What's new in the drug pipeline for dry eye?

Current therapies for dry eye mainly treat the symptoms, not its underlying causes. To make matters worse, most dry eye therapies require frequent reapplication and provide only short-term relief.

In an effort to improve dry eye therapy, the National Eye Institute (NEI) provides funding for research that may lead to better, longer lasting treatment for the estimated 12 million Americans who deal with dry eye symptoms on a daily basis.

Here's a roundup of some of the latest NEI-funded research for dry eye.

Lacritin

A novel therapy undergoing clinical trials is a synthetic form of lacritin, a protein that stimulates tear secretion and corneal epithelial renewal.

More than two decades ago, Gordon Laurie, PhD, a cell biologist at the University of Virginia, set out to identify a substance that the eye naturally produces to combat dryness. "Our goal was to find out what's going on before the inflammation starts," he said.

Dr. Laurie and his team screened eye proteins for regulators of basal tearing. "Our tears contain many components, including 1,500 proteins. Identifying the key substance that stimulates tear production was a hard and slow process," Dr. Laurie noted. "It was like looking for a needle in a haystack."

Using systematic oligonucleotide screening, they identified lacritin—a natural component of human tears that flows from the lacrimal gland (with contributions from the meibomian gland, conjunctiva, and cornea) onto the ocular surface.

Researchers don't understand exactly how lacritin works, but one hypothesis is that it directly stimulates corneal sensory neurons responsible for sensing dryness. Lacritin also appears to counter inflammatory cytokines and activate autophagy—a process that helps regulate homeostasis.

Low lacritin levels can disrupt homeostasis, Dr. Laurie explained. In an animal study, Dr. Laurie and colleagues confirmed that a single daily dose of lacritin, given for 2 weeks, elevated basal tearing and that the effect lasted for least 1 week after treatment ended.

Dr. Laurie patented the synthetic lacritin—dubbed Lacripep—and started a company to develop it. The company has begun a 27-site clinical trial to investigate the use of synthetic lacritin in people with Sjögren's syndrome-related dry eye. Results are expected in early 2018.

"We think that dry eye disease may be much simpler than people have thought in the past, sort of like insulin and type 1 diabetes," Dr. Laurie said. "With lacritin deficient in dry eye tears, topical Lacripep is a replacement therapy, which will probably not cure the disease. You would still have to keep treating your eyes, but maybe just once a day."

Because lacritin—or lack of it—is also diagnostic for Sjögren's syndrome, Dr. Laurie is currently developing a clinical test for lacritin deficiency to identify people who are candidates for the therapy.

Neural tear stimulation

In April 2017, the FDA granted Allergan marketing approval for TrueTear™ Intranasal Tear Neurostimulator. The idea for the device grew out of research at Stanford University, where a team of bioengineers and ophthalmic surgeons investigated whether electrically stimulating the lacrimal gland could produce tears, and thereby treat dry eye disease.

When the investigators delivered micro-electrical pulses to the anterior ethmoidal nerve in the nasal cavity, they observed that it stimulated the lacrimal gland to enhance secretion of tears.

In additional research in animals, they found that neurostimulation increased aqueous tear volume, reduced osmolarity, added lipid to stabilize the tear film, and increased the concentration of naturally secreted proteins.

TrueTear Intranasal Tear Neurostimulator is a handheld device with daily disposable tips that are inserted into the nasal cavities. It is typically used twice a day, 1 to 3 minutes at a time. It requires a prescription.

Sodium channel blocker

Sodium channels in the epithelium play a key role in regulating tear fluid levels by controlling the reabsorption of tears. With this in mind, researchers at Parion Sciences speculated that a successful treatment intervention for dry eye might be one that closes the sodium channels and blocks tear resorption, which would retain more tears.

Researchers had investigated similar drugs to increase the retention of moisture in mucosal tissue in the lungs of people with cystic fibrosis. So, with the help of NEI funding, Parion scientists applied this knowledge toward a possible treatment for dry eye. They came up with P-321, a novel small-molecule epithelial sodium channel (ENaC) inhibitor.

"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, PhD, Vice President of Research at Parion Sciences. "By maintaining a close-to-normal tear volume, the compound preserves the characteristics of a healthy eye."

Investigators undertook a phase 1/2a placebo-controlled dose escalation clinical trial to evaluate the safety and tolerability of P-321 in 53 patients with mild-to-moderate dry eye disease. Results showed that P-321 was safe and well tolerated, with no discomfort or irritation seen upon instillation. Adverse events in patients assigned to P-321 were generally similar to or fewer than those that occurred in the patients given placebo, and none of the adverse events were considered serious.

Although the study wasn't designed to assess efficacy, investigators observed "positive trends" in improvement of dry eye signs and symptoms in subsets of patients compared with placebo, with increases observed in the tear meniscus height and improvement of dry eye symptoms after 4 weeks of treatment.

Investigators expect to conduct a phase 2b study after consultation with health authorities.

Omega-3 fatty acids

Over-the-counter omega-3 dietary supplements are widely available, with claims that they lessen risk of heart disease, lower inflammation, fight cancer, help prevent Alzheimer's disease, moderate depression, and reduce dry eye—among other usages.

However, many of these claims are based on limited, small studies. "These studies lack consistency in terms of the type and dose of omega-3 therapy used," explained Penny Asbell, MD, Professor of Ophthalmology and Director of the Cornea Service and the Refractive Surgery Center at Icahn School of Medicine at Mount Sinai, in New York, NY.

Dr. Asbell is chairing the Dry Eye Assessment and Management (DREAM) Study, an NEI-funded clinical trial and the first large independent, multisite, double-blind investigation of omega-3s for dry eye. The study will involve 600 participants at approximately 25 eye centers across the United States. Participants will be randomly assigned to receive either omega-3 nutritional supplements (2,000 mg EPA and 1,000 mg DHA per day) or placebo (olive oil). Investigators will compare ocular surface disease index (OSDI) scores from baseline to 6 months and 12 months.

"In addition to evaluating the role of omega-3s in the outer, oily layer of tears, we expect to gain insights about the role of inflammation in dry eye. We hope to determine whether there are inflammatory biomarkers for dry eye," Dr. Asbell said.

Further information about NEI's research efforts can be found on the NEI website.