RPC4046, A Novel Anti-interleukin-13 Antibody, Blocks IL-13 Binding to IL-13 α1 and α2 Receptors: A Randomized, Double-Blind, Placebo-Controlled, Dose-Escalation First-in-Human Study

Abstract

IntroductionA unique anti-interleukin (IL)-13 monoclonal antibody, RPC4046, was generated on the basis of differential IL-13 receptor (R) blockade as assessed in a murine asthma model; the safety, tolerability, pharmacokinetics, and pharmacodynamics of RPC4046 were evaluated in a first-in-human study.MethodsAnti-IL-13 antibodies with varying receptor blocking specificity were evaluated in the ovalbumin-induced murine asthma model. A randomized, double-blind, placebo-controlled, dose-escalation first-in-human study (NCT00986037) was conducted with RPC4046 in healthy adults and patients with mild to moderate controlled asthma.ResultsIn the ovalbumin model, blocking IL-13 binding to both IL-13Rs (IL-13Rα1 and IL-13Rα2) inhibited more asthma phenotypic features and more fully normalized the distinct IL-13 gene transcription associated with asthma compared with blocking IL-13Rα1 alone. In humans, RPC4046 exposure increased dose-dependently; pharmacokinetics were similar in healthy and asthmatic subjects, and blockade of both IL-13Rs uniquely affected IL-13 gene transcription. A minority of participants (28%) had antidrug antibodies, which were transient and appeared not to affect pharmacokinetics. Adverse event profiles were similar in healthy and asthmatic subjects, without dose-related or administration route differences, systemic infusion-related reactions, or asthma symptom worsening. Adverse events were mild to moderate, with none reported as probably related to RPC4046 or leading to discontinuations. Non-serious upper respiratory tract infections were more frequent with RPC4046 versus placebo.ConclusionRPC4046 is a novel anti-IL-13 antibody that blocks IL-13 binding to both receptors and more fully blocks the asthma phenotype. These results support further investigation of RPC4046 for IL-13-related allergic/inflammatory diseases (e.g., asthma and eosinophilic esophagitis).FundingAbbVie Inc. sponsored the studies and contributed to the design and conduct of the studies, data management, data analysis, interpretation of the data, and in the preparation and approval of the manuscript. Electronic supplementary materialThe online version of this article (doi:10.1007/s12325-017-0525-8) contains supplementary material, which is available to authorized users.

Interleukin‐13: Targeting an underestimated cytokine in atopic dermatitis

“…Interestingly, this strategy has been postulated to be potentially more efficacious than blocking the binding to IL-13Rα1 alone. 94 Similar to lebrikizumab, the PoC phase II trial has been performed in moderate to severe patients having first been exposed to class III (potent steroids, according to European classification) TCSs in a run-in period and with continuous application as a background therapy for both placebo and active arms. 95 The adverse effects were similar in both groups and classified as mild to moderate.…”

“…Anrukinzumab (IMA‐638) is an anti‐IL‐13 with an analogous mode of action to lebrikizumab. In contrast, similar to tralokinumab, RPC4046 (ABT‐308) and CNTO 5825 block the binding of IL‐13 to both IL‐13Rα1 and IL‐13Rα2.…”

IL-13 Impairs Tight Junctions in Airway Epithelia

“…In particular, IL-13 plays a pivotal role in allergic asthma [4,5]. Novel treatment strategies follow approaches, where IL-13 signaling is inhibited either by immuno-inhibition of IL-13 dependent receptor signaling [6] or by immuno-neutralization of IL-13 itself [6,7,8,9,10]. Both strategies can improve asthma symptoms and reduce risk of exacerbations.…”

RPC4046, a Monoclonal Antibody Against IL13, Reduces Histologic and Endoscopic Activity in Patients With Eosinophilic Esophagitis

“…15 RPC4046 is a selective, high-affinity, humanized immunoglobulin G1 monoclonal antibody that recognizes wild-type and variant human IL13, and blocks its binding to the receptor subunits IL13Ra1 and IL13Ra2. 16 We evaluated the efficacy and safety of RPC4046 in adult patients with clinically and histologically active EoE.…”