Focus on Dry Eye

New options riding to the rescue of dry eyes

A review of diagnostics and treatments recently approved and in the pipeline.

By Tom Salemi, Contributing Editor, and Rich Kirkner, Executive Editor

Here’s a look at some of the newer and emerging approaches for the management of ocular allergies and dry eye.

EMERGING TREATMENTS

Liftegrast 5% solution

Shire (www.shire.com) announced last month that it plans to submit in the first quarter next year a new drug application for liftegrast 5% solution, a preservative-free, small-molecule integrin antagonist, for the treatment of dry eye disease. Liftegrast is believed to reduce inflammation by inhibiting lymphocyte function-associated antigen 1 (LFA-1) and prevents its binding to intercellular molecules that influence T-cell activation and cytokine release.

Liftegrast has been the focus of the OPUS-1 phase 3 study, results of which were published in Ophthalmology in February.¹ The prospective, randomized, double-masked, placebo-controlled multicenter clinical trial involved 588 adults with dry eye disease, and found that while the liftegrast group did not achieve the primary study endpoint — mean change from baseline in the visual-related function subscale score of the Ocular Surface Disease Index — the group showed reduced corneal staining and improved symptoms vs. placebo group.

John Sheppard, MD, MMSc, of Virginia Eye Consultants and professor at Eastern Virginia Medical School, presented early results from OPUS-2 phase 3 trial at ASCRS 2014 in Boston. All 588 participants in OPUS-2 used artificial tears within 30 days of screening for enrollment, whereas OPUS-1 included patients who had not used artificial tears.

Dr. Sheppard notes that Lifitegrast met the prespecified co-primary endpoint for the patient-reported symptom of eye dryness (change in Eye Dryness Score from baseline to week 12), but not the endpoint for reduced corneal staining. “Each OPUS-1 and OPUS-2 achieved the signs-and-symptoms endpoint,” Dr. Sheppard says. “This medication, when it is approved, could really grow the dry eye space.”

Protein-based therapies

Eleven Biotherapueutics (www.elevenbio.com) is designing and engineering protein therapies for ocular disease, including dry eye. The company is using its AMP-Rx platform to build a pipeline of protein-based therapies. Lead product EBI-005 is a topically administered IL-1 blocker in phase 3 clinical trials for dry eye condition. The company intends to file a BLA for the product in 2016. Eleven went public in February.

Eleven’s EBI-005 goes directly after IL-1 receptors found in neurons. As inflammation associated with dry eye sets in, the IL-1 receptors begin reacting, causing discomfort. Eleven’s EB1-005 was created to join with those receptors and alleviate inflammation. Patients on the drug also have been found to use far less artificial tears.

Eleven is running EBI-005 through a double-masked, vehicle-controlled study in the United States involving 650 patients. The endpoints included pain relief, and patients being treated will have limited access to artificial tears to ensure any relief comes from the drug.

In addition to its primary product, Eleven is testing two additional compounds targeting other receptors as treatments for diabetic macular edema and uveitis.

Mimicking NGF

A privately held clinical stage biotech, Mimetogen Pharmaceuticals (mimetogen.com) is conducting clinical trials on potential drugs that someday could alleviate the symptoms and discomfort associated with dry eye while repairing the ocular surface.

Mimetogen’s lead compound, MIM-D3, is undergoing a pivotal multi-center Phase III clinical trial. CEO Garth Cumberlidge reported at the Ophthalmology Innovation Summit (OIS) at ASCRS in April that the company anticipates results from the phase 3 pivotal trial this summer. Mr. Cumberlidge says MIM-D3 mimics the effects of neurotrophins, proteins that can help stimulate mucin levels and epithelial healing. The compound can restore tear flow to the eye, reduce sensitivity and enable the eye to heal.

MIM-D3 mimics a nerve growth factor, or NGF, which connects and activates the tyrosine kinase receptor agonist (TrkA) receptor but does not bind to the p75NTR receptor, two well-validated cell surface receptors.

Mr. Cumberlidge said early clinical data have demonstrated MIM-D3 is safe, but the nature of dry eye makes clinical testing difficult because the signs and symptoms can wax and wane, causing the clinician to confuse them with allergies. The multi-center, randomized, double-masked, placebo-controlled study involves 400 patients randomized into two groups: one receiving 1% MIM-D3 ophthalmic solution twice a day and the other a placebo. Bausch + Lomb holds the option to license MIM-D3 for dry eye.

DIAGNOSTIC TOOLS

Sjögren’s syndrome test

Nicox (www.nicox.com) introduced it’s test for diagnosing Sjögren’s syndrome, known as Sjö assay test, in the United States late last year. The test combines traditional markers with three novel, proprietary biomarkers. With 40 million dry eye sufferers in the United States, approximately one in 10, or 4 million, may have Sjögren’s syndrome, according to investigators at Wilmer Eye Institute of Johns Hopkins Hospital.² Of those, only approximately 1 million cases are thought to be diagnosed, according to the Sjögren’s Syndrome Foundation.

“The Sjö assay tests for traditional antibody markers of autoimmune disease including ANA, RF, SS-A (Ro) and SS-B (La), in addition to three novel proprietary biomarkers that markedly improve the sensitivity and specificity of laboratory testing for Sjögren’s Syndrome,” says Laura M. Periman, MD, at Redmond Eye Clinic in Seattle. She notes the three novel biomarkers are antibodies to carbonic anhydrase 6 (CA-6), a salivary buffering enzyme, parotid secretory protein (PSP) that binds and clears infectious agents and salivary protein 1 (SP 1) whose function is unknown.

“Antibodies to CA-6 occur very early in SS patients and add additional sensitivity to the diagnosis of early SS,” Dr. Periman says. “My patients with elevated CA-6 antibodies report dry mouth and dental problems. SP-1 proteins have the greatest specificity and sensitivity to Sjögren’s Syndrome.”

Allergy screening tool

A key part of the diagnostic work-up for ocular surface disease involves ruling out allergic conjunctivitis, notes Dr. Sheppard. The Ocular Allergy Diagnostic System from Doctor’s Allergy Formula (DAF) (www.drsallergyformula.com) is an in-office skin test that can identify 60 of the most common local environmental antigens that can contribute to ocular symptoms. It was made commercially available in the United States in the past year.

The test takes a trained technician about three minutes to perform and provides results in 10 to 15 minutes — and it is reimbursable, according to DAF. Dr. Sheppard further notes the test is tailored to 40 different zones in the United States — “So you don’t test for rag weed in California or fungi in Maine.” At his Virginia practice, he covers three different zones.

The Ocular Allergy Diagnostic System is a variation of the acute antigen panel that allergists have used for years, Dr. Sheppard says. “Now we can be much more scientific in our approach to allergic ocular surface disease,” he says. “Antigens and genetic predisposition prompt the allergic cascade, and we know prevention is the best medicine.” The test is a diagnostic tool that wasn’t available even a year ago, he adds.

Testing an inflammatory marker

Rapid Pathogen Screening (www.rpsdetectors.com) has developed a test to diagnose dry eye through an inflammatory marker. Its InflammaDry System is a point-of-care diagnostic that tests a small tear sample for the presence of proteolytic enzymes that the body produces by stress of the epithelial cells on the ocular surface. InflammaDry detects MMP-9, an inflammatory marker found in the tears of patients with dry eye. The microfiltration technology of the device identifies the protein within 10 minutes of the initial sampling taken from the palpebral conjunctiva.

CEO and President Robert P. Sambursky, MD, said at the OIS at ASCRS that rather than replace existing diagnostic tests including staining, Schirmer and TBUT, InflammaDry can help guide treatment. A technician can determine within 10 minutes whether a patient’s eye is inflamed. With a positive test, the clinician can begin immediate therapy with an anti-inflammatory agent.

The test results appear as colored lines in a tiny window of the diagnostic, which resembles a pregnancy test. A single blue line indicates no inflammation, whereas a blue line combined with a red line suggests the patient’s eyes are inflamed. Dr. Sambursky said clinical trials have shown the accuracy of the tests. One trial included 237 patients who were showing symptoms of dry eye. Standard testing revealed 61% of the patients actually had dry eye; of those, 80% tested positive for inflammation using InflammaDry. Nearly all of the 39% who tested negative for dry eye also tested negative for inflammation, demonstrating a tight correlation, he said.

Tear osmolarity testing

TearLab Corporation (www.tearlab.com) sells the TearLab Osmolarity System, a nanofluidic diagnostic system capable of diagnosing dry eye in the office. The FDA-approved diagnostic has secured a Clinical Laboratory Improvement Amendment waiver, CEO Elias Vamvakas told OIS at ASCRS. Medicare issued a CPT code that reimburses the test at $45.08 per patient. Mr. Vamvakas said the company gives physicians the Osmolarity System for free but charges for the test strip used in the diagnosis. Per patient costs run between $20 and $25.

The osmolarity test requires 50 nL of tears to obtain a measurement of tear salinity. The doctor tests both eyes and takes the highest result of the two to determine the “Osmolarity Number,” which determines the severity of dry eye. The company has placed approximately 2,500 units in more than 1,100 physician practices, Mr. Vamvakas said.

Targeting MGD

CEO Tim Willis told OIS at ASCRS that his nine-year-old TearScience (www.tearscience.com) is the only company to have obtained FDA clearance to treat evaporative dry eye. The company is ramping up plans to sell a product line that includes the LipiView Ocular Surface Interferometer, the Korb Meibomian Gland Evaluator and the LipiFlow Thermal Pulsation System.

The LipiView interferometer measures the absolute thickness of the lipid layer of a patient’s tears film and identifies partial blinking. The accompanying Korb Meibomian Gland Evaluator helps evaluate meibomian gland secretions during a routine examination. LipiFlow treats the root cause of evaporative dry eye disease, MGD, with thermal pulse technology.

Mr. Willis said the products will enable physicians to treat the 40% of patients who complain of dry eyes. Currently, he said, dry eye treatments account for less than 2% of physician revenue. Meanwhile, he noted, 84% of physician customers reported they paid off the capital costs for the equipment in less than a year. Patients typically pay for the procedure out of pocket and require a one-year follow-up treatment.

TearScience recently secured $70 million in financing as it begins to more aggressively market a line of diagnostic and treatment devices. OM

REFERENCES