Although estimates vary widely there could be as many as 25 million Americans suffering from dry eye disease (DED), with the majority of those affected being women. Millions more are believed to have similar, but less severe symptoms.

As the population ages the prevalence of the disease is on the rise and unfortunately, up until recently, patients have had few options to treat this debilitating chronic condition.

This is all changing thanks to research that has uncovered that DED is a multifactorial disorder caused by a dysfunction of tears with inflammation playing a central role.

Although for the past decade or so it was understood that there was an inflammatory component to dry eye disease it is only recently that some of the underlying molecular biology associated with the disease has been elucidated, Eleven Biotherapeutics Inc. president and CEO Abbie Celniker told BioWorld Insight.

Protein Engineering

Her Cambridge, Mass.-based company is using protein engineering to create differentiated protein-based biotherapeutics. From this drug discovery platform has emerged lead drug EBI-005, the first rationally designed topically administered IL-1 protein for the treatment of ocular diseases.

"We were able to engineer EBI-005 that strongly inhibits IL-1, a key player in the inflammatory process that leads to dry eye disease," noted Celniker. "In addition we were able to confer the protein with stability at room temperature, a property essential for use as topical eye drops."

The company recently released the results from a Phase Ib/IIa study of EBI-005 in DED. The six-week, randomized, double-masked, placebo-controlled trial showed statistically significant improvements in the signs and symptoms of the disease compared to baseline. It also met predefined efficacy criteria and demonstrated a differential effect between patients who received the drug and those who received vehicle control. (See BioWorld Today, June 28, 2013.)

The trial ran for six weeks, enrolling 74 subjects with DED at centers in the U.S. The primary endpoint of the study was safety and tolerability of EBI-005 compared to vehicle control, as measured by Ocular Surface Disease Index and corneal fluorescein staining.

"From our research we were encouraged by the fact that no patient administering EBI-005 dropped out of the study and reported that it made their eyes feel good," said Celniker.

The company is planning to begin a pivotal trial early in 2014, with completion of enrollment and data available by the end of 2014. The 12-week trial will enroll patients with moderate to severe DED, as patients with mild disease are usually started on artificial tears initially.

"The interesting thing about these trials is that they can enroll fairly quickly and since they typically last just 12 weeks within a year you can have your data read out," added Celniker.

The company's protein design technology has attracted Thrombogenics NV, of Leuven, Belgium, as a partner. The companies will use Eleven's technology to create a drug with improved pharmaceutical and therapeutic benefits for diseases of the back of the eye such as diabetic macular edema. Thrombogenics will pay Eleven an undisclosed up-front payment. Eleven also is eligible for undisclosed development, regulatory and sales milestones, as well as royalties on product sales. (See BioWorld Today, May 29, 2013.)

Crowded Disease Space

Eleven is just one of many companies targeting therapeutics at DED. Emphasizing the growing interest in the space, Shire plc shelled out $160 million up front to acquire Sarcode Bioscience Inc., which gave the it access to lifitegrast, an investigational small-molecule integrin antagonist which is undergoing a second pivotal Phase III trial in dry eye disease. (See BioWorld Today, March 26, 2013.)

The candidate drug disrupts the interaction between lymphocyte function-associated antigen-1 (LFA-1) and its ligand, intercellular adhesion molecule-1 (ICAM-1), central, the company said, to T-cell activation, proliferation, migration, and inflammatory cytokine release at sites of ocular surface stress.

Lifitegrast achieved a primary endpoint in one Phase III trial, called OPUS-1, which compared its effect on corneal staining scores – a proxy for ocular damage caused by dry eye disease – with that of placebo in 588 patients. A confirmatory trial in about 700 patients began recruitment last December, and a safety study in 300 patients, designated SONATA, is ongoing. (See BioWorld Today, March 19, 2013.)

Several other companies are developing compounds that employ a variety of therapeutic strategies targeting DED including OphthaliX Inc., of Carson City, Nev., that has initiated Phase III trials with an oral A3 adenosine receptor agonist, CF101 and Regenerx Biopharmaceuticals Inc., of Rockville, Md., has reported data suggesting RGN-249 (Thymosin beta 4 eye drops) demonstrated the ability to reduce symptoms of DED. (See BioWorld Today, March 21, 2012.)

Acucela Inc., of Seattle, began a Phase III trial of 2 percent rebamipide ophthalmic suspension for DED. The trial will support eventual U.S. regulatory submission for the product, already launched in Japan as Mucosta by Otsuka Pharmaceutical Co. Ltd.

The randomized, placebo-controlled, double-masked trial will enroll 560 subjects in two treatment groups, with completion anticipated by the end of 2013. (See BioWorld Today, July 20, 2012.)

Canadian company Mimetogen Pharmaceuticals Inc., of Montreal, is developing MIM-D3, a small molecule mimetic of nerve growth factor (NGF) that binds specifically to the TrkA receptor. MIM-D3 is designed to quickly and directly improve the quality of the tears produced by the eyes while also reducing clinical signs and symptoms of dry eye, such as chronic dryness and grittiness. The company has reported Phase II data showing that the drug is well tolerated and significantly improved signs and symptoms of dry eye at low and high doses.

Editor's Note: This is the first part in a series on diseases of the eye.