An investigational RNAi therapeutic targeting Factor XII (ALN-F12) for the treatment of hereditary angioedema

Abstract Hereditary angioedema (HAE) is a genetic disorder caused by a defect in the C1-inhibitor gene that results in poor control of contact pathway activation and bradykinin generation. Excessive bradykinin generation increases vascular permeability and is ultimately responsible for the episodes of swelling characteristic of HAE. We hypothesized that the use of RNA interference (RNAi) to knockdown Factor XII, which lies atop the contact pathway signaling cascade, would reduce contact pathway activation and prevent excessive bradykinin generation. To this end, a subcutaneously administered investigational RNAi therapeutic targeting F12 mRNA (ALN-F12) was developed and evaluated in mice and non-human primates. Administration of ALN-F12 resulted in dose-dependent reduction of vascular permeability in two different mouse models of bradykinin-driven vascular permeability, demonstrating that Factor XII knockdown can mitigate excess bradykinin stimulation. In Cynomolgus monkeys, single dose administration of ALN-F12 at 3 mg/kg resulted in >85% reduction of Factor XII. Further, Factor XII knockdown was durable with greater than 70% and 50% reduction at 2 and 3 months post-dose, respectively. Together, these data suggest that RNAi-mediated knockdown of Factor XII is a potentially promising approach for the prophylactic treatment of HAE.