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, Huamin Li, M. Magerl, I. Martinez-Saguer, S. M M Rehman, P. Staubach, H. Feuersenger, R. Parasrampuria, J. Sidhu, J. Edelman, T. Craig

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1319-1328
Number of pages10
JournalAllergy: European Journal of Allergy and Clinical Immunology
Volume70
Issue number10
DOIs
StatePublished - Oct 1 2015
Externally publishedYes

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Hereditary Angioedemas
Intravenous Injections
Hereditary Angioedema Types I and II
Therapeutics
Angioedema
Subcutaneous Injections
Cross-Over Studies
Outcome Assessment (Health Care)
Safety
Antigens
Pain

Keywords

  • Berinert
  • C1-esterase inhibitor
  • hereditary angioedema
  • long-term prophylaxis
  • subcutaneous treatment

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

Phase II study results of a replacement therapy for hereditary angioedema with subcutaneous C1-inhibitor concentrate. / Zuraw, B. L.; Cicardi, M.; Longhurst, H. J.; Bernstein, J. A.; Li, Huamin; Magerl, M.; Martinez-Saguer, I.; Rehman, S. M M; Staubach, P.; Feuersenger, H.; Parasrampuria, R.; Sidhu, J.; Edelman, J.; Craig, T.

In: Allergy: European Journal of Allergy and Clinical Immunology, Vol. 70, No. 10, 01.10.2015, p. 1319-1328.

Research output: Contribution to journalArticle

Zuraw, BL, Cicardi, M, Longhurst, HJ, Bernstein, JA, Li, H, Magerl, M, Martinez-Saguer, I, Rehman, SMM, Staubach, P, Feuersenger, H, Parasrampuria, R, Sidhu, J, Edelman, J & Craig, T 2015, 'Phase II study results of a replacement therapy for hereditary angioedema with subcutaneous C1-inhibitor concentrate', Allergy: European Journal of Allergy and Clinical Immunology, vol. 70, no. 10, pp. 1319-1328. https://doi.org/10.1111/all.12658
Zuraw, B. L. ; Cicardi, M. ; Longhurst, H. J. ; Bernstein, J. A. ; Li, Huamin ; Magerl, M. ; Martinez-Saguer, I. ; Rehman, S. M M ; Staubach, P. ; Feuersenger, H. ; Parasrampuria, R. ; Sidhu, J. ; Edelman, J. ; Craig, T. / Phase II study results of a replacement therapy for hereditary angioedema with subcutaneous C1-inhibitor concentrate. In: Allergy: European Journal of Allergy and Clinical Immunology. 2015 ; Vol. 70, No. 10. pp. 1319-1328.
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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.",
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T1 - Phase II study results of a replacement therapy for hereditary angioedema with subcutaneous C1-inhibitor concentrate

AU - Zuraw, B. L.

AU - Cicardi, M.

AU - Longhurst, H. J.

AU - Bernstein, J. A.

AU - Li, Huamin

AU - Magerl, M.

AU - Martinez-Saguer, I.

AU - Rehman, S. M M

AU - Staubach, P.

AU - Feuersenger, H.

AU - Parasrampuria, R.

AU - Sidhu, J.

AU - Edelman, J.

AU - Craig, T.

PY - 2015/10/1

Y1 - 2015/10/1

N2 - 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.

AB - 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.

KW - Berinert

KW - C1-esterase inhibitor

KW - hereditary angioedema

KW - long-term prophylaxis

KW - subcutaneous treatment

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