New Frontiers in Uveitis Treatment: Updates and Innovations  

What is Uveitis?

Uveitis is a rare condition in which all or part of the uvea becomes inflamed. The uvea includes the choroid, the ciliary body, and the iris. The disease is commonly associated with visual impairment, blindness, and decreased quality of life. It affects patients in their most active and economically productive years. 

Uveitis is broadly classified as infectious and noninfectious. Infectious uveitis can result from bacteria or viruses in the eye, while noninfectious uveitis (NIU) can occur with systemic autoimmune disease and autoimmune diseases localized to the eye. NIU represents the majority of uveitis cases. 

Based on the anatomical location of the inflammation in the eye, uveitis is categorized as anterior, posterior, intermediate, and pan uveitis. Anterior uveitis is defined by the anterior segment being the predominant site of inflammation. Intermediate uveitis is defined by inflammation of the vitreous cavity and pars plana, while posterior uveitis involves the retina and choroid. Inflammation in pan uveitis includes all layers. 

Early uveitis symptoms may be mild or severe, depending on which part of the uveal tract is affected and the amount of inflammation. Anterior uveitis symptoms are usually the most bothersome. They may include severe eye pain, redness of the conjunctiva, sensitivity to light, decreased vision, the presence of white blood cells floating in the aqueous humor (the fluid in the front part of the eye), the accumulation of white blood cells on the inner surface of the cornea, and other symptoms. Decreased vision and floaters are also common symptoms of posterior uveitis. Pan uveitis may cause any combination of these symptoms, whereas intermediate uveitis is usually without pain. The affected person may experience decreased vision and observe an increasing number of abnormal floating black spots. 

Though the uveitis causes are usually unknown, diseases like juvenile idiopathic arthritis (JIA), Behçet’s disease, Vogt–koyanagi–harada syndrome, sarcoidosis, and others are associated with uveitis. Macular edema, cataract, and glaucoma are the common complications of uveitis. 

Uveitis on the Rise: Contributing Factors for a Rise in Diagnosed Prevalence

Uveitis is a rare eye condition. As greater awareness is being raised about the disease in recent years and more advanced diagnostic techniques are being employed, prevalence has expanded dramatically. DelveInsight estimates that the diagnosed prevalent cases of uveitis in the US rose to almost 400,000 in 2022. About 90% of these cases were non-infectious and anterior NIU made up almost 70% of the cases. Idiopathic uveitis accounted for ~50% of all uveitis cases. 

Healthcare providers are now better equipped to detect and diagnose uveitis, allowing for earlier intervention and better outcomes. Optical coherence tomography (OCT) has played a critical role as a non-invasive imaging technique used to diagnose and monitor uveitis. Fluorescein angiography helps identify areas of inflammation and damage in the eye. Multiplex polymerase chain reaction (PCR) testing detects the presence of multiple pathogens in a single test and diagnose infectious causes of uveitis. Next-generation sequencing (NGS) is a high-throughput technique that rapidly sequences large amounts of genetic material. It can be used to identify genetic mutations that may contribute to the development of uveitis. Overall, these advancements in imaging and laboratory techniques have greatly improved the accuracy and efficiency of uveitis diagnosis, allowing for earlier detection.

The increasing prevalence of autoimmune diseases such as rheumatoid arthritis, lupus, multiple sclerosis, and others, have also greatly contributed to the cases of uveitis as a secondary condition. Certain infections, such as herpes simplex, tuberculosis, and toxoplasmosis, may also trigger uveitis. Susceptibility to the disease is greater in the elderly as immune functions decline.

Need for Improving Disease Reporting and Surveillance Systems

Though uveitis is a debilitating condition with a large socioeconomic impact, estimated to cause 10–15% of blindness in the US, there are only a few large studies that examine the real-world incidence and prevalence of uveitis. These may also be limited due to the heterogeneity of uveitis There is of course data variability depending on the causative agent and geography. The available incidence and prevalence estimates fluctuate with clinical settings, emergent infectious patterns, diagnostic testing, and novel diseases or disease definitions. Underreporting also impacts the understanding of disease prevalence. Country-specific data is limited for Europe, and most studies refer to older data.

Current Uveitis Treatment Approaches

The uveitis treatment typically involves a combination of medications and lifestyle changes. The most common uveitis medications are corticosteroids, which reduce inflammation. These may be given in the form of eye drops, injections, or oral pills. Nonsteroidal anti-inflammatory drugs (NSAIDs) may also be used to reduce pain and swelling. If the uveitis is caused by an autoimmune disorder, immunosuppressant drugs may be prescribed to reduce the immune system’s activity and prevent further damage to the eye. If the uveitis is caused by an infection, such as bacterial or viral, antibiotics may be recommended. 

Biologics have also come into force for the treatment of uveitis. The biologic HUMIRA (adalimumab) is approved for the treatment of non-infectious intermediate, posterior, and pan uveitis and works by targeting and blocking the action of a protein in the immune system that causes inflammation. REMICADE (infliximab), another biologic targets the same protein as HUMIRA. It is approved for the treatment of NIU in patients who have not responded to other treatments. 

The patent expiry of biologics (HUMIRA and REMICADE) has led to the use of cost-effective biosimilars such as Amjevita. This will result in a favorable impact on the healthcare budgets and a greater number of patients possibly gaining from access to biological uveitis treatments. According to new research, Amgevita is both safe and effective for the treatment of NIU, with a similar efficacy profile to the originator HUMIRA (adalimumab).

Innovative advances in ocular drug delivery have made it possible to deliver drugs directly to the site of inflammation in the eye, bypassing systemic side effects. Sustained-release implants that can deliver corticosteroids to the uveitis-infected eyes over a period of time have been developed. AbbVie’s OZURDEX (dexamethasone intravitreal implant) and Eyepoints’s YUTIQ (fluocinolone acetonide intravitreal implant) are approved for the treatment of NIU affecting the posterior segment of the eye. While YUTIQ consistently releases a low dose of fluocinolone for 36 months, OZURDEX is typically effective for about 3–4 months. On the other hand, Bausch & Lomb’s (acquired by Valeant Pharmaceuticals) surgically implanted RETISERT (fluocinolone acetonide intravitreal implant) is used to treat noninfectious uveitis, also lasts about 36 months, and is generally reserved for more severe presentations in which a higher dose of steroid is warranted. While these implants can reduce the need for frequent injections or oral corticosteroids and can improve treatment adherence, they should not be used on patients who have glaucoma, infection, or a history of ocular hypertension due to corticosteroids.

Macular edema is one of the most common complications of uveitis and is present in about 20–30% of uveitis patients. It is one of the main causes of blindness in NIU patients. Clearside Biomedical/Bausch/Arctic Vision’s product, XIPERE, a triamcinolone acetonide injectable suspension,  has a novel delivery mechanism for suprachoroidal use to treat macular edema associated with uveitis in the United States. Delivering the medicine to the suprachoroidal space allows targeted delivery of the therapy with low levels elsewhere in the eye. The drug was approved in 2021 and hit a home run with a revenue of approximately USD 10 million in 2022 in the United States.

Uveitis still has significant unmet treatment needs despite the availability of authorized medicines in this therapeutic category. While the drugs are effective in treating uveitis, they may not work for every patient. A trial-and-error approach may be necessary to find the right medication or combination of medications that work for an individual patient. Besides, all medications come with the risk of side effects and the drugs for uveitis treatment are no exception. Biologic drugs increase the risk of infections, and corticosteroids cause elevated eye pressure, cataracts, and glaucoma. Some of these drugs are expensive and not covered by insurance, making them inaccessible for some patients. The drugs administered through injections or implants may require additional visits to the doctor or surgery. This becomes inconvenient and uncomfortable for patients. Patients taking these therapies need to be closely monitored for side effects or complications and this may involve specialized testing, which is time-consuming and costly. 

“There is a requirement for enhanced initial treatment of inflammation, improved maintenance of persistent chronic inflammation, and better handling of disease complications like macular edema. Although there are some encouraging advancements like small molecules and gene therapy that are expected to tackle some unmet market demands, there is still a need for additional molecule options.”

– Key Opinion Leader

Advancements in Uveitis Treatment

The treatment of uveitis is evolving with newer drugs and innovative advances in ocular drug delivery. This is due to a better understanding of the pathophysiology of the disease and the barriers to drug delivery. Several emerging therapies for uveitis treatment show promise in improving outcomes for patients. 

Some of the late-stage assets under development include TRS01, RG6179, and OCS-02. Tarsier Pharma’s TRS01 is a topical immune modulator agent with the potential to treat active noninfectious anterior uveitis with or without uveitic glaucoma. With a moderate uptake, the drug is projected to peak in the 7^th year from launch. RO7200220/RG6179 is a monoclonal antibody being developed by Hoffmann-La Roche for a target patient pool having uveitic macular edema. Oculis’s OCS-02, a topical biologic, is an anti-TNFα, being developed to treat acute anterior uveitis.

Janus kinase (JAK) inhibitors are a new class of medications that target the JAK-STAT signaling pathway, which is involved in the immune response. JAK inhibitors are effective in treating inflammatory conditions, and recent studies have shown their potential in treating uveitis. Baricitinib, a product of Eli Lilly and Company, is a JAK (Janus kinase) 1/2 selective inhibitor that works by interfering with cytokine signaling to influence immune cell function and inflammation by reducing phosphorylation and activation of STATs (signal transducers and activators of transcription). It is currently being developed in the Phase III trial initiated in patients with active JIA-associated uveitis or chronic anterior antinuclear antibody-positive uveitis. OLUMIANT (baircitinib) is already approved for the treatment of several indications including rheumatoid arthritis, COVID-19, atopic dermatitis, and alopecia areata. Brepocitinib, a lead molecule of Priovant Therapeutics, is an orally available, selective inhibitor of nonreceptor tyrosine-protein kinase TYK2 (tyrosine kinase 2) and tyrosine-protein kinase JAK1 with potential immunomodulatory and anti-inflammatory activities. It is currently being investigated in Phase II clinical trials in patients with active noninfectious intermediate, posterior, and pan uveitis.

Gene therapy has the potential to modulate the immune response and reduce inflammation in the eye. EYS606, being developed by Eyevensys, is a novel non-viral gene therapy approach being developed for treating chronic NIU. EYS606 combines plasmids encoding a potent fusion protein that neutralizes the activity of TNF-α and the proprietary Eyevensys Electrotransfection System used to introduce the plasmids into the eye. The drug has completed evaluation in Phase II and has received Orphan Drug Designation from the European Medicines Agency (EMA) to treat NIU

Stem cell therapy can help reduce inflammation and restore vision by replacing damaged or lost cells in the eye of uveitis patients. Nanoparticle therapy also has the potential to deliver drugs directly to the site of inflammation in the eye of a uveitis patient, improving treatment efficacy and reducing the risk of systemic side effects. Recent studies have shown that photobiomodulation therapy may be effective in treating uveitis and other ocular inflammatory conditions. 

Emerging therapies for uveitis treatment are filled with promise in improving treatment outcomes and reducing side effects associated with current therapies. While further research is needed to establish their safety and efficacy, these therapies offer newer possibilities for alternatives or adjuncts to traditional therapies for patients with uveitis. 

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