Reviewed by Dr. Nimish Shah
Longhurst H, et al. N Engl J Med 2017;376:1131-40

Hereditary angioedema is a rare condition characterized by potentially fatal episodic attacks of localized swelling without urticaria or pruritus. It is caused by deficiency or dysfunction of the C1 inhibitor protein, promoting bradykinin-mediated capillary hyperpermeability. Current standard prophylaxis is replacement with intravenous C1 inhibitor, which is effective at reducing the frequency and severity of attacks, but carries several risks and burdens associated with requiring reliable intravenous access, including infection, thrombosis, and phlebitis.

The Clinical Study for Optimal Management of Preventing Angioedema with Low-Volume Subcutaneous C1-Inhibitor Replacement Therapy (COMPACT) study was a phase 3, international, prospective, double-blind, randomized controlled trial that tested whether subcutaneous CSL830, a human plasma-derived C1 inhibitor preparation, could reduce the frequency of attacks in patients with angioedema when compared with placebo. The trial recruited individuals diagnosed with hereditary angioedema with significant functional impairment not already receiving IV C1 inhibitor. Participants were randomized to receive either 40 IU per kilogram body weight or 60 IU per kilogram body weight of CSL830 twice weekly for 16 weeks followed by placebo for 16 weeks or vice versa in an intention-to-treat analysis. The primary endpoint was the number of angioedema attacks per treatment period, while secondary endpoints included the percentage of participants with >50% reduction in the number of attacks and the number of times rescue medication was used.

The mean difference in attacks compared with placebo was 2.42 fewer attacks per month with 40 IU CSL830 and 3.51 fewer attacks per month with 60 IU CSL830. While the rate of attacks did not differ significantly between the two doses, the percentage who had a response was greater in the 60 IU group (90% vs 76%). The severity of attacks was also lower than in those receiving placebo. The mean frequency of rescue medication use was reduced compared to placebo. Strikingly, nearly 40% of participants in each CSL830 group did not have an attack, compared with up to 9% of participants in the placebo groups. Most adverse events were mild, and only one serious adverse event occurred – urosepsis in a patient receiving the 40-IU dose.

Given the rarity of this disease, the present study demonstrates considerable efficacy of subcutaneous C1 inhibitor in reducing attack rate and severity with a high response rate, comparable to that of IV C1 inhibitor. However, the follow up period is too limited to remark on long term adverse events or sustained efficacy. Further, the doses used in the present study are 3-4 times greater than the 1000IU twice weekly dose of IV C1 inhibitor, suggesting costs would be even higher than that of IV C1 inhibitor which already costs over $4000 per dose. While subcutaneous administration offers the potential for increased accessibility, the novelty and associated cost may make it very difficult to offer to patients.