New for 2020 and beyond: Dry eye disease agents in pipeline

Originally believed to be primarily a disease of postmenopausal women with or without autoimmune disorders, it is now recognized that dry eye disease (DED) affects patients of both sexes at younger ages.

DED is a chronic condition, and although pharmacological and procedural treatments can improve clinical signs, there is no cure.
Artificial tears generates close to $540 million in annual sales globally,¹ and the U.S. spends more than $2 billion yearly on pharmaceuticals to treat DED.²

Patients with Sjögren’s syndrome dry eye spend 78% more on western medicine than those without the autoimmune disorder DED.³ There continues to be an unmet need for more effective treatments for DED, as is evidenced from the multitude of clinical studies listed in Clinicaltrials.gov that are under way or not yet recruiting.

Here is a brief overview of studies that’s are nearing completion and some products that have been filed for regulatory approval.

RELATED: Understanding prevalence, demographics of dry eye disease

On the horizon
Kala Pharmaceuticals has submitted a new drug application to the U.S. Food and Drug Administration (FDA) for KPI-121 (0.25%) for the treatment of dry eye based on the strength of one phase 2 trial and two phase 3 trials, STRIDE 1 and STRIDE 2. 

The trials enrolled almost 2,000 patients, and indicated statistical significance for the primary endpoint of conjunctival hyperemia, as well as the primary symptom endpoint of ocular discomfort severity.

If approved, KPI-121 would be first product indicated for the temporary relief of the signs and symptoms of dry eye disease and flares. The agent uses Kala’s AMPPLIFY drug delivery technology to better penetrate the target tissues.
Data from the phase 3 clinical trial, STRIDE 3 (ClinicalTrials.gov Identifier: NCT03616899), is expected to be released later this year.

In the pipeline
Aldeyra Therapeutics is now enrolling patients into the RENEW phase 3 clinical trial, which will evaluate the efficacy of reproxalap ophthalmic solution (0.25%) versus vehicle in 400 patients with moderate and severe DED.

Co-primary endpoints are ocular dryness and fluorescein nasal region ocular staining (ClinicalTrials.gov Identifier: NCT03879863).

The phase 3 trial comes on the heels of successful phase 2b trial results, which demonstrated statistical superiority of reproxalap versus vehicle across multiple dry eye signs and symptoms.

In the new study, patients will be randomly assigned to one of four arms: reproxalap 0.25% administered QID for 12 weeks; reproxalap 0.25% administered QID for four weeks, then BID for eight weeks, or vehicle comparators to each of the active arms. Targeted trial completion is April 2021.

Aurinia Pharmaceuticals recently announced phase 2 data of its 100-person, double-masked, head-to-head trial comparing voclosporin ophthalmic solution (VOS) to Restasis. Both drugs were well-tolerated and there was no statistical difference between VOS and Restasis for the primary endpoint; both drugs exhibited low drop-discomfort scores.
VOS did show statistically significant improvements over Restasis at week 4 for objective tests, including Schirmer’s and fluorescein corneal staining.

RELATED: Rethinking clinical strategy for treating dry eye disease

Lacripep is currently in a phase 2 trial to compare its efficacy versus placebo in patients with Sjogren’s syndrome dry eye (ClinicalTrials.gov Identifier: NCT03226444). The primary endpoint is change in fluorescein corneal staining score at week four from baseline.

Secondary endpoints include changes in eye dryness, mean SANDE 2 scores, and individual symptom assessments, among others.

Mitotech is developing a few drug formulations of SkQ1, such as Visomitin, which is currently in phase 3 trials for the treatment of DED (ClinicalTrials.gov Identifier: NCT03764735).

Visomitin is already approved for this indication in Russia. Clinical trials have shown that Visomitin is efficacious in improving corneal and conjunctival staining, tear quality, and other DED symptoms.

According to the company website, one part of SkQ1 functions as a molecular “tow truck,” carrying the other part of the molecule - an extremely active antioxidant plastoquinone - into mitochondria.

The molecule was designed to act as a mitochondria-targeted ROS scavenger in general and as a very efficient cardiolipin peroxidation inhibitor, in particular. Mitotech is also developing SkQ1 as a potential treatment for uveitis and dry age-related macular degeneration.

Novaliq has two DED products in the pipeline: NOVO3 (100% perfluorohexyloctane) and CyclASol (ophthalmic solution of 0.1% cyclosporine A in EyeSol). NOVO3 is being developed for evaporative DED from meibomian gland dysfunction. The SEECASE-1 U.S. study, enrolled 336 patients, and the SEECASE-2 study, which is beginning this year. CyclASol is in development for the treatment of aqueous deficient DED. The ESSENCE-1 U.S. study enrolled 328 patients; the ESSENCE-2 study is beginning this year. New Drug Application submissions for both drugs are expected in 2021.

Oyster Point Pharma has two nasal spray therapeutics in clinical trial development for the treatment of DED. OC-01 (ClinicalTrials.gov Identifier: NCT03873246) and OC-02 are selective nicotinic acetylcholine receptor (nAChR) agonists that harness the trigeminal parasympathetic pathway to improve tear film production.

RELATED: Report promotes step therapy approach to dry eye disease management

The OC-02 RANIER and PEARL studies are complete, but data have not been released. The OC-01 MYSTIC (ClinicalTrials.gov Identifier: NCT03873246) and IMPERIAL (ClinicalTrials.gov Identifier: NCT03688802) studies are recruiting with an expected study completion date in August; the ONSET-1 study is complete, but data have not been released. According to the company, in Phase 2b clinical studies patients administered either OC-01 or OC-02 experienced rapid and significant improvements in both the signs and symptoms of DED.

Both were well-tolerated with no significant ocular adverse events or drug-related serious adverse events.

ReGenTree will begin enrolling patients into ARISE-3, a phase 3 trial designed to evaluate RGN-259 for the treatment of DED (ClinicalTrials.gov Identifier: NCT03937882).

RGN-256 is a preservative-free sterile eye drop solution containing Thymosin beta 4 designed for direct instillation into each eye.

ARISE-3 is designed to compared RGN-259, dosed QID for 14 days, against placebo. The trial is expected to enroll 700 patients in 15 sites across the United States.

The primary completion date is expected to be April 2020, with final completion in July 2020.

TearCare, from Sight Sciences, is a wearable, open-eye technology that delivers regulated, localized heat to the eyelids to clear the meibomian glands of obstructions and restore the production of healthy meibum.

Sight Sciences is now enrolling patients into OLYMPIA, a prospective, multicenter, randomized, controlled study designed to compare the safety and efficacy of TearCare to the LipiFlow Thermal Pulsation System (Johnson & Johnson Vision) in patients with dry eye disease. The TearCare SmartLids will be applied to the external surface of each eyelid.

The TearCare System will be turned on and heat will be delivered to the eyelids for 15 minutes. Immediately following the thermal portion of the procedure, the SmartLids will be removed and the doctor will manually express the meibomian glands.

The LipiFlow activators will be placed between the inner eyelid and the corneal surface of each eye. The LipiFlow System will be turned on and heat and pressure will be delivered to each eyelid for 12 minutes. OLYMPIA will enroll 138 patients across 10 centers in the United States and has a target completion date of October 2019. (ClinicalTrials.gov Identifier: NCT03857919)

Topivert Pharma’s TOP1630, a novel anti-inflammatory kinase inhibitor, is in a multicenter, randomized, placebo-controlled phase 2b/3 trial that will enroll 200 patients with moderate and severe DED compared to placebo (ClinicalTrials.gov Identifier: NCT03833388). Primary endpoints include ocular grittiness and ocular surface lissamine green staining at day 29. Top line data are expected later this year.

References:

1. Moshirfar M, Pierson K, Hanamaikai K, et al. Artificial tears potpourri: a literature review. Clin Ophthalmol 2014;8:1419-33.
2. Hawkes N. US's $2bn annual spend on dry eye disease "brings tears to your eyes," say critics. BMJ 2018;360:k492.
3. Yao W, Le Q. Social-economic analysis of patients with Sjogren's syndrome dry eye in East China: a cross-sectional study. BMC Ophthalmol 2018;18(1):23.