Safety, Pharmacokinetics and Preliminary Efficacy of IL4-Rα Monoclonal Antibody AK120 in Both Healthy and Atopic Dermatitis Subjects: A Phase I, Randomized, Two-Part, Double-Blind, Placebo-Controlled, Dose-Escalation, First-In-Human Clinical Study.

INTRODUCTION: Interleukin-4 (IL-4) and interleukin-13 (IL-13) are two essential cytokines involved in the T helper 2 (Th2)-mediated inflammatory response to diseases, such as atopic dermatitis (AD). AK120 is a humanized immunoglobulin G subclass 4 (IgG4) monoclonal antibody (mAb) directed against the IL-4 receptor alpha (IL-4Rα) subunit shared by the IL-4 and IL-13 receptor complexes. This mAb inhibits the signaling of the IL-4 and IL-13 cytokines. METHODS: The study consisted of two parts. Part 1 was a single ascending dose (SAD) study with five cohorts (receiving 15, 50, 150, 300 or 600 mg of AK120, respectively) of healthy subjects; part 2 was a multiple ascending dose (MAD) study with four cohorts (receiving AK120 at doses of 300 mg once every 2 weeks [Q2W], 300 mg once weekly [QW], 150 mg QW or 75 mg QW) of subjects with AD. A total of 81 subjects (40 in part 1, 41 in part 2) were enrolled in the study. RESULTS: The compound was safe and well tolerated in both a SAD up to 600 mg in healthy subjects and in a MAD from 75 to 600 mg in subjects with AD. The exposure of AK120 increased in an approximately dose-dependent manner upon subcutaneous dosing. The levels of the biomarkers serum thymus and activation-regulated chemokine ligand 17 (TARC/CCL17) and immunoglobulin E decreased from baseline after AK120 administration, indicating the inhibition of the IL-4/IL-13 signaling pathways. AK120 showed improved Eczema Area and Severity Index (EASI) scores, and the proportion of subjects with Investigator Global Assessment (IGA) score 0/1 increased after AK120 treatment. CONCLUSIONS: AK120 exhibited an acceptable safety profile in healthy and AD subjects, and showed preliminary efficacy. These findings support the continued investigation of AK120 for treating AD. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identification number: NCT04256174.