1. An oral dose of sebetralstat increased the time to conventional treatment use and lead to faster symptom relief in acute hereditary angioedema attacks compared to control.
2. Sebetralstat was well tolerated and was demonstrated to rapidly reduce activity of plasma kallikrein.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Hereditary angioedema is a rare disease that causes episodic attacks of tissue swelling. Current treatments include on-demand and prophylactic medications, but these are parenterally administered. This phase 2 drug study aims to evaluate the use of an oral plasma kallikrein inhibitor, sebetralstat, for the on-demand treatment of angioedema attacks. This study had two parts. Part 1 was a safety, pharmacokinetics, and pharmacodynamics assessment where all enrolled patients received the study drug of 600 mg oral sebetralstat after the screening. The drug was found to be well tolerated and led to rapid suppression of plasma kallikrein activity. In Part 2, the participants were randomized to either sequence 1 (sebetralstat, then placebo) or sequence 2 (placebo, then sebetralstat). In summary, the time to conventional treatment usage within 12 h of the study drug administration was significantly longer with sebetralstat versus placebo. In addition, symptom relief was much faster with the use of sebetralstat versus placebo. There were no serious adverse events. Limitations of this study include the within-participant dependence of endpoints due to the crossover. Nevertheless, this study shows promising early results for the safety and efficacy of sebetralstat. A larger confirmatory phase 3 trial is currently underway.
Click to read the study in The Lancet
In-Depth [randomized controlled trial]: This international phase 2 drug trial evaluated the use of a novel oral plasma kallikrein inhibitor, sebetralstat, for the on-demand treatment of acute flares of hereditary angioedema. Eligible participants were aged over 18 years old and had a confirmed diagnosis of hereditary angioedema type 1 or 2 with three or more attacks in the past 93 days. Life-threatening attacks, such as laryngeal or facial attacks, were also excluded due to safety. The mean age of the enrolled participants (n=68) was 38.3 years and 54% were female. In part 1, all participants were given sebetralstat as a single oral dose within 28 days of their screening visit. In part 2, participants were randomized 1:1 to either sequence 1 (600 mg sebetralstat, then placebo) or sequence 2 (placebo, then 600 mg sebetralstat). For example, in sequence 1, patients were to self-administer 600 mg sebetralstat after their first attack and placebo after their second attack. The primary endpoint for part 2 was time to use of conventional attack treatment within 12 h of study drug administration.
Part 1 was a safety, pharmacokinetics, and pharmacodynamics assessment which 42 (62%) of 68 participants completed. The drug was well tolerated and demonstrated evidence of rapid suppression of plasma kallikrein activity. In part 2, the time to use conventional treatment was significantly longer with sebetralstat versus placebo (at quartile 1: >12 h [95% CI 9.6 to >12] versus 8.0 h [3.8 to >12]; p=0.0010). Time to symptom relief was additionally faster with sebetralstat compared to placebo (1.6 h [1.5 to 3.0] versus 9.0 h [4.0 to 17.2]; p<0.0001). No drug-related serious adverse events or discontinuations were recorded.
Image: PD
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