To the layperson, dry eye disease (DED), technically xerophthalmia, often is dismissed as an innocuous nuisance that can be treated with over-the-counter eye drops. But Anat Galor, an ophthalmologist in Miami and clinical expert with the American Academy of Ophthalmology (AAO), said the disease name "is a little bit of a misnomer" for a chronic indication that encompasses a variety of symptoms and can have serious consequences for patients. The multifactorial disease of the tears and ocular surface can result not only in burning and aching but also in visual disturbances and tear film instability that have the potential to damage the ocular surface.

"This is probably not a disease that's going to make you legally blind, but it has a lot of implications for quality of life," Galor told BioWorld.

Indeed, research conducted by the AAO suggested that fewer individuals diagnosed with DED actually present with dryness due to lack of sufficient tears as a symptom than from inflammation on the ocular surface or dysfunctional tear composition – lacrimal fluid that is too salty, insufficient in volume or displaying increased osmolarity.

Correspondingly, treatment for DED isn't a one-size-fits-all affair. Lifestyle modifications, including environmental strategies and dietary changes, often are recommended. Pharmacotherapy traditionally starts with artificial tears products, which vary in viscosity, composition and formulation. Other drug therapies include mucin production enhancers and, increasingly, anti-inflammatory agents. In 2016, the small-molecule LFA1/ICAM-1 antagonist Xiidra (lifitegrast) from Shire plc became the first FDA-approved integrin-targeted anti-inflammatory developed specifically for ocular use, though it first had to overcome a complete response letter requesting additional data from a phase III study that, fortuitously, was already underway. (See BioWorld Today, Oct. 20, 2015.)

The FDA had previously approved Restasis (cyclosporine) from Allergan Inc. (now Allergan plc) as the only other anti-inflammatory indicated to treat DED.

Xiidra contributed $259 million in revenues to Shire's bottom line during 2017, its first full year on the market, and the five-year consensus forecast is $1.1 billion, according to Cortellis Competitive Intelligence. Restasis pulled in $1.5 billion in 2017 sales, though revenues are expected to decline over the next five years as its patents begin to expire, despite last year's widely criticized and ultimately unsuccessful move by Allergan to shield the drug's intellectual property from inter partes review by offloading it to the Saint Regis Mohawk Tribe. (See BioWorld, Sept. 20, 2017, and Feb. 27, 2018.)

The anti-inflammatories approved to treat DED are low-risk, Galor said, but have their downsides. Restasis can cause a burning sensation in the eyes while Xiidra can cause an unpleasant taste – side effects that are poorly tolerated by some patients. However, the biggest problem with both medications is that, in many patients, they simply don't work.

Some turn to products that are generally but not specifically indicated for DED, such as Avenova, a pure hypochlorous acid developed by Novabay Pharmaceuticals Inc. A non-antibiotic designed to treat the underlying cause of bacterial dry eye, Avenova "is the only commercial product that is clinically proven to reduce bacteria on ocular skin surfaces, [so] sales of the product could continue to inch higher as the dry eye market grows with novel therapeutics, in our view, though the pace of market adoption could be slower than our original forecast," H.C. Wainwright analyst Raghuram Selvaraju wrote this month after Emeryville, Calif.-based Novabay expanded its marketing effort.

Research 'exploring many different pathways'

The dedicated DED pipeline also is alive and well, with nearly three dozen assets in the clinic and a dozen more in preclinical studies, according to Cortellis Competitive Intelligence.

"Researchers are exploring many different pathways," Galor said, citing efforts such as long-acting formulations, different anti-inflammatory mechanisms, nerve growth factor blockers and activators, ion channel inhibitors and cell-based therapies. Although most clinical candidates are not yet ready for prime time, some are moving through or toward pivotal trials.

At the head of the class is OTX-101, a cyclosporine nanomicellar solution developed by Sun Pharmaceuticals Industries Ltd., of Mumbai, India, which acquired the rights in 2016 from Auven Therapeutics Management LLLP, of St. Thomas, U.S. Virgin Islands, and filed for U.S. approval last year, according to Cortellis Disease Briefings.

A half-dozen agents also are in phase III development in DED. Kala Pharmaceuticals Inc. earlier this year reported outcomes from the phase III STRIDE 1 (Short Term Relief In Dry Eye) and STRIDE 2 trials of KPI-121 (loteprednol etabonate) 0.25 percent vs. placebo using the company's mucus-penetrating particle technology (MPP) to enhance delivery into target tissue of the eye. Those findings showed the drug met statistical significance in the primary endpoint of conjunctival hyperemia change, compared to placebo. But STRIDE 1 missed the mark for another pre-specified primary sign endpoint – inferior corneal staining change from baseline to day 15 (p=0.1128) – though a positive treatment effect for ocular discomfort was observed in the intent-to-treat population at day eight (p=0.0011). (See BioWorld, Jan. 8, 2018.)

Under the FDA's guidance, Kala disclosed Tuesday that the first patient was dosed in the third pivotal phase III STRIDE 3 trial of KPI-121 0.25 percent, expected to enroll 900 participants and designed to confirm the primary symptom endpoint of day 15 ocular discomfort severity. Data from the trial are expected to report in the fourth quarter of 2019, but Kala won't wait that long to move forward with regulatory plans. The Waltham, Mass.-based company plans to file a new drug application with the FDA during the second half of the year that includes data from one phase II, safety studies and the STRIDE 1 and 2 trials that, collectively, enrolled approximately 2,000 participants.

"We believe KPI-121 0.25 percent could obtain marketing approval for DED in 2020," Wainwright's Selvaraju wrote last month in a report initiating coverage on Kala with a buy and $35 price target, noting that the company's MPP technology "allows drugs loaded into specially designed nanoparticles to avoid the problem of washout that typically occurs via the mucus secreted at the ocular surface within the tear film. Through optimization of delivery, Kala's solutions permit lower concentrations of existing APIs to be used, enhancing safety and tolerability. More importantly, Kala's candidates can be dosed less frequently, meaningfully improving patient compliance and thus clinical outcome."

'Patients drop off pretty rapidly'

The richest portion of the DED pipeline belongs to midstage candidates. Oyster Point Pharma Inc. reported in July that the highest dose (2 percent) in its phase II PEARL trial of nicotine acetylcholine receptor (nAChR) agonist OC-02 showed a mean change in Schirmer's score of 19.3 mm compared to 2.6 mm for the control (p<0.0001). Mean change in Eye Dryness Scale score was -19 mm for the 2 percent dose compared to -6.8 mm for placebo (p=0.0006), and the 0.2 percent and 1 percent doses also were statistically significant on both measures, compared to placebo, in a dose-dependent manner.

The study was funded by a $22 million series A the Princeton, N.J.-based company landed last year in its effort to target the root cause of DED. At the time, CEO Jeffrey Nau told BioWorld that the potential to improve DED therapy loomed large.

"We have these two big drugs, [Restasis and Xiidra], a huge market, and big numbers behind both of these drugs, but those numbers should actually be exponentially higher, because patients drop off pretty rapidly," Nau pointed out. "The data we have say patients get their scripts filled for those drops two or three times" before they discontinue, he said. "These drugs are worth $1.5 billion, with [patients] only getting a couple of scripts filled." (See BioWorld, Nov. 8, 2017.)

Oyster Point has a second selective nAChR agonist, OC-1, in phase II development. In general, both compounds leverage the trigeminal parasympathetic pathway to activate the glands that comprise the lacrimal functional unit and promote tear film production, delivered as a nasal spray.

In July, Aldeyra Therapeutics Inc. said the last patient completed dosing in its 300-patient study comparing two doses of the topical formulation of reproxalap to vehicle over 12 weeks of treatment. The trial, designed to determine the optimal dose of the aldehyde scavenger to test in phase III and to assess the size of the next study, is expected to report top-line data in the second half of the year. The Lexington, Mass.-based firm also is testing the ocular version of reproxalap in allergic conjunctivitis and noninfectious anterior uveitis and the dermal version in ichthyosis associated with Sjögren-Larsson syndrome. (See BioWorld, July 25, 2018.)

Also last month, Aurinia Pharmaceuticals Inc., of Victoria, British Columbia, started a 90-patient phase II study designed to compare the tolerability of its calcineurin inhibitor, voclosporin, to Restasis after four weeks of treatment using the Ocular Surface Disease Index, System Assessment in Dry Eye, Individual Symptom Severity Assessments and Drop Discomfort Visual Analog Scale scores, along with fluorescein corneal staining and the Schirmer tear test. That trial also is expected to read out by year-end.

And Ocugen Inc., which is advancing its alpha-2 adrenergic agonist, OCU-300, into phase III development in ocular graft-vs.-host-disease using the 505(b)(2) pathway, has a separate candidate, OCU-310, with a different concentration of the active ingredient, brimonidine tartrate, in DED. In a phase II trial completed earlier this year, OCU-310 produced meaningful improvements across a number of endpoints related to the signs and symptoms of dry eye disease when compared to placebo. The company plans to move OCU-310 into phase III development this year. (See BioWorld, July 3, 2018.)

In all, 19 assets are in or have completed phase II development, according to Cortellis.

'Signs and symptoms don't correlate' in DED

The design of clinical trials in dry eye is, for now, a major obstacle to move new therapies to the finish line. To consider a filing for approval, the FDA wants to see pivotal trials that show improvement in one sign and one symptom of DED, Galor said, but there's more to that standard than meets the eye.

"One of the challenges of dry eye is that signs and symptoms don't correlate with each other due to the biology of the disease," she pointed out. "You can have a patient who feels much better but the eye surface looks the same, and you can have other patients where the surface looks much better but the patient doesn't notice any improvement. Because of that, many drugs that looked promising don't meet their primary efficacy endpoints when they get to large phase III studies."

She wasn't referring just to Kala. Another phase III victim was Rockville, Md.-based Regenerx Biopharmaceuticals Inc., which last year completed the phase III DED trial sponsored by its U.S. joint venture, Regentree LLC, of Princeton, N.J. Called ARISE-2, the trial investigated the safety and efficacy of RGN-259, a formulation of thymosin beta 4, compared to placebo in 601 patients. The experiment, conducted with Andover, Mass.-based Ora Inc., showed a number of statistically significant improvements in both signs and symptoms with 0.1 percent RGN-259 vs. placebo, along with good safety, comfort and tolerability profiles. Specifically, the ocular discomfort symptom showed a statistically significant reduction in the RGN-259-treated group at day 15 as compared to placebo (p=0.0149) in the change from baseline.

But ARISE-2 did not duplicate the results of the earlier ARISE-1 phase III study, which Wainwright's Selvaraju attributed to a more diversified patient population.

After meeting with the FDA, Regentree confirmed in April that the agency was insisting on an additional phase III trial (ARISE-3), expected to begin this year, to demonstrate efficacy in both signs and symptoms of DED in a larger patient population. The agency did, however, accept safety data from ARISE-1 and ARISE-2 and also said additional nonclinical efficacy and safety studies would not be required.

There's also the former Eleven Biotherapeutics Inc., now Sesen Bio Inc., whose lead candidate, EBI-005, failed to outperform a vehicle control, missing both co-primary endpoints in a phase III study in moderate to severe DED. Eleven called off an additional planned phase III study to concentrate instead on the drug's potential in allergic conjunctivitis, where it also proved a dud. (See BioWorld Today, May 19, 2015, and Jan. 20, 2016.)

The company's technology seemed sound – so much so that EBI-031, a humanized monoclonal antibody that Eleven said binds IL-6 and inhibits all known forms of IL-6 cytokine signaling, later sparked an exclusive licensing deal worth as much as $270 million with Roche Holding AG, granting the Basel, Switzerland-based pharma global rights to develop and commercialize EBI-031 and all other IL-6 antagonist antibody technology owned by Eleven. (See BioWorld Today, Aug. 18, 2016.)

A month later, the Cambridge, Mass.-based company engineered a merger with Viventia Bio Inc. to exploit its protein engineering platform in antibody-drug conjugates rather than ophthalmology. (See BioWorld Today, Sept. 22, 2016.)

Late-stage trial designs aren't the cause of every, or even most, drug failures across the board, and there's no reason to believe DED is any different. But in addition to the challenge of syncing up signs and symptoms in DED, the indication is notorious for its plethora of subtypes, and existing diagnostics fall short in parsing out differences among patients. So, while there's no shortage of DED patients, "right now it's a little bit of trial and error in trying to determine which patients will respond to which drugs," Galor acknowledged.

Companies in the DED space are working with the FDA to suggest adaptive trial designs that align better with the biology of the disease, Galor said, but progress has been slow.

Despite the challenges, "it's an exciting time" to be working in DED, she said. Although a curative approach is not yet in sight, Galor added, with so many candidates in development the odds are better than ever of "finding regimens that work for patients and give them back their lives."

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