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The Future of Dry Eye Treatment: A Glance into the Therapeutic Pipeline

Dry eye syndrome is both a primary disease and a secondary result of many pathological states of the eye. The symptoms range from mild to severe itching, burning, irritation, eye fatigue, and even vision loss that can lead to disability. Dry eye affects approximately 60 million people worldwide; as a result, medications to treat dry eye comprise approximately 15% of the ophthalmic pharmaceutical market. While doctors and patients eagerly await new treatments, pharmaceuticals in the pipeline are moving through the approval process with several promising drugs having completed phase 3 clinical testing. This review summarizes the findings of studies of the most promising, upcoming dry eye treatments in phase 2 and 3 clinical trials in the USA.


INTRODUCTION
Dry eye disease (DED) affects millions of people around the world [1]. Whether due to aqueous deficiency or evaporative dry eye (or most commonly a combination of factors), it is a potentially debilitating condition. Functional limitation is variable, but moderate to severe DED may make it difficult for patients to do computer work, reading, and other activities that limit their daily lives and productivity. DED was traditionally thought to be a disease of age and more common in females. In recent years, a younger population is the most rapidly growing segment of dry eye sufferers, likely in part to shifts in our lifestyles toward frequent computer and visual display tasking.
Post-refractive surgery (e.g., post-LASIK) dry eye is also a significant clinical obstacle [2]. The current mainstay treatment for mild dry eye includes various types of lubricating drops and ointments. These must be frequently re-applied and do not resolve the underlying disease process, often only temporarily relieving the symptoms.
human or animal subjects performed by any of the authors.

Dry Eye as an Inflammatory State-Current Treatments and Implications for Pharmaceutical Development
Dry eye has been recognized and treated as an inflammatory process. The first pharmaceutical to target an inflammatory pathway in order to treat dry eye is cyclosporine 0.05% (Restasis, Allergan; Irvine, CA, USA), which has become a mainstay of treatment for moderate to severe dry eye disease. While many patients benefit from this drug, some also have mixed reactions and may discontinue it over time due to intolerance of associated side effects (temporary redness and/or burning upon instillation) [3]. The need for additional treatments for dry eye is clear to patients and physicians alike, and the recognition of dry eye as an inflammatory process has opened the door to pharmaceuticals targeting the inflammatory cascade. Fortunately for dry eye patients, there are numerous promising pharmaceuticals in the pipeline, some borrowing insight from treatment of inflammatory conditions in other parts of the body, and many of them having completed or currently undergoing phase 3 clinical testing. Additionally, dry eye has become a target for device development, Tokyo, Japan) is a mucin secretogogue initially marketed in Japan for the treatment of gastric mucosal disorders and gastritis [12][13][14][15][16]. As decreased numbers of goblet cells have been observed in the conjunctiva and decreased mucin at the corneal surface has been observed in patients with dry eye, rebamipide was thus a potential target for dry eye treatment by stabilizing the mucin component of the tear film. Early studies demonstrated an increased production of periodic acid-Schiff-positive cells (goblet cells) when rebamipide was instilled into rabbit eyes and increased mucin-like glycoprotein when rebamipide was incubated with human corneal epithelial cells [17,18]. Recent phase 2 and phase 3 studies have yielded promising results for clinical use of rebamipide in the treatment of dry eye [13,16] [27,28]. IL-1 is an inflammatory mediator of dry eye in addition to multiple systemic diseases.
Notably it has been successfully targeted for the treatment of inflammatory conditions such as rheumatoid arthritis. A topically administered ocular therapeutic formulation IL-1 inhibitor was investigated in 2012, and the result, EBI-005, was found to bind its target, IL-1R1, with high specificity, which conferred a high in vivo potency in a therapeutic rat model [27].
A phase 2 study was completed in 2015, investigating the use of EBI-005 5 mg/ml three times daily for the treatment of allergic conjunctivitis [28]. One hundred fifty-six patients with moderate to severe allergic conjunctivitis were randomized to EBI-005 or vehicle groups and were subjected to aerosolized allergen challenge or direct conjunctival allergen challenge. In the conjunctival allergen challenge test, EBI-005-treated subjects showed statistically significant improvement in ocular itching compared to vehicle. Treated patients also showed greater improvement compared to vehicle in tearing and nasal symptoms. Of note, the primary pre-specified endpoint of ocular itching was not met in the aerosolized challenge test. Further phase 3 clinical testing is under way and will elucidate the role for EBI-005 in both allergic conjunctivitis and dry eye in the clinic.

Diquafosol: P2Y 2 Receptor Agonist
Diquafosol is a purinergic agonist of the ocular surface P2Y 2 receptor, which promotes fluid transfer and mucin secretion via a pathway involving the activation of phospholipase proteins [29]. Diquafosol was approved in 2010 in Japan for use in treating dry eye, and it recently concluded a phase 3 study in the US [30]. In earlier randomized clinical trials of this medication, mucin production and ocular surface damage appear to be improved, while effects on aqueous production are less certain [29,31,32]. There have been no serious ocular side effects reported. Similar to other compounds for treating dry eye, heterogeneity in study design in evaluating clinical endpoints may have contributed to inconsistent findings among the several randomized trials that have been completed for this drug. Further larger trials with longer follow-up periods may better demonstrate its efficacy.  Inflammation is a common feature in multiple ocular surface diseases in addition to dry eye, including blepharitis, allergic conjunctivitis, and others. Thus, agents designed to treat dry eye may have cross-over benefit to those suffering from other ocular surface conditions, and vice versa. Further study of some of these medications for patients with other inflammatory diseases is merited and in some cases is already underway. Patients with more than one inflammatory ocular surface disease (as is often the case) represent an important cohort to study as well. The future is bright as medications and devices continue to flow into the pipeline. Dry eye sufferers and physicians alike can only hope that in the decade to come we will have many more approved therapeutics available to treat dry eye.

ACKNOWLEDGMENTS
No funding or sponsorship was received for this study or publication of this article.
All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval for the version to be published.