title: Phase II study results of a replacement therapy for hereditary angioedema with subcutaneous C1-inhibitor concentrate.
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.
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
authors.forename: B L
authors.initials: BL
authors.lastname: Zuraw
authors.affiliation: Department of Internal Medicine, Universita degli Studi di Milano, Ospedale L. Sacco, Milan, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Cicardi
authors.affiliation: Department of Immunology, Barts Health NHS Trust, London, UK.
authors.forename: H J
authors.initials: HJ
authors.lastname: Longhurst
authors.affiliation: Department of Immunology/Allergy, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Bernstein
authors.affiliation: Institute for Asthma and Allergy, Chevy Chase, MD, USA.
authors.forename: H H
authors.initials: HH
authors.lastname: Li
authors.affiliation: Charité, Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Magerl
authors.affiliation: HZRM Haemophilia Centre Rhine Main, Mörfelden-Walldorf, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Martinez-Saguer
authors.affiliation: Toledo Institute Asthma and Allergy Center, Toledo, OH, USA.
authors.forename: S M M
authors.initials: SM
authors.lastname: Rehman
authors.affiliation: University Medical Center, Mainz, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Staubach
authors.affiliation: CSL Behring GmbH, Marburg, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Feuersenger
authors.affiliation: CSL Behring, King of Prussia, PA, USA.
authors.forename: R
authors.initials: R
authors.lastname: Parasrampuria
authors.affiliation: CSL Limited, Parkville, Vic., Australia.
authors.forename: J
authors.initials: J
authors.lastname: Sidhu
authors.affiliation: CSL Behring, King of Prussia, PA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Edelman
authors.affiliation: Departments of Medicine and Pediatrics, Penn State University, Hershey, PA, USA.
authors.forename: T
authors.initials: T
authors.lastname: Craig
mesh_terms: D000328:Adult; D054179:Angioedemas, Hereditary / Q000188:drug therapy* / Q000276:immunology; D050718:Complement C1 Inhibitor Protein / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007279:Injections, Subcutaneous; D008297:Male; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D050718:Complement C1 Inhibitor Protein
keywords: Berinert; C1-esterase inhibitor; hereditary angioedema; long-term prophylaxis; subcutaneous treatment