Pharmacokinetics, Pharmacodynamics, Safety, Tolerability, and Immunogenicity of the QX002N anti-IL-17 Monoclonal Antibody: A Phase I, Randomized, Double-Blind, Single Ascending Dose Study in Healthy Chinese Volunteers.

Min Wu,Qianqian Li,Yanhua Ding,Hong Zhang,Min Fang,Lizhi Yang,Hong Chen

doi:10.3389/fphar.2021.794054

Abstract

Background: The innovative injection of interleukin 17 A (IL-17A) monoclonal antibody QX002N is being developed to treat active ankylosing spondylitis and plaque psoriasis in adults. Objective: This study investigated the pharmacokinetics (PKs), pharmacodynamics (PDs) safety, tolerability, and immunogenicity of single ascending subcutaneous injections of QX002N in healthy Chinese volunteers. Methods: A total of 65 healthy subjects were enrolled in a randomized, double-blind, placebo-controlled, single ascending dose phase I study (10–320 mg). Ten subjects were allocated to each cohort (containing 8 subjects treated with QX002N and 2 with placebo), except cohort 1 (only 4 subjects treated with QX002N and 1 with placebo). The studies on PKs, PDs, tolerability, and immunogenicity of QX002N were performed. Results: Our study showed that QX002N injection was well tolerated, without deaths, serious adverse events, or discontinuations due to treatment-emergent adverse events (TEAEs). Neither more frequency nor high severity of the drug-related adverse reaction was observed with increasing QX002N dose. The TEAEs in all subjects were considered Grades 1–2 (CTCAE 5.0) except for one case of Grade 3 (hypertriglyceridemia). Tmax of QX002N was obtained from 168 to 240 h across the dose range after administration. The Cmax and area under the curve of QX002N increased in proportion to dose, and showed linear PKs. Anti-drug antibody positivity was detected in one (1.9%) subject after drug administration. Conclusion: QX002N was well tolerated in our study. Based on the PKs and safety results of QX002N, 80 mg is recommended as the effective dose for a future phase Ib study. Clinical Trial Registration: https://www.chinadrugtrials.org.cn/, identifier ChiCTR1900023040.

Highlights

Interleukin 17A (IL-17A) is a naturally occurring cytokine that links T-cell activation to neutrophil mobilization and activation, and is one of the principal pro-inflammatory cytokines in some autoimmune diseases
Our study showed that QX002N can inhibit keratinocyte-derived cytokine (KC) releases induced by human IL-17A in mice
65 cases of treatment-emergent adverse events (AEs) (TEAEs) in 30 subjects were reported as adverse drug reactions (ADRs)

Summary

Introduction

Interleukin 17A (IL-17A) is a naturally occurring cytokine that links T-cell activation to neutrophil mobilization and activation, and is one of the principal pro-inflammatory cytokines in some autoimmune diseases. The neutralization of IL-17A is considered a therapeutic approach for immune-mediated diseases, such as inflammation and tissue destruction, as well as symptom relief (Blauvelt, 2008; Krueger et al, 2012; Lynde et al, 2014). IL-17A, a principal effector cytokine of Th17 cells, stimulates keratinocytes to produce chemokines, cytokines, and other proinflammatory mediators, thereby enabling IL-17A to bridge the innate and adaptive immune systems to sustain chronic inflammation. Inhibition of the IL-17 pathway may provide a new therapeutic approach for patients with moderate to severe psoriasis and ankylosing spondylitis (AS) (Lynde et al, 2014; Chyuan and Chen, 2018). The innovative injection of interleukin 17 A (IL-17A) monoclonal antibody QX002N is being developed to treat active ankylosing spondylitis and plaque psoriasis in adults

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Conclusion