Pharmacokinetics and pharmacodynamics of itepekimab in adults with moderate-to-severe atopic dermatitis: Results from two terminated phase II trials

Abstract

Interleukin-33 (IL-33) is a proinflammatory alarmin cytokine released by damaged epithelial tissue cells that initiates and amplifies both type 1 and type 2 inflammatory cascades. A role for IL-33 in atopic dermatitis (AD; a chronic, relapsing type 2 inflammatory disease of the skin) has been proposed. Itepekimab is a novel human IgG4P monoclonal antibody against IL-33, currently in clinical development for chronic obstructive pulmonary disease (COPD). Two global phase II studies-a dose-ranging itepekimab monotherapy study (NCT03738423) and a proof-of-concept study of itepekimab alone and in combination with dupilumab (NCT03736967)-were conducted in patients with moderate-to-severe AD to assess safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy; both studies were terminated following an interim analysis of the proof-of-concept study, which failed to demonstrate the efficacy of itepekimab. In these two studies, itepekimab exhibited linear and dose-proportional pharmacokinetics. Pharmacodynamics of total IL-33 indicated that itepekimab saturated binding to the target in serum at 300 mg q2w and q4w doses, and decreased blood eosinophil counts. Concentration-time profiles of itepekimab and total IL-33 were similar for itepekimab with or without dupilumab, and between East Asian and non-East Asian subgroups. Itepekimab was generally well tolerated, both alone and in combination with dupilumab. The lack of clinical efficacy for itepekimab observed in these studies suggests that IL-33 may not be a key pathogenic driver in moderate-to-severe AD.

FIGURE 1

Study designs of the (a) dose‐ranging study and (b) proof‐of‐concept study. Dupilumab arms included a 600 mg loading dose on day 1. Following an interim analysis of the proof‐of‐concept study indicating a lack of efficacy, both studies were terminated; once discontinued, patients in the treatment period entered the 20‐week follow‐up period at their next study visit. AD, atopic dermatitis; D, day; EASI, Eczema Area and Severity Index; EOS, end of study; EOT, end of treatment; N, enrolled population; q2w, every 2 weeks; q4w, every 4 weeks; q8w, every 8 weeks; R, randomization; SC, subcutaneous; W, week.

FIGURE 2

Concentration–time profiles of itepekimab during the study period in the (a) dose‐ranging study and (b) proof‐of‐concept study. Concentrations below the lower limit of quantitation (LLOQ) were set to LLOQ/2. Patients who prematurely discontinued treatment were censored at timepoints more than one dosing interval after the last administered dose.

FIGURE 3

Concentration of total IL‐33 (a, b) in serum and blood eosinophils (10⁹/L) (c, d) during the study period in the dose‐ranging study and proof‐of‐concept study, respectively. For (a, b): Concentrations below the LLOQ were set to zero. Patients who prematurely discontinued treatment were censored at timepoints more than one dosing interval after the last dose. Data are shown as mean (SD). For (c, d): Change from baseline in blood eosinophils presented in the SAF population. Data are shown as median. IQR, interquartile range; LLOQ, lower limit of quantitation; q2w, every 2 weeks; q4w, every 4 weeks; q8w, every 8 weeks; SAF, safety.