New clinical trial to tackle dry eye

Dry eye is one of the most common of all eye conditions, primarily affecting adults 45 years and older. Many different things can cause dry eye, including environmental exposure, medications, eye surgery (such as laser correction surgery), immune system disorders such as Sjogren's syndrome, lupus, or rheumatoid arthritis, and an increasingly common cause -- staring at computer or video screens for too long without blinking. So it's not surprising that experts estimate that more than 12 million Americans may be dealing with dry eye symptoms on a daily basis.

Despite its prevalence, there are relatively few treatments available. There are lubricating drops, which must be applied multiple times during the day, to replace natural tears. Restasis® drops (the only drug currently approved by the FDA for dry eye disease) increase natural tear production in the eye. But those with severe dry eye might need surgical insertion of lacrimal or punctal plugs to block the eyes' drainage ducts and keep tears in place.

"Dry eye is a major unmet medical need," said Jerome Wujek, Ph.D., a program director at NEI who manages the Small Business Innovation Research (SBIR) grants. "Restasis® drops work for some people, but they don't work for everyone, and it can take them two months or more to become effective."

Supporting research into a better treatment for dry eye has been one of Dr. Wujek's tasks for the past eight years and has just begun to reach fruition with the launch of an FDA-approved Phase I clinical trial that will test the safety and efficacy of a novel drug called P-321 Ophthalmic Solution. The drug is applied as an eye drop and targets a unique mechanism involved in maintaining moisture in the eye. Its development was supported through two NEI SBIR grants to Parion Sciences, Inc. and through the NCATS Bridging Interventional Development Gaps (BrIDGs) program, which gives investigators access to NIH subcontractors who conduct preclinical safety studies necessary for an FDA Investigational New Drug (IND) application.

Tears are a complex mix of water, lipids, and proteins such as mucin, and minerals such as sodium and potassium. They are produced by the lacrimal glands, located above and to the outside of the eye socket, with stimulation from the trigeminal and facial nerves. This involvement of the nervous system is why emotions can produce tears. The volume of tears is maintained by the epithelium, which is the outermost layer of the cornea and the conjunctiva, a protective membrane that lines the eyelids and the sclera (the whites of the eyes).

As it turns out, tiny cellular pores called sodium channels located in the epithelium play a key role in the regulation of tear fluid levels, by controlling the reabsorption of tears by the epithelium. This suggested to scientists at Parion that a successful treatment intervention might be to explore mechanisms that close the channels and block tear resorption.

"In the body, sodium is a key regulator of water volumes. Where sodium goes, water follows," said Dr. Wujek. "Parion Sciences had already been using this kind of approach when they developed similar drugs to increase the retention of moisture in mucosal tissue in the lungs of people with cystic fibrosis. So we thought it made sense to expand this work into a possible treatment for dry eye."

"What it does in the eye is inhibit the tear resorption pathway to retain more of the tears that you naturally have," said Bill Thelin, Ph.D., executive director of research at Parion Sciences. By maintaining a close to normal tear volume, the compound preserves the characteristics of a healthy eye."

Parion secured outside investors to fund its clinical studies of P-321 Ophthalmic Solution in human subjects - a prime marker of success for an SBIR grant -- which is supposed to get technologies or treatments to the place where they are viable for FDA testing and on the path to commercial application. Parion enrolled their first patient in the Phase 1/2a trial this past July, and expect to add another 47 or so people with dry eye in the coming months.

They will be testing four different concentrations of P-321 to determine safety and tolerability of the compound. The SBIR-supported preclinical studies indicated that the treatment is effective when administered twice a day, but a daily drop is not out of the question. After the initial clinical trial, a much larger Phase II trial will continue to get the compound ready for the marketplace, which Dr. Thelin estimates will be another four to five years away.

"We're hoping this compound will be able to successfully treat many more people with dry eye than what is currently available," says Dr. Wujek. "It might also be used to complement drugs that treat the inflammatory aspects of dry eye, such as Restasis®, and could be especially helpful for people with severe dry eye disease."