Table 3: A Summary of the Published Clinical trials of Recombinant Human C1-inhibitor in Patients with Hereditary Angioedema
Study Aims Phase
I Study the blood levels of functional
C1INH after various doses of recombinant human C1INH
Test the ability of recombinant human C1INH to relieve acute HAE attacks
Participants Recombinant Results
Human C1INH Dose (U/kg)
asymptomatic 50, 100 adults with HAE
treated for 13 acute HAE attacks
European and North American studies Evaluate safety and efficacy of
recombinant human C1INH for treating acute HAE attacks relative to saline placebo
70 adults with HAE
50, 100 100
6.25, 12.5, 25, 50 and 100U/kg doses of recombinant human Van Doorn C1INH increased functional C1INH to a level sufficient to restore normal physiological function
All doses were well tolerated
Median (range) time to initial symptom relief* Choi et al., of 0.5 (0.25–12) hours and to minimal symptoms† of 8 (0.25–48) hours
100U/kg of recombinant human C1INH was well tolerated
50 and 100U/kg doses of recombinant human Zuraw et al., C1INH significantly reduced both the time to 201027 relief of symptoms* and the time to minimal
symptoms† versus placebo (all p<0.05) 50 and 100U/kg doses of recombinant human C1INH were well tolerated
*Initial symptom relief was defined as a reduction of at least 20mm on the Visual Analog Scale (VAS); †Minimal symptoms were defined as a VAS score <20mm. C1INH = C1-inhibitor; HAE = hereditary angioedema.
of acute HAE attacks.23,27 This approval of rhC1INH has provided
patients in Europe with an alternative treatment option to plasma-derived C1INH, with better purity and batch consistency and no risk of human virus transmission.8
It also provides patients with a
dose-optimised treatment: the 20U/kg recommended dose of plasma-derived C1INH was the highest dose tested in randomised controlled trials, whereas the 50U/kg dose approved for rhC1INH has now been shown to provide optimal efficacy.
Indeed, 50U/kg of rhC1INH has a higher therapeutic success rate than 20U/kg of plasma-derived C1INH (Berinert), with 95%, rather than 69.8%, of attacks showing symptom relief within four hours of treatment.8,28
1. Bork K, Meng G, Staubach P, Hardt J, Hereditary angioedema: new findings concerning symptoms, affected organs, and course, Am J Med, 2006;119(3):267–74.
2. Cicardi M, Zanichelli A, Angioedema due to C1 inhibitor deficiency in 2010, Intern Emerg Med, 2010;5(6):481–6.
3. Cicardi M, Agostoni A, Hereditary angioedema, N Engl J Med, 1996;334(25):1666–7.
4. Roche O, Blanch A, Caballero T, et al., Hereditary angioedema due to C1 inhibitor deficiency: patient registry and approach to the prevalence in Spain, Ann Allergy Asthma Immunol, 2005;94(4):498–503.
5. Zuraw BL, Clinical practice. Hereditary angioedema, N Engl J Med, 2008;359(10):1027–36.
6. Prematta MJ, Kemp JG, Gibbs JG, et al., Frequency, timing, and type of prodromal symptoms associated with hereditary angioedema attacks, Allergy Asthma Proc, 2009;30(5):506–11.
7. Kusuma A, Relan A, Haase G, et al., Clinical value for the treatment with rhC1-INH of patients with hereditary angioedema (HAE) suffering from an acute peripheral angioedema attack, Allergy, 2010;65(s92):1182.
8. Longhurst H, Rhucin, a recombinant C1 inhibitor for the treatment of hereditary angioedema and cerebral ischemia, Curr Opin Investig Drugs, 2008;9(3):310–23.
9. Cugno M, Zanichelli A, Foieni F, et al., C1-inhibitor deficiency and angioedema: molecular mechanisms and clinical progress, Trends Mol Med, 2009;15(2):69–78.
10. Kaplan AP, Ghebrehiwet B, The plasma bradykinin-forming pathways and its interrelationships with complement, Mol Immunol, 2010;47(13):2161–9.
11. Bowen T, Cicardi M, Farkas H, et al., 2010 International Conclusion
HAE is a potentially life-threatening condition, with common delays in diagnosis and inappropriate treatment due to the rarity of the disease and low physician awareness. rhC1INH (Ruconest) is an alternative replacement C1INH treatment for acute HAE attacks, which provides patients with both efficacy and safety benefits.25,28
approved dose of rhC1INH has shown improved therapeutic success relative to 20U/kg of C1INH in the treatment of acute HAE attacks, and avoids the risk of human virus transmission. All patients receiving rhC1INH treatment will receive a patient information card, both as a record of their treatment history, but also to increase physician awareness of HAE and help ensure that patients receive appropriate care and treatment when they experience an attack. n
consensus algorithm for the diagnosis, therapy and management of hereditary angioedema, Allergy Asthma Clin Immunol, 2010;6(1):24.
12. Prematta M, Gibbs JG, Pratt EL, et al., Fresh frozen plasma for the treatment of hereditary angioedema, Ann Allergy Asthma Immunol, 2007;98(4):383–8.
13. Nzeako UC, Frigas E, Tremaine WJ. Hereditary angioedema: a broad review for clinicians, Arch Intern Med, 2001;161(20):2417–29.
14. FDA. Approval Letter – Berinert. 2009. Available at: www.fda.gov/BiologicsBloodVaccines/BloodBloodProducts/A
m (accessed January 2011).
15. 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(4):801–8.
16. Longhurst HJ, Management of acute attacks of hereditary angioedema: potential role of icatibant, Vasc Health Risk Manag, 2010;6:795–802.
17. Stolz LE, Horn PT, Ecallantide: a plasma kallikrein inhibitor for the treatment of acute attacks of hereditary angioedema, Drugs Today (Barc), 2010;46(8):547–55.
18. Longhurst HJ, Carr S, Khair K, C1-inhibitor concentrate home therapy for hereditary angioedema: a viable, effective treatment option, Clin Exp Immunol, 2007;147(1):11–7.
19. Longhurst HJ, Farkas H, Craig T, et al., HAE international home therapy consensus document, Allergy Asthma Clin Immunol, 2010;6(1):22.
20. Kreuz W, Martinez-Saguer I, Aygoren-Pursun E, et al., C1-inhibitor concentrate for individual replacement therapy
in patients with severe hereditary angioedema refractory to danazol prophylaxis, Transfusion, 2009;49(9):1987–95.
21. Zuraw BL, Busse PJ, White M, et al., Nanofiltered C1 inhibitor concentrate for treatment of hereditary angioedema, N Engl J Med, 2010;363(6):513–22.
22. FDA. Approval Letter – Cinryze. 2008. Available at: www.fda.gov/BiologicsBloodVaccines/BloodBloodProducts/A
m (accessed January 2011).
23. van Doorn MB, Burggraaf J, van Dam T, et al., A phase I study of recombinant human C1 inhibitor in asymptomatic patients with hereditary angioedema, J Allergy Clin Immunol, 2005;116(4):876–83.
24. Cugno M, Nuijens J, Hack E, et al. Plasma levels of C1- inhibitor complexes and cleaved C1- inhibitor in patients with hereditary angioneurotic edema, J Clin Invest, 1990;85(4):1215–20.
25. Ruconest Summary of Product Characteristics, 2010. Available at: www.ema.europa.eu/docs/en_GB/document
_library/EPAR_-_Product_Information/human/001223/ WC500098542.pdf (accessed December 2010).
26. Choi G, Soeters MR, Farkas H, et al., Recombinant human C1-inhibitor in the treatment of acute angioedema attacks, Transfusion, 2007;47(6):1028–32.
27. Zuraw B, Cicardi M, Levy RJ, et al., Recombinant human C1- inhibitor for the treatment of acute angioedema attacks in patients with hereditary angioedema, J Allergy Clin Immunol, 2010;126(4):821–7 e14.
28. Berinert® C1 Esterase Inhibitor (Human) US Package Insert. Revised: November 2009. Available at: www.be
rinert .com/docs/Berinert_pi.pdf (accessed December 2010).
et al., 200523 Reference
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