Investigational IRAK-4 inhibitors for the treatment of rheumatoid arthritis

ABSTRACT

Introduction

Rheumatoid arthritis (RA) is a chronic inflammatory auto-immune disease that can lead to permanent disability and deformity. Despite current treatment modalities, many patients are still unable to reach remission. Interleukin-1 receptor-associated kinase 4 (IRAK-4) inhibitors are novel agents designed to suppress immune signaling pathways involved in inflammation and joint destruction in RA. Four IRAK-4 inhibitors have entered clinical trials.

Areas covered

This review summarizes the current stage of development of IRAK-4 inhibitors in clinical trials, detailing their chemistry, pharmacokinetics, and therapeutic potential in the treatment of RA. PubMed, Embase and restricted Google searches were conducted using the term ‘IRAK-4ʹ, and publicly accessible clinical trial databases were reviewed.

Expert opinion

IRAK-4 inhibitors are an exciting therapeutic option in RA management because unlike other targeted disease-modifying agents, they target the innate immune system. The role of IRAK-4 as a key component of Toll/Interleukin-1 receptor signaling and its potential for a low rate of infectious complications is particularly exciting and this may facilitate their use in combination treatment. A key aspect of upcoming clinical trials will be the identification of biomarkers predictive of treatment efficacy, which will help to define if and how they will be used in the clinic.

KEYWORDS:

• Rheumatoid arthritis
• interleukin-1 receptor associated kinase 4
• toll-like receptors
• BAY1834845
• CA-4948
• PF-06650833
• IRAK-4

Article Highlights

• Interleukin-1 Receptor Associated Kinase 4 (IRAK-4) is a serine-threonine kinase that is a key messenger in signaling initiated by toll-like receptors and Interleukin-1 receptors.

• Adults deficient in IRAK-4 do not have a significant increase in the risk of serious infections, so inhibitors of IRAK-4 will be particularly useful therapeutic agents if clinical trials demonstrate lower rates of infectious complications compared to other disease modifying agents.

• IRAK-4 inhibitors are orally bioavailable small molecules that are upstream inhibitors of nuclear factor-kappa of B cell (NF-κB) mediated secretion of tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), and interleukin-6 (IL-6).

• Four IRAK-4 inhibitors have reached clinical trials (PF-06650833, BAY1834845, BAY1830839, and CA-4948) and are being investigated for RA, other auto-immune conditions, and hematological malignancies.

• In a phase II trial with PF-06650833, just 12 of 187 (6.4%) of participants ceased treatment due to treatment emergent adverse effects.

• Predictive biomarkers of efficacy for IRAK-4 inhibitors are likely required if they are to establish a clear role in the management of RA.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.