Pharmacokinetics,Pharmacodynamics, and Exposure‐Response of Lanadelumab for Hereditary Angioedema

Hereditary angioedema (HAE) with C1 inhibitor deficiency is a rare disorder characterized by unpredictable, potentially life‐threatening recurrent angioedema attacks. Lanadelumab is a fully human monoclonal antibody with selective binding to active plasma kallikrein, and prevents the formation of cleaved high molecular weight kininogen (cHMWK) and bradykinin, thereby preventing HAE attacks. The clinical pharmacology of lanadelumab was characterized following subcutaneous administration in 257 subjects (24 healthy subjects and 233 patients with HAE). The pharmacokinetics of lanadelumab were described using a one‐compartment model with first‐order rate of absorption and linear clearance, showing slow absorption and a long half‐life (14.8 days). A covariate analysis retained body weight and health status on apparent clearance (CL/F) and body weight on volume of distribution (V/F). Population estimates of CL/F and V/F were 0.0249 L/hour (0.586 L/day) and 12.8 L, respectively. An indirect‐response Imax model showed 53.7% maximum suppression in cHMWK formation with a low potential for interactions with concomitant medications (analgesic, anti‐inflammatory, and antirheumatic medications). A 300 mg dose administered Q2W was associated with a mean steady‐state minimum concentration (C_min,ss; 25.4 μg/mL) that was ~ 4.5‐fold higher than the half‐maximal inhibitory concentration for cHMWK reduction (5.71 μg/mL). Exposure‐response analyses suggest that 300 mg Q2W dosing was associated with a significantly reduced HAE attack rate, prolonged time to first attack after treatment initiation, and lower need for concomitant medications. The response was comparable across patient body weight groups. Findings from this analysis support the dosing rationale for lanadelumab to prevent attacks in patients with HAE.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

☑ Hereditary angioedema (HAE) is a long‐term, debilitating, and potentially life‐threatening disease caused by C1‐inhibitor deficiency. Lanadelumab is a fully human monoclonal antibody inhibitor of plasma kallikrein that is effective in preventing attacks in patients with HAE.

• WHAT QUESTION DID THIS STUDY ADDRESS?

☑ What are the pharmacokinetic and pharmacodynamic characteristics of lanadelumab, and how are they related to the observed efficacy of lanadelumab in preventing HAE attacks?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

☑ Lanadelumab clearance and volume of distribution are dependent on body weight; however, significant attack rate reduction is still observed in patients with high body weight, and dose adjustment is not necessary. The findings of this study provide a greater understanding of the factors driving the efficacy and safety of lanadelumab to ensure optimal use.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

☑ Selective binding of lanadelumab to plasma kallikrein provides a novel approach for long‐term prophylaxis against HAE attacks.

Hereditary angioedema (HAE) is a rare, debilitating, and potentially life‐threatening disease with an estimated prevalence of 1 in 50,000. ¹ It manifests clinically as unpredictable, intermittent attacks of subcutaneous or submucosal edema of the face, larynx, gastrointestinal tract, limbs, and/or genitalia. Swelling may last several days, and most patients have multiple attacks per year. ² Symptoms usually begin during childhood, sometimes as young as age 2 years, and persist throughout life. ² HAE is caused by mutations in SERPING1, the gene encoding C1 inhibitor (C1‐INH), resulting in deficiency of C1‐INH protein or function. ³ C1‐INH is involved in regulating the contact, complement, and coagulation systems. ³ In the contact system, C1‐INH is the natural inhibitor of plasma kallikrein. Dysregulated contact system activation and subsequent uncontrolled plasma kallikrein activity lead to production of cleaved high molecular weight kininogen (cHMWK) and the edema‐inducing peptide bradykinin, which initiates signaling pathways leading to HAE attacks. Management of patients with HAE involves on‐demand medications to treat attacks when they occur, and long‐term or short‐term prophylaxis to prevent attacks. ¹ , ² Lanadelumab is a fully human immunoglobulin G1 monoclonal antibody that binds specifically to active plasma kallikrein. ⁴ It is approved in several countries for the prevention of HAE attacks in patients ≥ 12 years of age. In clinical trials, treatment with lanadelumab significantly reduced attack rates in patients with HAE, and this was associated with a reduction in cHMWK levels. ⁵ , ⁶ The pharmacokinetics (PK), pharmacodynamics (PD), exposure‐response relationships, and potential interactions of lanadelumab with rescue medications (for treatment of attacks that occur during long‐term prophylaxis), and with medications commonly used concomitantly in patients with HAE, were characterized using data from clinical studies to support the dosing rationale for long‐term prophylaxis with lanadelumab in patients with HAE.