June 2012




Pharmaceutical focus

The next wave of novel dry eye therapies

by Maxine Lipner Senior EyeWorld Contributing Editor

Dry eye

Novel therapies are in development they may help patients with dry eye (pictured here) Source: Alan N. Carlson, M.D.

New agents poised for takeoff

Let's face it: Dry eye is everywhere, with many patients suffering from this all- too-common condition. EyeWorld looked at some novel therapies working their way through the pipeline that could help bring additional relief to some of these dry eye sufferers.

New T-cell modulator

Mention T-cell modulator to practitioners and Restasis (cyclosporine, Allergan, Irvine, Calif.) immediately comes to mind. Now a new T-cell modulator, SAR 1118 (lifitegrast, SARcode Bioscience, Brisbane, Calif.), is winding its way through channels. Eric D. Donnenfeld, M.D., co-chairman, Cornea, Nassau University Medical Center, East Meadow, N.Y., sees this as an exciting new technology. "It works similarly in many ways to Restasis," he said. "It's a T-cell modulator but it works more quickly, and in the FDA Phase II trials it worked better than what we saw with Restasis."

The new drug helps to tamp down on inflammation. "SAR 1118 is a lymphocyte function-associated antigen inhibitor of the intracellular adhesion molecule I-CAM-1, which prevents binding of T-cell mediated inflammation in dry eye," Dr. Donnenfeld said. He sees the mechanism of action here as supporting the concept that inflammation drives dry eye disease. "The binding of LFA-1 to I-CAM-1 is basically the central event that occurs in T-cell activation migration and proliferation," he said. "This new drug reduces T-cell mediation inflammation by preventing the LFA-1/I-CAM-1 binding, and the Phase II trials were overwhelmingly successful." In Phase II trials, investigators found that there was a rapid improvement in dry eye symptoms. In addition to being well tolerated, one of the things that makes SAR 1118 promising is how rapidly it appeared to work. "The onset of action is only 2 weeks," Dr. Donnenfeld said. This speed he attributes to the novel mechanism of action, which is to act as an LFA-1 antagonist. "By blocking this interaction, it acts on active T-lymphocytes and prevents them from working, while Restasis works on the production of T-lymphocytes," Dr. Donnenfeld said. "So it takes a full cycle of inflammation, which is about 100-110 days, for Restasis to have the full effect." Because there are differences in the mechanism of action, Dr. Donnenfeld sees the potential for SAR 1118 and Restasis to be used in concert. "They are both T-cell lymphocyte inhibitors, and we can postulate that there might be a synergistic effect by using them together, but no one has looked at that," Dr. Donnenfeld said. "We don't know if there's an advantage to using them together or not, but I'm certain that's one thing we'll be looking at." Currently SAR 1118 is in Phase III FDA trials, which should be completed shortly. Dr. Donnenfeld will look to the trials to clarify SAR 1118's potential role in controlling dry eye. "That's going to give us a lot of information on where this drug is best used," he said.

Oils in action

Also piquing interest are some novel agents that appear to have promise in keeping dry eye symptoms at bay. One product approved for over-the-counter use in the E.U., T-Clair SPHP700-3 (Sinclair Pharma, London), continues to be eyed with interest in the U.S. The agent, which is a combination of linseed extract and polyvinylpyrrolidone, showed promise in a March 2011 study published in Cornea. In the study, 60 patients with mild to moderate dry eye were given either the preservative-free T-Clair or a placebo. After 2 and 4 weeks of treatment, results showed significant differences between the two groups. No adverse events were reported here. Investigators concluded that in mild to moderate dry eye, the agent appeared to be safe and effective in improving tear film stability, ocular surface lubrication, and patient symptoms.

Dr. Donnenfeld sees nutritional supplements such as fish oil, rich in omega-3 fatty acids, as being useful here. "Oral nutritional supplements have become very interesting to me in the management of dry eye," he said. While there is some evidence that omega-3 fatty acids have poor absorption and cause gastrointestinal side effects, this is not so for newer formulations, finds Dr. Donnenfeld. "Some of the more modern omega-3 fatty acids are the triglyceride forms, which have been processed and have much better absorption, much better purity, and achieve much higher blood stream levels of omega-3s, and seem to be more efficacious," he said. "I think that we're going to see nutritional supplements play a major role in the management of dry eye and meibomian gland dysfunction as well."

There are also new polyunsaturated fatty acid agents known as Resolvin analogues (Resolvyx Pharmaceuticals, Cambridge, Mass.) that hold promise when applied topically as drops. Stephen C. Pflugfelder, M.D., professor of ophthalmology, Cullen Eye Institute, Baylor College of Medicine, Houston, sees these as acting like super fish oil. "The company has claimed that they're about 10,000 times more potent than fish oil in their anti-inflammatory effects," he said. These work on pathways involved in resolving inflammation.

Dr. Pflugfelder, who was involved in pre-clinical testing with several Resolvin compounds, sees these as having intriguing possibilities. "They were found to improve corneal epithelial disease and also to increase the density of goblet cells," he said. "That would indicate that they have promise for treating dry eye syndrome." He pointed out that the company has already performed and completed Phase II clinical trials in humans, which showed efficacy. Plans are under way to move to Phase III clinical trials shortly. These have been found to be very well tolerated. "They seem to be extremely safe since they're natural molecules that are produced by the body," Dr. Pflugfelder said. "They're synthesized from dietary lipids like fish oils into these Resolvin molecules."

Overall, he is hopeful that the novel drop will gain clinical traction. "I think that it remains to be seen how [this molecule] will do in Phase III trials," Dr. Pflugfelder said. "If it does get approved I think that it's a great addition to the armamentarium."

Editors' note: Dr. Donnenfeld has financial interests with SARcode Bioscience. Dr. Pflugfelder has financial interests with Allergan and Resolvyx.

Contact information

Donnenfeld: 516-446-3525, eddoph@aol.com
Pflugfelder: 713-798-4732, stevenp@bcm.tmc.edu

Related articles:

Dry eye effects on corneal refractive procedures by Ellen Stodola EyeWorld Staff Writer

Omega-3 and dry eye by Vanessa Caceres EyeWorld Contributing Writer

Treating dry eye by Vanessa Caceres EyeWorld Contributing Editor

Dry eye remains a complicated issue by Michelle Dalton EyeWorld Contributing Editor

Unraveling dry eye by Maxine Lipner Senior EyeWorld Contributing Editor

The next wave of novel dry eye therapies The next wave of novel dry eye therapies
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