Phase II study results of a replacement therapy for hereditary angioedema with subcutaneous C1-inhibitor concentrate
B L Zuraw, M Cicardi, H J Longhurst, J A Bernstein, H H Li, M Magerl, I Martinez-Saguer, S M M Rehman, P Staubach, H Feuersenger, R Parasrampuria, J Sidhu, J Edelman, T Craig, B L Zuraw, M Cicardi, H J Longhurst, J A Bernstein, H H Li, M Magerl, I Martinez-Saguer, S M M Rehman, P Staubach, H Feuersenger, R Parasrampuria, J Sidhu, J Edelman, T Craig
Abstract
Background: Hereditary angioedema (HAE) due to C1 inhibitor deficiency manifests as recurrent swelling attacks that can be disabling and sometimes fatal. Long-term prophylaxis with twice-weekly intravenous injections of plasma-derived C1-inhibitor (pdC1-INH) has been established as an effective treatment. Subcutaneous (SC) administration of pdC1-INH has not been studied in patients with HAE.
Methods: This open-label, dose-ranging, crossover study (COMPACT Phase II) was conducted in 18 patients with type I or II HAE who received two of twice-weekly 1500, 3000, or 6000 IU SC doses of highly concentrated volume-reduced CSL830 for 4 weeks each. The mean trough plasma levels of C1-INH functional activity, C1-INH and C4 antigen levels during Week 4, and overall safety and tolerability were evaluated. The primary outcome was model-derived steady-state trough C1-INH functional activity.
Results: After SC CSL830 administration, a dose-dependent increase in trough functional C1-INH activity was observed. C1-INH and C4 levels both increased. The two highest dose groups (3000 and 6000 IU) achieved constant C1-INH activity levels above 40% values, a threshold that was assumed to provide clinical protection against angioedema attacks. Compared with intravenous injection, pdC1-INH SC injection with CSL830 showed a lower peak-to-trough ratio and more consistent exposures. All doses were well tolerated. Mild-to-moderate local site reactions were noted with pain and swelling being the most common adverse event.
Conclusions: Subcutaneous volume-reduced CSL830 was well tolerated and led to a dose-dependent increase in physiologically relevant functional C1-INH plasma levels. A clinical outcome study of SC CSL830 in patients with HAE warrants further investigation.
Keywords: Berinert; C1-esterase inhibitor; hereditary angioedema; long-term prophylaxis; subcutaneous treatment.
© 2015 The Authors. Allergy Published by John Wiley & Sons Ltd.
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Source: PubMed