1. The self-administered, subcutaneous C1-inhibitor CSL830 demonstrated a dose-dependent high efficacy in the prophylactic treatment of hereditary angioedema (HAE) attacks compared to placebo.
2. CSL830 was well-tolerated and not associated with significant adverse events.
Evidence Rating Level: 1 (Excellent)
HAE is a rare genetic disorder resulting from a deficiency (type 1) or dysfunction (type II) of C1INH. Although the characteristic attacks of skin and mucosal swelling spontaneously resolve, these episodes are disabling and potentially life-threatening. Current prophylactic treatment for acute HAE is limited to regular intravenous C1 inhibitor replacement and is therefore associated with the risks of regular venous access and indwelling catheterization. This trial examined the efficacy and safety of a subcutaneously injected, nanofiltered C1 inhibitor (CSL830) for the prevention of angioedema at two different doses. The primary end point – the number of angioedema attacks – was significantly reduced at both CSL830 40 and 60 IU/kg doses compared to placebo. Among secondary endpoints, the percentage of patients that demonstrated a response to CSL830 treatment was significantly increased and the number of times rescue medication was needed for an acute attack was significantly reduced with CSL830. The most common adverse effect with CSL830 and placebo was mild injection site reactions and no other significant adverse events were reported with CSL830. The results suggest that CSL830 may be an effective prophylactic agent for HAE to overcome the technical challenges and associated risks of current intravenous therapy.
This was a multicenter, randomized, double-blind, placebo controlled, and dose-ranging trial. A crossover design was used for the four treatment arms and high and low volume placebos were used to maintain blinding. An observation period of 14 weeks would be considered a limitation because it may have prevented assessment of potential long-term adverse effects.
In-Depth [randomized controlled trial]: This multicenter, double-blind, dose-ranging trial randomized 90 patients to one of four treatments in a crossover design: 16-week treatment with 40IU/kg or 60IU/kg CSL830 twice-weekly followed by 16-week treatment with placebo, or placebo followed by CSL830. 79 patients completed the study. The primary end point was the time-normalized number of HAE attacks. Secondary efficacy end points included the percentage of responders to CSL830 (defined as >50% reduction in time-normalized HAE attacks versus placebo) and time-normalized number of rescue medications needed. Adverse events were monitored throughout the study period.
CSL830 resulted in a mean difference of -2.42 with 40 IU/kg (95%CI -3.38 to -1.46; p < 0.001) and -3.51 with 60 IU/kg (95%CI -4.21 to -2.81; p < 0.001) attacks per month compared to placebo. Response rates were 76% (95%CI 62 to 87) and 90% (95%CI 77 to 96) for 40 IU/kg and 60 IU/kg, respectively. The mean number of times rescue medication was needed was 1.13 (95%CI -1.44 to 3.69) for 40 IU/kg and 0.32 (95%CI -0.33 to 0.97) for 60 IU/kg, both significantly reduced compared to placebo (p < 0.001). No significant difference in adverse events was reported. The most common adverse event was injection site reactions (31% with CSL830, 24% with placebo). No viral seroconversions were observed during the trial. The trial’s observational period was 14 weeks for each treatment period which made assessment of the safety and preventative effects of long-term continuous prophylaxis with CSL830 difficult.
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