Table 1.

Lanadelumab characterization based on preclinical and phase I studies

Preclinical [50]	Phase Ia [72]	Phase Ib [82]
Fully human monoclonal antibody (IgG1, kappa light chain) [72] Expressed from Chinese hamster ovary cells [72] Highly potent (Ki = 125 pM in vitro) [72] Binds to active site of plasma kallikrein Binds free soluble plasma kallikrein, as well as plasma kallikrein bound to HMWK Fully occludes the prekallikrein active site PK/PD in cynomolgus monkeys  Inhibits plasma kallikrein-mediated proteolysis of HMWK   Inhibition of active plasma kallikrein is highly specific  High bioavailability (66%) and prolonged serum half-life in cynomolgus monkeys (~ 12.5 and ~ 19.3 days post single SC or IV dose, respectively); in humans, the equivalent half-life is ≥ 2 weeks In vivo efficacy in carrageenan induced paw edema model  Dose dependently inhibited induction of paw edema with SC administration  Lanadelumab 30 mg/kg reduced paw edema by 55.6% 8 h after dosing compared with vehicle	Randomized, double-blind single-center study evaluating a single SC administration of one of the following four sequential lanadelumab doses in patients with HAE: 0.1, 0.3, 1.0, or 3.0 mg/kg 32 eligible subjects were randomized (24 received lanadelumab, eight received placebo) Safety  No serious TEAEs or deaths or clinically significant changes in vital signs or laboratory measures; headache was most commonly reported TEAE  No antidrug antibodies in participants treated with lanadelumab PK/PD profile  Dose-proportional drug exposure and consistent mean elimination half-life regardless of dose (range 16.8–21.2 days)  Long-lasting dose-dependent inhibition of plasma kallikrein activity with the 1.0- and 3.0-mg/kg doses	Randomized, multicenter, double-blind, placebo-controlled, multiple ascending dose study in patients with C1-INH-HAE  Patients received two doses, 14 days apart 37 patients were randomized (24 received lanadelumab, 13 received placebo) Safety  Most common AE in the lanadelumab vs. placebo groups was injection-site pain and headache  No AE-related deaths or discontinuations, serious AEs, or clinically meaningful changes in vital signs or laboratory measures  Antidrug antibodies developed in two patients; both were non-neutralizing and did not impact the PK/PD profiles of lanadelumab PK/PD profile  Dose-proportional drug exposure and consistent mean elimination half-life regardless of dose (13.8–15.0 days)  Significant decreases in cleaved HMWK plasma levels (compared with predose levels) with lanadelumab 300- and 400-mg doses on days 8 and 22  Dose-dependent inhibition of plasma kallikrein with the 100-, 300-, and 400-mg doses Prespecified efficacy analysis in higher dose groups  Patients in the combined 300- and 400-mg groups had 91% fewer attacks than patients receiving placebo

AE adverse event, C1-INH-HAE hereditary angioedema with C1 inhibitor deficiency, HMWK high-molecular-weight kininogen, IgG immunoglobulin, IV intravenous, K_i inhibition constant, PK/PD pharmacokinetics/pharmacodynamics, SC subcutaneous, TEAE treatment-emergent adverse event