Estimates put the number of Americans afflicted with dry eye disease (DED) at more than 16 million to as many as 30 million.^1,2 An estimated 6 million people report having experienced DED symptoms but had not been diagnosed with the condition, according to one survey.¹ Two times more women than men endure the condition, and age is a factor as well. In addition, lifestyle demands, specifically digital screen habits, are making Americans’ eyes increasingly more dry.³ The market value of the dry eye space in North America was $1.98 billion in 2018 and projected to reach a value of $2.79 billion by 2024.³

Taking these numbers into account, one is not surprised to learn that more than 225 dry eye disease studies are currently underway, including 150 in Phase 3 clinical trials, according to Clinicaltrials.gov .

“Dry eye is an extremely common and still under-recognized condition that causes a wide variety of symptoms with a wide variety of presentations in individual patients,” says John Sheppard, MD. “Because of the heterogeneity of the disease, it appears that there may be drugs better suited to specific patients compared with other drugs. The four currently approved drugs we have in the United States are meeting the needs of more and more patients; but, at the same time, they have their limitations, including side effects.” Dr. Sheppard is professor of ophthalmology, microbiology & molecular biology at Eastern Virginia Medical School and president of Virginia Eye Consultants in Norfolk.

“Having different mechanisms of action and different vehicles will benefit practitioners, because we can become better and better at picking the right drug for that patient sitting in front of us in the exam chair,” Dr. Sheppard adds.

Here are some promising agents in the DED pipeline (for other ocular surface disease [OSD] therapeutics, see below).

ALDEYRA THERAPEUTICS INC.

Aldeyra Therapeutics is investigating reproxalap, a novel small-molecule immune-modulating covalent inhibitor of reactive aldehyde species (RASP), for the treatment of DED and allergic conjunctivitis, which frequently coexist. RASP are elevated in ocular and systemic inflammatory disease; the drug’s mechanism of action has been validated with the demonstration of statistically significant and clinically relevant activity in multiple physiologically distinct late-phase clinical indications.⁴

Reproxalap is being developed as a 0.25% ophthalmic solution. During the run-in cohort of the Phase 3 TRANQUILITY clinical trial, 23 patients with DED patients were randomized to receive four doses one day prior to and two doses on the day of exposure to a 90-minute dry eye chamber with minimal humidity, high airflow and forced visual tasking. Over all time points, reproxalap was observed to be statistically superior to vehicle for the two assessed symptoms, visual analog scale, ocular dryness score (P = .001) and ocular discomfort score (P < .0001). Consistent with clinical experience in more than 1,100 patients, no adverse findings on safety assessments were observed, and reproxalap was well-tolerated.

“This is an entirely novel pathway,” says Dr. Sheppard. “Because of the ubiquity of this mechanism, I believe that it will be beneficial for patients with both dry eye and ocular allergy as evidenced by successful clinical trial outcomes in both diseases. A ‘holy grail’ of ocular surface disease is controlling multiple conditions; the big three are meibomian gland disease (MGD), allergy and DED. Although steroids are very effective for these conditions, there can be concerning side effects. RASP inhibitors have a mechanism of action that mimics that of steroids using an entirely novel pathway, with steroid side effects. This drug is promising for the now underserved intersection of allergy and DED, which could afflict as many as 30 million patients in this country.”

Recently published data from the Phase 2a trial of three topical formulations in 51 patients with DED “suggest that the novel RASP inhibitor reproxalap has the potential to mitigate the signs and symptoms of DED and may represent a new, rapidly and broadly active treatment approach for DED,” the authors wrote in the Journal of Ocular Pharmacology and Therapeutics.⁵

MIMETOGEN PHARMACEUTICALS INC.

Mimetogen Pharmaceuticals is focused on the development of tavilermide (MIM-728), a first-in-class nerve growth factor mimetic for the treatment of DED. It has completed enrollment of its 600-patient MIM-728 Phase 3 clinical trial comparing the efficacy of 5% tavilermide and 1% tavilermide ophthalmic solutions to vehicle, each dosed b.i.d. for 12 weeks.⁶ Change in eye dryness score as measured by the visual analog scale and change in total corneal fluorescein staining are the primary endpoints.

According to the company, tavilermide is differentiated from other investigational therapies in the dry eye pipeline because it addresses some of the multifactorial mechanisms of DED by facilitating protein secretions from the conjunctival glands.

In a press release, Edward Holland, MD, professor of ophthalmology, University of Cincinnati, Ohio, said he was encouraged to see Mimetogen pursuing development of tavilermide, with its multifactorial mechanism of action that addresses many underlying pathologies of DED.

MITOTECH S.A.

Mitotech announced completion of enrollment in its pivotal Phase 3 VISTA-2 study of SkQ1 ophthalmic solution in patients with moderate to severe DED.⁷ SkQ1 is a cardiolipin peroxidation inhibitor developed for treatment of a spectrum of age-related disorders. VISTA-2 is a multicenter, randomized, double-blind, placebo-controlled clinical study with two treatment arms: SkQ1 ophthalmic solution and vehicle solution, administered b.i.d. Across multiple centers in the United States, 610 patients have been enrolled to receive treatment over a 2-month period.

VISTA-2 is the company’s first pivotal study in DED designed to confirm the VISTA-1 study conducted in 2019. VISTA-1 facilitated dose and primary endpoint selection for VISTA-2 having demonstrated statistically significant SkQ1 impact against vehicle on multiple signs and symptoms of DED over a 2-month course of treatment, according to a news release. Also, the study highlighted excellent safety profile of the drug with tolerability statistically similar to that of an artificial tear.

NEUROPTIKA

Neuroptika has completed enrollment in a Phase 2 clinical controlled, double-masked trial of NRO-1, a novel therapeutic with the potential to regenerate corneal nerves in ophthalmic diseases. NRO-1 releases glial cell-derived neurotrophic factor, which recovers ocular surface function through regenerating corneal nerves and accelerating corneal wound healing directly, the company says.⁸

The Phase 2 clinical trial is a multicenter, randomized, double-masked, vehicle-controlled clinical trial that evaluates the safety and efficacy of NRO-1 in patients with DED. The Phase 2 clinical trial compares two concentrations of NRO-1 against vehicle during 28 days of treatment in 124 patients with moderate-to-severe DED, including postsurgical patients. The endpoints will include standard signs and symptoms characteristic of DED as well as nerve morphology imaging and biomarker analysis, the company says.

NOVALIQ

Novaliq initiated the randomization of patients in its Phase 3 clinical trial ESSENCE-2 that is designed to replicate efficacy results of the previous Phase 2/3 ESSENCE-1 trial of CyclASol, the company says. CyclASol is a topical anti-inflammatory and immunomodulating ophthalmic solution containing 0.1% cyclosporine A in EyeSol. The company notes that its water-free formulation has led to a differentiated therapeutic profile with an early onset of efficacy and improved tolerability. The previous trial demonstrated statistically significant improvements with CyclASol in both sign and symptom endpoints compared to its vehicle after 4 weeks.

Additionally, the trial demonstrated that reading speed improves with corneal staining reduction. The drop was safe and well-tolerated in the trial as well.⁹

“CyclASol is an intriguing attempt to enhance the delivery of cyclosporine API, which is known to be safe and effective but not necessarily universally tolerable,” says Dr. Sheppard. “I foresee water-free, preservative-free, semi-fluorinated alkane delivery systems as an exciting development in the pipeline.”

OCULAR THERAPEUTIX

Ocular Therapeutix is developing two products: OTX-DED (dexamethasone intracanalicular insert) for the short-term treatment of the signs and symptoms of DED as well as OTX-CSI (cyclosporine intracanalicular insert) for chronic treatment in a Phase 2 clinical trial. In addition, the company submitted a supplemental New Drug Application for Dextenza for the treatment of ocular itching associated with allergic conjunctivitis.¹⁰ That product is FDA approved for the treatment of ocular inflammation and pain following ophthalmic surgery.

OTX-CSI combines the clinical benefits of cyclosporine with the advantages of punctal occlusion to provide two therapeutic approaches to DED with a single device. The insert contains 0.36 mg of cyclosporine and is designed to deliver therapeutic levels of drug to the ocular surface along with punctal occlusion for a duration of approximately 12 weeks. Two active formulations are being studied.

“The pharmacokinetics of the sustained-release punctal plug are very well-established and can be titrated to acute delivery and then a tapering, or to consistent first-order delivery, depending upon the dissolution characteristics of the plug polymer,” Dr. Sheppard says. “The plug itself is an added bonus as it provides increased retention of the natural tears.”

OYSTER POINT PHARMA

Oyster Point announced that the FDA accepted its NDA for OC-01 (varenicline) nasal spray for the treatment of signs and symptoms of DED.¹¹ The company says the submission is supported by safety and efficacy results from the Phase 3 ONSET-2, Phase 2b ONSET-1 and Phase 2 MYSTIC clinical trials in more 1,000 subjects. The PDUFA target action date is Oct. 17, 2021.

The MYSTIC, ONSET-1 and ONSET-2 clinical trials showed statistically significant improvements in Schirmer score compared to control, the primary endpoint in all studies. Key secondary endpoints in ONSET-1 and ONSET-2 included change from baseline in symptoms as assessed by the Eye Dryness Score (visual analog scale, range 0-100 [0=no discomfort, 100=maximum discomfort]). In both of these pivotal studies, there was statistically or nominally statistically significant improvement in symptom scores at day 28 — in ONSET-2, patients saw statistically significant improvement as early as day 14 compared to control. All doses studied in the clinical trial program were well-tolerated with no serious drug-related adverse events.

OC-01 is a highly selective cholinergic agonist with novel mechanism of action that activates the trigeminal parasympathetic pathway in the nasal cavity to stimulate natural tear film production.

“For a wide variety of reasons, patients struggle with drops,” Dr. Sheppard says. “The alternate delivery route and new mechanism of action of OC-01 may be synergistic with other interventions including device-based procedures, and it may suit the needs of some patients who were previously poorly served by currently available medications.”

REGENERX BIOPHARMACEUTICALS

RegeneRx Biopharmaceuticals is investigating its RGN-259 proprietary eyedrop that demonstrated fast onset efficacy in two Phase 3 clinical trials: ARISE-1 and ARISE-2.¹² It was found to be safe and well-tolerated and has not shown adverse side effects such as eye irritation, stinging and visual disturbance.

The drug is based on the novel therapeutic peptide, Thymosin beta 4, according to the company. The ARISE-3 trial is sponsored by ReGenTree, a U.S. joint venture company owned by RegeneRx, and G-treeBNT, a Korean biopharmaceutical company.

TEARSOLUTIONS

TearSolutions announced the completion and preliminary outcomes of a Phase 1/2 trial of Lacripep in primary Sjögren’s Syndrome patients. The trial was designed to test proof of concept and optimize the design for the next planned study, the company says.¹³ Sjögren’s patients suffer from a severe and often debilitating form of DED and are known to be deficient in lacritin. Lacripep is the bioactive 19 amino acid fragment of lacritin.

Two strengths of Lacripep were tested and demonstrated evidence of efficacy in both a sign (inferior corneal staining) and a symptom (burning and stinging). The lower strength exhibited a highly statistically significant reduction in inferior corneal staining. Lacripep was well tolerated, and there were no serious treatment-related adverse events, according to the company. Lacripep was patented by Gordon Laurie, PhD, a professor at the University of Virginia, based on his NIH-funded research into the composition of human tears.

CONCLUSION

DED is a “critical and significant public health issue” in the United States.¹⁴ Studies indicate that when a DED diagnosis is made, clinicians frequently underestimate its severity. One study found that clinicians underestimated DED severity in more than half of patients over age 65 and 43% of female patients.¹⁵ Another study revealed clinicians’ assessment underestimated disease in 41% of patients compared with the patients’ self-assessment.¹⁶

“For 13 years, we had one drug approved for DED,” Dr Sheppard says. “Now we have four. In 4 more years, we may have more than 10 viable approved products. Soon we hope to have a larger palette to paint for our patients the most appropriate, science- and evidence-based therapeutic intervention.” OM

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