Garadacimab in hereditary angioedema due to normal C1INH with F12/PLG mutations.

Abstract

Hereditary angioedema (HAE) with normal C1 inhibitor (HAE-nC1INH), including HAE arising from F12 (HAE-FXII) or PLG (HAE-PLG) mutations, has a high unmet therapeutic need. Our aim was to explore long-term prophylaxis with monthly subcutaneous garadacimab (anti-activated factor XII mAb) in patients with HAE-FXII or HAE-PLG. Efficacy and safety were evaluated for HAE-FXII or HAE-PLG in open-label phase 2 (a 13-week treatment period [TP1] and subsequent ≥44-week extension period [TP2]; 600 mg of garadacimab during each period) and ongoing phase 3 open-label extension (OLE; garadacimab dose 200 mg) studies. Patients 1 and 2 (HAE-FXII) completed phase 2 and then continued into OLE (total exposure time 42.9 and 40.2 months, respectively); patient 3 (HAE-FXII) discontinued TP1 (because of lack of efficacy). Patients 4 to 6 (HAE-PLG) completed TP1 only. Patients 1 and 2 (HAE-FXII) had a reduction in monthly attack rate (AR) of 88% or more versus run-in during phase 2 (TP1 AR = 0.4 and 0.0 and TP2 AR= 0.1 and 0.2, respectively; run-in = 3.2 for both) and were attack-free during the OLE. The AR was increased for patients 4 and 5 (HAE-PLG) and reduced for patient 6 (HAE-PLG). During TP1, 4 of 6 patients (HAE-FXII [n = 2]; HAE-PLG [n = 2]) experienced treatment-emergent adverse events (TEAEs): patient 1 (HAE-FXII) experienced a garadacimab-related TEAE (mild injection-site reaction), and patient 3 (HAE-FXII) experienced an unrelated serious TEAE (severe HAE attack). Patients 1 and 2 (HAE-FXII) collectively experienced 13 mild or moderate TEAEs during TP2 and 2 mild TEAEs during the OLE. Garadacimab showed a favorable safety profile in all 6 patients with HAE-nC1INH. Garadacimab also demonstrated efficacy in 2 of the 3 patients with HAE-FXII; a reduction in AR was observed in 1 of the 3 patients with HAE-PLG.