Oral Sebetralstat for On-Demand Treatment of Hereditary Angioedema Attacks

To compare the efficacy and safety of up to 2 oral doses of sebetralstat (300 mg or 600 mg) compared with placebo for the treatment of hereditary angioedema (HAE) attacks.The study included 136 participants, at least 12 years of age or older, with type 1 or type 2 HAE. Participants had to have had at least 2 documented attacks within 3 months before screening or randomization and access to conventional on-demand therapy.The “KONFIDENT” study is a double-blind, randomized, placebo-controlled, 3-way crossover trial. For each eligible attack, participants were instructed to administer 300 mg of sebetralstat (plus one 300 mg placebo tablet), 600 mg of sebetralstat (two 300-mg tablets), or placebo (two 300 mg placebo tablets). The primary end point was the beginning of symptom relief, as measured using a 7-point (PGI-C) scale at 2 or more consecutive time points within 12 hours after administration of the trial agent. Key secondary endpoints assessed in a time-to-event analysis evaluated for reduction in the severity of the attack and complete resolution of the attack.There were 110 participants administered the assigned trial agent for at least one attack, with 264 attacks included in the analysis. The beginning of symptom relief was reached faster with the 300 mg and 600 mg doses of sebetralstat than with placebo (P < .001 and P = .0001 for comparisons with the 300 mg and 600 mg doses, respectively). The median time to the beginning of symptom relief was 1.61 hours with the 300 mg dose, 1.79 hours with the 600 mg dose, and 6.72 hours with placebo. A reduction in the severity of the attack within 12 hours after the first administration of trial agent was reached faster with the 300 mg and the 600 mg dose than placebo. The percentage of attacks with complete resolution within 24 hours after the first administration of trial agent was 42.5% with the 300 mg dose, 49.5% with the 600 mg dose, and 27.4% with placebo. The observed safety profile of sebetralstat was no different from that of placebo.Sebetralstat administered orally at doses of 300 mg or 600 mg for the on-demand treatment of HAE attacks is superior to placebo and resulted in a faster time to symptom relief, reduction in severity of episodes, and increased percentage of attacks, with complete resolution within 24 hours of administration of trial agent.All first-line on-demand treatment options for HAE attacks are administered parentally, which can introduce barriers to rapid administration of drug. With a median time to treatment of 41 minutes, this oral treatment option is an efficacious and safe treatment option for HAE patients, which can improve prompt treatment of attacks.