Effect of Lanadelumab on Coagulation Parameters in Patients With Hereditary Angioedema: Findings From The Phase 3 HELP Study

Hereditary angioedema (HAE) results from a deficiency of C1 esterase inhibitor, allowing for excessive conversion of prekallikrein (PK) into plasma kallikrein. Lanadelumab specifically inhibits plasma kallikrein, and prevented HAE attacks in the HELP Study (NCT02586805). Plasma kallikrein contributes to the aPTT coagulation test; therefore, a prolonged aPTT is an expected effect of lanadelumab. No effect on prothrombin time (PT) is expected. We evaluated the effects of lanadelumab on coagulation parameters in HAE patients. Patients ≥12 years old with type I/II HAE and ≥1 attack during a 4-week run-in received subcutaneous lanadelumab 150mg q4wks, 300mg q4wks, 300mg q2wks, or placebo over 26 weeks. Coagulation testing was performed at screening and throughout the study using standard laboratory tests. Lanadelumab reduced plasma kallikrein activity (indicated by cleaved high molecular weight kininogen; cHK) by mean±SD 31.9%±37.6–48.2%±19.3 from baseline to Day 182. At baseline, mean±SD (range) aPTT was 28.21±3.013s (22.2-34.1), 28.46±4.066s (19.6-37.2), and 28.61±5.465s (20.0-42.3) in the lanadelumab 150mgq4wks, 300mgq4wks, 300mgq2wks groups vs 28.38±3.835s (24.3-40.5) for placebo. At Day 182, mean±SD (range) aPTT was 30.60±3.013s (25.5-35.3), 34.06±4.979s (27.0-46.8), and 35.26±4.764s (26.9±44.3) with increasing lanadelumab doses vs 27.15±2.857s (21.4-33.9) with placebo. These data show the prolongation in aPTT assay with lanadelumab as expected. PT was not altered. These data indicate that lanadelumab prolonged aPTT in treated groups, but not outside the normal range and with no association with abnormal bleeding events. Based on these data, lanadelumab inhibition of plasma kallikrein activity is sufficient for effective HAE prophylaxis without alteration of hemostasis or thrombosis in vivo.