Summary of the Clinical Data Of Subcutaneous C1-Inhibitor For Prophylaxis of Hereditary Angioedema
Hereditary Angioedema (HAE) is a potentially fatal medical condition characterized by attacks of angioedema without pruritus or urticaria. It is caused by deficiency of (type I) or dysfunction of (type II) C1 inhibitor. The abnormally low function of C1-inhibitor (C1-INH) leads to increase bradykinin level resulting in increase hyper-permeability leading to episodes of edema and swelling.These episodes are known clinically as angioedema attacks. Diagnosis of (HAE) is based on low levels of C1 inhibitor protein antigen or low functional level of C1-INH activity and also low level of complement C4. According to studies C1-INH levels above a threshold level of 40% of C1 INH protein can give protection against attacks of (HAE).1
Presently, patients with HAE can be treated with “on demand therapy” (treatment of attacks) or prophylaxis. Approved therapies for on demand therapy are intravenous C1-INH (both human derived and recombinant), subcutaneous kallikrein inhibitor, subcutaneous B2 bradykinin inhibitor and anti fibrinolytic drugs. Before the recent approval of the therapy discussed the drugs available for prophylaxis included intravenous C1-INH, androgen and anti fibrinolytics. The concern for prophylaxis with the above drugs is toxicity associated with androgens, intravenous injection for C1-INH and limited efficacy of anti- fibrinolytics.2
In previous studies with intravenous C1 inhibitor 1000 units twice weekly has showed 50 % reduction in the frequency and the severity of the attack.3
A phase 2 trial has demonstrated that administration of CSL830, a C1-INH preparation suitable for subcutaneous injection, can increase plasma level of C1-INH protein above 40%, which will be very useful in the prophylaxis of attacks.
The study was an international, perspective, multicenter, randomized, double-blind, placebo-controlled, dose- ranging, phase 3 trial to evaluate the efficacy and safety of self-administered subcutaneous CSL830 in patients with type1 or type 2 (HAE) who had had four or more attacks in a consecutive 2-month period within 3 months before screening. They randomly assigned the patients to one of four treatment sequences in a crossover design, each involving two 16-week treatment periods: either 40 IU or 60 IU of CSL830 per kilogram of body weight twice weekly followed by placebo, or vice versa. The primary efficacy end point was the number of attacks of angioedema. Secondary efficacy end points were the proportion of patients who had a response (≥50% reduction in the number of attacks with CSL830 as compared with placebo) and the number of times that rescue medication was used.4
The Study demonstrated that both doses of CSL830 reduced the attacks of HAE. Response rates were 76% in the 40 IU group and 90% in the 60 IU group.The need for rescue medication was reduced from 5.55 uses per month in the placebo group to 1.13 uses per month in the 40-IU group and from 3.89 uses in the placebo group to 0.32 uses per month in the 60-IU group. Adverse events are most commonly mild and transient local reactions.4
In conclusion, administration of CSL830 twice weekly at doses 40 IU per kilogram or 60 IU per kilogram has a significant preventive effect and was associated with reduced need for rescue medication . Side effects were minimal and many limited to injection side reaction. Lastly, there appears to be a correlation between suppression of attacks and levels of C1-INH and at 60 units/kg C1-INH levels are often within normal levels.
- Zuraw B, Cicardi M, Longhurt H et al. Prevention of hereditary angioedema attacks with a subcutaneous inhibitor. Allergy. 2015; 70 (10):1319-28.
- Craig T, Aygören-pürsün E, Bork K et al. WAO Guidlines for the management of hereditary angioedema. World Allergy Organ J. 2012; 5(12):182-99. 23282420.
- Zuraw B, Busse PJ, White M et al. Safety and efficacy of nanofiltered C1-Inhibitor concentrate for acute and prophylactic treatment of hereditary angioedema due to C1 Inhibitor deficiency. New Engl J Med. 2010;363:513-22.
- Longhurst H, Cicardi M, Craig T at al. Prevention of hereditary anagioedema attacks with a subcutaneous inhibitor. N Engl J Med. 2017;376 (12):1131-1140.