:311-317.
6.
Bork K: Diagnosis and treatment of hereditary angioedema with normal C1 inhibitor. Allergy Asthma Clin Immunol 2010;6:15.
7.
Cicardi M, Banerji A, Bracho F, et al: Icatibant, a new bradykinin-receptor antagonist, in hereditary angioedema. N Engl J Med 2010;363:532-541.
8.
Lumry WR, Li HH, Levy RJ, Potter PC, Farkas H, Moldovan D, Riedl M, Li H, Craig T, Bloom BJ, Reshef A: Randomized placebo-controlled trial of the bradykinin B2 receptor antagonist icatibant for the treatment of acute attacks of hereditary angioedema: the FAST-3 trial. Ann Allergy Asthma Immunol 2011;107:529-537.
9.
Malbrán A, Riedl M, Ritchie B, Smith WB, Yang W, Banerji A, Hébert J, Gleich GJ, Hurewitz D, Jacobson KW, Bernstein JA, Khan DA, Kirkpatrick H, Resnick D, Li H, Fernández Romero S, Lumry W: Repeat treatment of acute hereditary angioedema attacks with open-label icatibant in the FAST-1 trial. Clin Exp Immunol 2014;177:544-553.
10.
Bas M, Greve J, Hoffmann TK, Reshef A, Aberer W, Maurer M, Kivity S, Farkas H, Floccard B, Arcoleo F, Martin L, Sitkauskiene B, Bouillet L, Schmid-Grendelmeier P, Li H, Zanichelli A: Repeat treatment with icatibant for multiple hereditary angioedema attacks: FAST-2 open-label study. Allergy 2013;68:1452-1459.
11.
Cicardi M, Bork K, Caballero T, Craig T, Li HH, Longhurst H, Reshef A, Zuraw B; HAWK (Hereditary Angioedema International Working Group): Evidence-based recommendations for the therapeutic management of angioedema owing to hereditary C1 inhibitor deficiency: consensus report of an International Working Group. Allergy 2012;67:147-157.
12.
Craig T, Aygören-Pürsün E, Bork K, Bowen T, Boysen H, Farkas H, Grumach A, Katelaris CH, Lockey R, Longhurst H, Lumry W, Magerl M, Martinez-Saguer I, Ritchie B, Nast A, Pawankar R, Zuraw B, Maurer M: WAO guideline for the management of hereditary angioedema. World Allergy Organ J 2012;5:182-199.
13.
Banerji A: The burden of illness in patients with hereditary angioedema. Ann Allergy Asthma Immunol 2013;111:329-336.
14.
Lumry WR, Castaldo AJ, Vernon MK, Blaustein MB, Wilson DA, Horn PT: The humanistic burden of hereditary angioedema: impact on health-related quality of life, productivity, and depression. Allergy Asthma Proc 2010;31:407-414.
15.
Lumry WR, Bernstein JA, Li HH, MacGinnitie AJ, Riedl M, Soteres DF, Craig TJ, Campion M, Iarrobino R, Stolz LE, Pullman WE: Efficacy and safety of ecallantide in treatment of recurrent attacks of hereditary angioedema: open-label continuation study. Allergy Asthma Proc 2013;34:155-161.
16.
Craig TJ, Bewtra AK, Hurewitz D, Levy R, Janss G, Jacobson KW, Packer F, Bernstein JA, Rojavin MA, Machnig T, Keinecke HO, Wasserman RL: Treatment response after repeated administration of C1 esterase inhibitor for successive acute hereditary angioedema attacks. Allergy Asthma Proc 2012;33:354-361.
17.
Riedl MA, Levy RJ, Suez D, Lockey RF, Baker JW, Relan A, Zuraw BL: Efficacy and safety of recombinant C1 inhibitor for the treatment of hereditary angioedema attacks: a North American open-label study. Ann Allergy Asthma Immunol 2013;110:295-299.
18.
Li HH, Campion M, Craig TJ, Soteres DF, Riedl M, Lumry WR, MacGinnitie AJ, Shea EP, Bernstein JA: Analysis of hereditary angioedema attacks requiring a second dose of ecallantide. Ann Allergy Asthma Immunol 2013;110:168-172.
19.
Craig TJ, Bewtra AK, Bahna SL, Hurewitz D, Schneider LC, Levy RJ, Moy JN, Offenberger J, Jacobson KW, Yang WH, Eidelman F, Janss G, Packer FR, Rojavin MA, Machnig T, Keinecke HO, Wasserman RL: C1 esterase inhibitor concentrate in 1085 Hereditary Angioedema attacks - final results of the I.M.P.A.C.T.2 study. Allergy 2011;66:1604-1611.
20.
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.
21.
Longhurst HJ, Farkas H, Craig T, Aygören-Pürsün E, Bethune C, Bjorkander J, Bork K, Bouillet L, Boysen H, Bygum A, Caballero T, Cicardi M, Dempster J, Gompels M, Gooi J, Grigoriadou S, Huffer U, Kreuz W, Levi MM, Long J, Martinez-Saguer I, Raguet M, Reshef A, Bowen T, Zuraw B: HAE international home therapy consensus document. Allergy Asthma Clin Immunol 2010;6:22.
22.
Zuraw B, Banerji A, Bernstein JA, Busse PJ, Christiansen SC, Davis-Lorton M, Frank MM, Li HH, Lumry WR, Riedl M: US Hereditary Angioedema Association Medical Advisory Board 2013 recommendations for the management of hereditary angioedema due to C1 inhibitor deficiency. J Allergy Clin Immunol Pract 2013;1:458-467.
23.
Zuraw BL, Bernstein JA, Lang DM, Craig T, Dreyfus D, Hsieh F, Khan D, Sheikh J, Weldon D, Bernstein DI, Blessing-Moore J, Cox L, Nicklas RA, Oppenheimer J, Portnoy JM, Randolph CR, Schuller DE, Spector SL, Tilles SA, Wallace D; American Academy of Allergy, Asthma and Immunology; American College of Allergy, Asthma and Immunology: A focused parameter update: hereditary angioedema, acquired C1 inhibitor deficiency, and angiotensin-converting enzyme inhibitor-associated angioedema. J Allergy Clin Immunol 2013;131:1491-1493.
24.
Maurer M, Aberer W, Bouillet L, Caballero T, Fabien V, Kanny G, Kaplan A, Longhurst H, Zanichelli A; IOS Investigators: Hereditary angioedema attacks resolve faster and are shorter after early icatibant treatment. PLoS One 2013;8:e53773.
25.
Aberer W, Maurer M, Reshef A, Longhurst H, Kivity S, Bygum A, Caballero T, Bloom B, Nair N, Malbrán A: Open-label, multicenter study of self-administered icatibant for attacks of hereditary angioedema. Allergy 2014;69:305-314.
26.
Farkas H, Csuka D, Zotter Z, Varga L, Böröcz Z, Temesszentandrási G, Jakab L, Karádi I: Home treatment of hereditary angioedema with icatibant administered by health care professionals. J Allergy Clin Immunol 2012;129:851-852.
© 2015 S. Karger AG, Basel
2015
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.