As we learn more about ocular surface disease (OSD), our historical simplistic treatments are being advanced by many companies looking at innovative solutions to this growing market. When the already sizable list of risk factors for OSD grew following the pan-generational lifestyle shift to spending more time in front of screens (computers, tablets, cell phones), the OSD epidemic exploded, creating a wider need for improved therapeutics.

Cyclosporine A 0.05% (Restasis, Allergan) changed our approach in treating dry eyes — by interrupting the inflammatory cycle on the ocular surface that perpetuates dryness.¹ With our deeper understanding of DED’s pathophysiology the focus on treatment has shifted from supplementing the tear film with lubricants and punctal plugs to addressing its pathophysiology, microchemistry and structural components. Interventions such as amniotic membrane grafts/rings, autologous serum tears, thermal pulsation and microblepharoexfoliation are now aimed at interfering with complex cycles that underlie OSD.

Some of the challenges to overcome when attacking OSD include creating medications that can penetrate the ocular surface more effectively, improving patient compliance issues, and decreasing local adverse effects with some of the currently available medications. This review will cover some of the recently approved medications as well as compounds and treatments that are in the pipeline, and is not meant to be all-inclusive.

TARGETING SURFACE INFLAMMATION:

Preservative free cyclosporine 0.1% cationic emulsion (Santen Pharmaceutical): One of the greatest barriers to compliance with cyclosporine 0.05% is burning pain at the time of instillation.² Studies on human corneal epithelial cells and in rabbit eyes showed that preservative-free cyclosporine delivered in a cationic emulsion was less toxic to the ocular surface.³ The one year results of 0.1% cyclosporine A cationic emulsion in the treatment of severe DED showed that it was well tolerated and reduced surface inflammation in patients with severe keratitis (grade 4 fluorescein staining).⁴ Santen has released a cationic emulsion of cyclosporine A (1mg/mL), which is available in Europe as Ikervis.

Amniotic cytokine extract (Ocular Science): ACE is a novel drop marketed as Genesis that contains various cytokines, growth factor, and anti-inflammatory molecules. It was shown to be effective in a small pilot study.^5,6

KPI-121 (Kala Pharmaceuticals): This mucous-penetrating particle (MPP) enhances the delivery of loteprednol etabonate into the eye. Initially studied as a means to deliver intraocular steroid in cataract surgery patients, researchers learned that attaching loteprednol to a nanoparticle can improve penetration into the mucin layer on the ocular surface, which shows promise for the temporary relief of dry eye disease flares. Recently, Kala Pharmaceuticals released its top line results for two Phase 3 trials (STRIDE 1 and STRIDE 2) of KPI-121 0.25% in DED. The trials showed favorable results for both the primary sign endpoint (conjunctival hyperemia) and primary symptom endpoint (ocular discomfort) at 15 days with IOP elevations similar to placebo.⁷ For DED patients, this medication may prove to be very effective for episodic flares.

cis-UCA (Herantis Pharma Plc): This is an early stage drug with anti-inflammatory properties shown to be protective against damage from UVB light. A study involving rats has shown that cis-UCA may have anti-allergic properties against both immediate and delayed onset reactions.⁸ A Phase I clinical study with 37 adults compared two doses of cis-UCA eyedrops to placebo and found this drug to be safe and well tolerated.⁹ A completed Phase 2 trial, comparing cis-UCA to placebo, was completed in April 2015.¹⁰

RGN-259 (RegeneRx Biopharmaceuticals, Inc.): Thymosin β-4 binds to G-actin protein in platelets, macrophages and neutrophils (all cells involved in wound repair), and down-regulates the transcription of inflammatory mediators such as chemokines, cytokines and metalloproteinases. It also up-regulates laminin-5, promotes cell migration and cell survival and is involved in recruitment and maturation of stem cells.¹¹ On the cornea, thymosin β-4, known as RGN-259, promotes ocular surface healing by stimulating corneal epithelial cell migration and decreasing inflammatory cytokines. The ARISE-2 trial was a second Phase 3 clinical trial which showed significant improvement in the signs and symptoms of dry eyes with 0.1% RGN-259 compared to placebo within 15 days of starting the drug. Improvement in corneal staining continued through day 29. It has already been assigned orphan drug status in the US for treatment of neurotrophic keratopathy.¹²

One point to mention: Restasis will soon be coming off patent. This opens the door to various generic formulations that one would expect to enter into market in the near future.

CHANGING TEAR COMPOSITION

Outside of the United States, rebamipide, a mucin secretagogue that increases mucous levels on the conjunctiva and cornea to stabilize the tear film, has been approved in Asia.¹³ Diquafosol tetrasodium, a P2Y2 receptor agonist which has been shown to increase mucin and fluid production on the ocular surface,¹⁴ has been approved in Japan and concluded a Phase 3 clinical trial in the United States.¹⁵ Other treatments in development include:

OTX-101 (Sun Pharma): OTX-101 is a dry eye treatment created from a nanomicellar formulation of cyclosporine A, 0.09%. In December 2016, a Phase 3 trial for OTX-101 involving 745 patients was completed; the randomized, double-masked trial evaluated the safety and efficacy of the aqueous solution in the treatment of keratoconjunctivitis sicca at 12 weeks. The primary outcome measure was tear production, with secondary outcomes set as conjunctival staining, central corneal staining and changes from baseline in a modified SANDE score.²³ The FDA accepted OTX-101’s New Drug Application in December, and has scheduled a Prescription Drug User Fee Act deadline of Aug. 16 for its decision on OTX-101.

NovaTears and CyclASol (Novaliq): NovaTears is a lubricating lipid layer stabilizer used to treat meibomian gland dysfunction (MGD) by preventing evaporative tear loss. It is a water-free therapy – 100% perfluorohexyl octane – that requires neither surfactants nor preservatives. In a study of 72 people with MGD and evaporative DED, the endpoints were dry eye symptom relief and stabilization of the tear film. Other goals included the effect on signs of blepharitis and drug tolerability. Tear film break-up time, results from the OSDI-like questionnaire, and corneal and conjunctival fluorescein staining improved significantly, according to the study.¹⁶ The product has been reported to stay on the eyes for up to four hours and stabilizes the lipid layer of the tear film. In addition, during a Phase 2 study, CyclASol (0.1% cyclosporine A in EyeSol (perfluorobutylpentane)) demonstrated earlier onset of efficacy for improving corneal and conjunctiva staining.¹⁷

ECF843 (Lubris LLC): ECF843 is a recombinant form of human lubricin, an endogenous glycoprotein that protects ocular surface tissues from shear stress and friction. In a small Phase 2 clinical study, ECF843 demonstrated immediate improvement of dry eye symptoms and improvement of clinical signs within 14 days. There were no treatment-related adverse events.¹⁸

Tavilermide (MIMD3, Mimetogen Pharmaceuticals USA, Inc.): Tavilermide is a cyclic peptidomimetic of nerve growth factor, a naturally occurring protein in the eye responsible for the maintenance of corneal nerves and epithelium. Tavilermide acts to increase the mucus component in the tear film and has completed Phase 3 trials.^19,20 Allergan bought Mimetogen in 2017.

RU-101 (R-Tech Ueno, Ltd.): RU-101 is a topical drop containing recombinant human serum albumin. Serum contains numerous growth factors and nutrients that aren’t available in lubricating drops. Serum albumin increases mucin secretion by the conjunctival mucous goblet cells. A Phase 2 study demonstrated improvement in corneal staining with topical recombinant human serum albumin, although statistical significance was not achieved when compared to the placebo vehicle group. This drug continues to be studied.²¹

SkQ1 (Mitotech, SA): SkQ1 is a mitochondria-targeted antioxidant. Mitochondria have been shown to be a source of oxidative stress by generating reactive oxygen species when disruption to the organelle occurs. Antioxidants specific to the mitochondria can “soak up” released reactive oxygen species and neutralize damage. In doing so, it can delay age-related diseases like dry eye. SkQ1 is a mitochondria-specific antioxidant that reduces oxidative stress by stimulating antioxidants in the cornea like glutathione peroxidase and glutathione reductase. Dietary supplementation with SkQ1 as well as topical administration has been studied. A Phase 2 trial with 91 human subjects showed that SkQ1 is safe and, though not statistically significant, was better than placebo at decreasing corneal staining with fluorescein and lissamine green.²²

A LOOK AT THE LIDS

There have been many studies looking at the efficacy of thermal pulsation for addressing meibomian gland disease and its effect on OSD. With the recent acquisition of TearScience by Johnson & Johnson Vision, one would expect further innovations to the LipiFlow platform.²⁴

Also, we are beginning to evaluate the eye’s microbiome to determine if there is any correlation with dry eye patients. There is research showing that the microbiome serves an immunoregulatory function. Patients with Sjogren’s syndrome have a significant alteration of their gut microbiome, but no significant changes in the ocular microbiome. This is partly due to the eye microbiome having the lowest biomass of any tissue in the body, so subtle differences might not be picked up.²⁵ Microblepharoexfoliation (BlephEx, RySurg) has also been found to be effective in treating MGD and blepharitis by removing the biofilm on eyelids and eyelashes.

Another product on the market is the iLux device (Tear Film Innovations), a handheld device designed to identify and unblock meibomian glands. Similarly, NuLids (NuSight Medical) is performed at home by patients and essentially allows for a gentle cleansing of the eyelids and eyelashes with a handheld unit.

As we delve deeper into the pathophysiology of dry eye disease, we are discovering specific pathways for targeting treatment. It is an exciting time to be a dry eye specialist as promising therapeutics are on the horizon. OM

REFERENCES

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About the Authors

Allison Jarstad, DO, is a clinical instructor, Gavin Herbert Eye Institute University of California – Irvine. She has no financial disclosures. Contact her at ajarstad@uci.edu.

Sumit Garg, MD, is associate professor of Ophthalmology, vice chair of Clinical Ophthalmology, and medical director, Gavin Herbert Eye Institute, UC – Irvine. He is a consultant to Johnson & Johnson, Kala Pharmaceutical, and RySurg. Contact him at 949-824-0327 or gargs@uci.edu.