A phase I study of recombinant human C1 inhibitor in asymptomatic patients with hereditary angioedema

Background: Hereditary angioedema (HAE) is a congenital disorder with recurrent attacks of localized swelling of submucosal tissue, subcutaneous tissue, or both caused by a deficiency of the plasma protein C1 inhibitor (C1 esterase inhibitor [C1INH]). Objective: We sought to evaluate the effects of recombinant human C1INH (rhC1INH) isolated from the milk of transgenic rabbits in 12 asymptomatic patients with HAE. Methods: rhC1INH was intravenously administered at doses of 6.25 to 100 U/kg on 2 occasions. Results: rhC1INH appeared safe and was well tolerated. The course of functional C1INH in plasma showed a full initial recovery (dose-normalized maximum concentration of about 0.02 U/mL/U/kg) and a dose-dependent clearance of rhC1INH. After infusion of rhC1INH at 100 U/kg, a clearance of approximately 13 mL/min, a half-life of approximately 3 hours, and a volume of distribution of approximately 3 L were observed. Infusion at this dose led to functional C1INH levels in plasma of at least twice the normal level for about 2 hours and greater than 0.4 U/mL for about 9 hours. rhC1INH displayed dose-dependent biologic activity by increasing the C4 level, which was about 2-fold at 12 hours after rhC1INH at 100 U/kg, and decreasing levels of cleaved C4. Conclusion: The observed safety profile and biologic activity of rhCIINH warrants further clinical studies to assess its efficacy in treating HAE attacks.