Nancy A. Melville

May 01, 2014

BOSTON — Two new therapies tackle the tough-to-treat symptoms of dry eye disease by targeting the inflammation associated with the condition.

The need for more treatments is pressing, said Michael Goldstein, MD, from Tufts Medical Center in Boston.

Approximately 7 million Americans experience moderate to severe dry eye syndrome, but the only product approved by the US Food and Drug Administration to treat dry eye syndrome is cyclosporine 0.05% (Restasis, Allergan).

"There is a large unmet clinical need for therapies," he said.

Dr. Goldstein presented 1 of 2 studies on therapies designed to meet that need presented here at the American Society of Cataract and Refractive Surgery 2014 Symposium.

In the double-blind study conducted at 8 sites in the United States, Dr. Goldstein's team evaluated EBI-005, a novel topical interleukin (IL)-1 receptor blocker. IL-1 plays a key role in initiating the inflammatory response in diseases, including dry eye disease.

The 74 patients with moderate to severe dry eye disease were randomized to EBI-005, either 5 mg/mL or 20 mg/mL, 3 times a day for 6 weeks or placebo.

After 6 weeks, patients in the EBI-005 groups had a 33% improvement from baseline in total corneal fluorescein staining, a measure of dry eye disease (P < .001).

In addition, patients in the EBI-005 groups had a 36% improvement from baseline in total Ocular Surface Disease Index (OSDI) score and a 46% improvement in eye pain.

Patients in the EBI-005 groups with baseline OSDI scores below 50 had a 39% improvement in total corneal fluorescein staining, a 41% improvement in total OSDI score, and a 61% improvement in eye pain. All improvements exceeded those seen with placebo.

Patients in the EBI-005 groups also used significantly fewer rescue artificial tears than those in the placebo group (< .029).

No serious adverse events were reported, and no patients dropped out of the study. On Cochet-Bonnet esthesiometry, there were no signs of neurotrophy, which is associated with treatment, Dr. Goldstein reported.

Dry eye signs and symptoms will be further investigated as coprimary end points in phase 3 trials of the therapy, he said.

"What most people think is symptomatic relief in dry eye syndrome is secondary to decreasing inflammation," he explained. "That may be how cyclosporine makes people feel better."

Research is ongoing to better understanding how IL-1 works. "IL-1 is unique, in that the IL-1 receptors are on peripheral nerves, so there is another mechanism on which we believe IL-1 is working. That will be the focus in larger trials," he said.

A Disconnect Between Symptoms and Signs

In the second presentation, Joseph Tauber, MD, from the Tauber Eye Center in Kansas City, Missouri, discussed findings from the phase 3 randomized placebo-controlled OPUS-2 trial on lifitegrast ophthalmic solution 5.0% (Shire PLC).

Lifitegrast is an ICAM-1 decoy designed to target T-cell-mediated chronic inflammation.

Over 12 weeks of treatment, symptom improvement was robust, but improvement in actual signs of disease, which had been achieved in the phase 3 OPUS-1 trial, was not met in the second trial.

Results from the OPUS-2 and OPUS-1 trials were previously reported by Medscape Medical News.

This stumbling block is not uncommon in trials of dry eye disease, said Dr. Tauber. "The disconnect between symptoms and signs is something that everyone who treats dry eye patients is intimately familiar with," he said.

"Explaining why we're able to see improvement in one and not the other is a question that has perplexed all of us for years, including every company that has tried to get a product approved, so I don't have any scientific explanation for this," he said.

When it comes to dry eye disease, improving symptoms is the bottom line, he emphasized.

"If you look at dry eye, you see that this is a disease of symptoms. Making patients feel better — that's what we're all trying to do," he said. "If you change a sign but not a symptom, I don't think that's going to be a popular treatment option with patients."

Symptoms are typically seen as the more subjective measure of disease, said session comoderator Keith Walter, MD, professor in ophthalmology at Wake Forest University in Winston-Salem, North Carolina. However, in this case, the signs can be subjective as well, possibly explaining the trial's disconnected results.

This disconnect probably "has to do with the study design of looking at inferior corneal staining," he told Medscape Medical News. "This can be very subjective, depending on the observer and how it was done."

True objectivity, in general, can be a tough measure to achieve with dry eye disease, he added.

"Symptomatically, the study patients were much better, and that says a lot, but the problem is there aren't really any great objective signs to look for with dry eye disease," Dr. Walter said.

"Tear osmolarity sounds promising. If that was done, it might have helped the study reach a better conclusion," he explained.

Dr. Goldstein reports equity and salary with Eleven Biotherapeutics. Dr. Tauber reports receiving research funding from SARcode Bioscience, a wholly owned subsidiary of Shire. His coauthors — Aparna Raychaudhuri, PhD, and Charles Semba, MD — are full-time employees of Shire. Dr. Walter has disclosed no relevant financial relationships.

American Society of Cataract and Refractive Surgery (ASCRS) 2014 Symposium. Presented April 27, 2014.

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