Challenges for further successful development of tumor necrosis factor targeting therapies for uveitis

ABSTRACT

Introduction

Uveitis is a heterogeneous group of ocular conditions characterized by inflammation of the uveal tract and is one of the leading causes of vision impairment. In developed countries, noninfectious uveitis (NIU) represents most cases and is challenging to treat due to its severity, chronicity, and high recurrence rates. The advent of anti-tumor necrosis factor-α (anti-TNF-α) agents have dramatically improved outcomes and changed treatment paradigms in NIU.

Areas covered

The index article summarizes the present experience of anti-TNF-α agents in NIU pharmacotherapy and highlights the barriers to further research and development of anti-TNF-α agents for uveitis. Common challenges faced in NIU clinical drugs trials, specific difficulties in anti-TNF-α drug development, and promising competitor drug candidates are discussed and evaluated.

Expert opinion

Anti-TNF-α agents have revolutionized NIU pharmacotherapy and greatly improved outcomes with good safety profiles. The great success of systemic infliximab and adalimumab in NIU treatment has resulted in little impetus for further development of this class of medication. Attempts have been made to deliver anti-TNF-α agents intravitreally but that has not been successful thus far. With expiring patents, competition from biosimilars and newer, novel molecules, it may not be viable to continue pursuing anti-TNF-α drug development.

KEYWORDS:

• Adalimumab
• autoimmune
• biologics
• corticosteroids
• infliximab
• noninfectious
• tumor necrosis factor alpha inhibitor
• uveitis

Article highlights

• Anti-tumor necrosis factor-α (anti-TNF-α) agents especially infliximab and adalimumab are important first or second-line options for the treatment of noninfectious uveitis (NIU). However, a proportion of patients still fail on these drugs and the long-term safety profile is unclear.

• Inherent challenges in uveitis clinical drug trials include recruitment difficulties and lack of easily quantifiable disease biomarkers and endpoints. These pose barriers to further anti-TNF-α drug research for NIU.

• Intravitreal anti-TNF-α delivery is an area that holds promise to push the boundaries of NIU pharmacotherapy. Unfortunately, initial studies have been fraught with adverse events.

• New competitor molecules such as Janus Kinase inhibitors and anti-interleukin 6 monoclonal antibodies are currently undergoing clinical drug trials for NIU and other indications and if successful will further reduce interest in future anti-TNF-α drug development.

• Anti-TNF-α agents are likely to continue to play a major role in the stepladder approach for NIU treatment in conditions like Adamantiades-Behçet’s disease and juvenile idiopathic arthritis. Future research, however, is likely to be focused on newer molecules.

Abbreviation

ABD → Adamantiades-Behçet’s disease; ADA → adalimumab; Anti-TNF-α → anti-tumor necrosis factor-α; CZP → certolizumab; DME → diabetic macular edema; ETA → etanercept; GOL → golimumab; IFX → infliximab; IL → interleukin; IMT → immunomodulatory therapies; IV → intravenous; IVT → intravitreal; JAKi → Janus kinase inhibitor; NIU → noninfectious uveitis; nvAMD → neovascular age-related macular degeneration; OCT → optical coherence tomography; SC → subcutaneous; UME → uveitic macular edema; U.S. FDA → United States Food and Drug Administration.

Declaration of interest

QD Nguyen has chaired the Steering Committees for the SAKURA, VISUAL, STOP-Uveitis, and LINNAEA Studies. QD Nguyen also serves on Scientific Advisory Boards for Affibody, Acelyrin, Genentech, and Regeneron.

Research to Prevent Blindness Department Challenge Award, National Eye Institute of the National Institutes of Health P30 Award (EY026877), and funding support from the Global Ophthalmic Research Center have been awarded to the Byers Eye Institute at Stanford University.

All other 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 disclosure

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

Supplementary Material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/13543784.2024.2311186

Additional information

Funding

This paper was not funded.