George W. Ousler III

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Several new dry eye drug candidates are currently under evaluation and show great potential. SAR1118 (SARCode) is a selective small-molecule LFA-1 antagonist, inhibiting T-cell migration, proliferation, adhesion, and cytokine release thus preventing T-cell mediated chronic inflammation.

  A phase III study evaluating the efficacy of SAR 1118 (5.0%) compared with placebo in the treatment of dry eye is currently ongoing.

Mimetogen has developed a family of small-molecule tyrosine kinase receptor agonists that are powerful mucin secretagogues that have been shown to stimulate MUC 5AC secretion from conjunctival goblet cells. MIM-D3 is a small-molecule mimetic of nerve growth factor (NGF) and has completed a phase II study designed to compare the safety and efficacy of 1% MIM-D3 and 5% MIM-D3 with placebo for the treatment of the signs and symptoms of dry eye.

Also on the docket and of obvious interest is Allergan's Restasis X, a new variation of cyclosporine, which is listed in phase II.

At Ora, we have studied more than 10,000 patients across 150 dry eye trials. One core concept we've learned is that dry eye symptoms fluctuate as the seasons come and go, with many patients experiencing a worsening of signs and symptoms during heightened dry eye seasons. For example, patients living in the Northeast region of the United States may find the winter months especially challenging, because the air is drier and the humidity is decreased both indoors and outdoors. Traditionally, environmental studies investigating dry eye therapies have been conducted across many seasons, some continuing for many years. 

In order to minimize the environmental influences, a clinical trial is best conducted during a single season to reduce the unpredictability of environmental factors. Trying to control for environmental factors is also challenged by numerous situational factors that may further exacerbate dry eye, such as prolonged visual tasking, ocular surgery, aging, and certain medications that cause ocular drying. 

By reducing the variability caused by environmental and situational factors using an environmental model like the Controlled Adverse Environment (CAE), which was designed to exacerbate the signs and symptoms of dry eye by regulating humidity, temperature, airflow, lighting conditions, and visual tasking, we are able to study dry eye in a more controlled manner.

  The CAD model has been shown to be a valuable tool for screening and enriching patient populations in environmental trials, measuring the impact of therapeutic regimens on various subjective and objective endpoints before and after CAD exposure, and understanding of dry eye. 

Articles

The acceleration of research focused on dry eye over the past several decades has led to an increase in knowledge regarding the pathophysiology of the disease.

Dry eye brimming with innovation

Dry eye syndrome has been estimated to affect more than 5 million Americans,

  yet there is only one FDA-approved eye drop, cyclosporine ophthalmic emulsion 0.05% (Restasis, Allergan), for its treatment. A recent survey found that about 94% of eye-care practitioners have expressed dissatisfaction with existing treatments for dry eye and want more treatment options.

An array of therapeutic approaches to treating dry eye are currently under investigation and show potential. One of the most commonly studied topics is anti-inflammatories, many of which are based on existing systemic medications that have been reformulated for topical delivery to the eye. 

Another anti-inflammatory in the pipeline is an LFA-1 antagonist (SAR 1118, SARcode) that targets a broad range of ocular inflammatory conditions, and has demonstrated significant potency in preventing cell adhesion and cytokine production, which can be associated with ocular surface inflammation. In a phase II, randomized, multicenter, double-masked study comparing SAR 1118 (0.1%, 1%, 5%) with placebo, a total of 230 subjects received drops twice daily for 12 weeks.

  Results from the phase II study were reported in May 2010 and showed improvement for signs and symptoms of dry eye in only 12 weeks, which suggests a more rapid method of improvement.

Resolvins, naturally occurring lipid mediators that inhibit the production and transportation of inflammatory cells, also are being investigated heavily for the treatment of dry eye. Resolvins have been used preclinically for the treatment of a variety of diseases including rheumatoid arthritis and retinal disease. 

One such resolvin (RX-10045, Resolvyx) is scheduled to enter a phase III randomized, placebo-controlled, multicenter study this year. Phase II trials for the resolvin were conducted with a 28-day, randomized, multicenter, placebo-controlled study in 232 patients with moderate dry eye, in which the drug was administered twice daily. The results from the trial showed significant dose-dependent improvement from baseline in symptoms, with improvement observed across all symptoms evaluated in the study, including dryness, ocular discomfort, and effect of corneal staining in the CAE model.

Dry eye syndrome has been estimated to affect more than 5 million Americans, yet there is only one FDA-approved eye drop, cyclosporine ophthalmic emulsion 0.05%, for its treatment.

George W. Ousler III

Articles

Dry eye brimming with innovation

Dry eye pipeline full of potential