Hereditary angioedema (HAE) is a rare genetic disease that affects approximately 1 in 50,000 individuals worldwide, causing severe and potentially life-threatening swelling of the skin, gastrointestinal tract, and upper airway. Until recently, prophylactic treatment options have been limited to injectables, such as Cinryze and Takhzyro, which present patients with a significant treatment burden that drives the need for the development of oral drugs. HAE is caused primarily through deficiency or dysfunction of the C1 esterase inhibitor, an important physiological inhibitor of plasma kallikrein, a serine protease that mediates the cleavage of kininogen to generate the vasoactive peptide bradykinin. The development of potent and selective plasma kallikrein inhibitors represent a promising approach for the treatment of HAE. Here we report the discovery of an orally bioavailable, once-daily, small-molecule plasma kallikrein inhibitor, berotralstat (<b>BCX7353</b>), obtained through a structure-guided drug design strategy. Berotralstat (Orladeyo<sup>TM</sup>) has successfully completed a Phase III clinical trial, met its primary endpoint, and has recently received approvals from the US Food and Drug Administration (FDA) and the Ministry of Health, Labor and Welfare (MHLW) of Japan for the prophylactic treatment of HAE attacks in patients 12 years and older.

Discovery of a potent, selective, and oral plasma kallikrein inhibitor, berotralstat (BCX7353), as prophylactic treatment for hereditary angioedema (HAE)

ACS Fall 2021

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.