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.

Keywords: Berinert; C1-esterase inhibitor; hereditary angioedema; long-term prophylaxis; subcutaneous treatment.

Figure 1

Study schema. (A) Dosing scheme and sample collection during the study, (B)  = single dose of IV C1‐INH;  = single dose of subcutaneous (SC) CSL830;  = assessment of C1‐INH functional activity and plasma C1‐INH and C4 antigen concentrations;  = additional assessments of plasma C1‐INH functional activity.

Figure 2

Pharmacokinetic (PK) results. Modeled steady‐state trough C1‐INH functional activity (primary endpoint; red rectangles) and as‐observed C1‐INH functional activity (black triangles). Data points show the mean and 95% CI.

Figure 3

Final population pharmacokinetic (PK) model of as‐observed C1‐INH functional activity vs individual predictions of C1‐INH functional activity. The line of identity (solid red) is included as a reference.

Figure 4

Modeled biweekly C1‐INH functional activity after IV administration of (A) a therapeutic dose of 1000 IU pdC1‐INH concentrate, or subcutaneous (SC) administration of (B) 1500 IU, (C) 3000 IU, or (D) 6000 IU of CSL830. Median functional activity (solid lines), 5th and 95th percentiles (shaded areas) and 40% C1‐INH functional activity (dashed black line) are shown.