Surfing the dry eye pipeline

There remains a major unmet medical need for more effective dry eye treatments, and several companies have innovative new options in their pipeline. Current options have limited efficacy.

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.

A chronic inflammatory disease, DED is the most common eye disease. It can have a significant impact on the quality of life of a sufferer. There remains a major unmet medical need for more effective treatments, as currently available treatments for DED have limited efficacy (particularly over the long-term), provide only symptomatic improvement and or are associated with safety and tolerability issues, such as burning or stinging, on instillation that limit their use.

Related: Using IPL to treat glaucoma patients with dry eye disease

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 an overview of studies nearing completion and products that have been filed for regulatory approval.

On the horizon
Kala Pharmaceuticals has submitted a new drug application to the FDA for KPI-121 (0.25%) for the treatment of dry eye based on the strength of one phase II trial and two phase III 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 DED and flares. The agent uses Kala’s AMPPLIFY drug delivery technology to better penetrate the target tissues.

Related: Getting to the root of dry eye: Know clues to MGD, Sjögren’s diagnosis 

In August, the company received a complete response letter (CRL) from the FDA regarding its new drug application (NDA) for KPI-121. 

The STRIDE 3 trial is a multicenter, randomized, double-blind, placebo-controlled, parallel-arm study, comparing KPI-121 0.25% to vehicle (placebo), each dosed four times a day (QID) for two weeks in approximately 900 patients with DED.

Subjects who meet initial screening and inclusion/exclusion criteria undergo a two-week run-in period with vehicle. Subjects who continue to meet inclusion/exclusion criteria after the run-in are randomly assigned to receive either KPI-121 0.25% or vehicle for two weeks. 

Data from the phase III clinical trial, STRIDE 3 (ClinicalTrials.gov Identifier: NCT03616899), is expected to be released by the end of the year.

In the pipeline
Aldeyra Therapeutics is now enrolling patients into the RENEW phase III 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 III trial comes on the heels of successful phase IIb trial results, which demonstrated statistical superiority of reproxalap versus vehicle across multiple dry eye signs and symptoms.

Related: Rethinking clinical strategy for treating dry eye disease 

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 II 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: Novel compound shows promise for dry eye in proof-of-concept study 

Lacripep is currently in a phase II 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 III 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.

Related: Brimonidine therapy well tolerated for treatment of dry eye disease 

The molecule was designed to act as a mitochondria-targeted ROS scavenger. Mitotech is 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 are expected in 2021.

Related: Detecting dry eye: What to keep, obtain, or omit 

OC-01 and OC-02, Oyster Point’s lead product candidates, are nicotinic acetylcholine receptor (nAChR) agonists that bind specifically to receptors on the trigeminal nerve and are currently in phase II development for the treatment of DED, according to the company.

The OC-01 ONSET study was a dose-ranging, randomized, double-masked, vehicle-controlled phase 2b clinical trial that evaluated the safety and efficacy of OC-01 in 182 subjects with DED in the United States. OC-01’s novel mechanism of action re-establishes tear film homeostasis by activating the trigeminal parasympathetic pathway to stimulate the glands and cells responsible for natural tear film production, known as the lacrimal functional unit.

The study compared three different doses of OC-01 nasal spray to vehicle control nasal spray (1:1:1:1 randomization). The pre-specified primary endpoint was the assessment of tear production as measured by Schirmer’s score at Day 28 and the two pre-specified secondary endpoints were patient-reported symptoms of DED as measured by the Eye Dryness Scale (EDS) at Day 21 and Day 28.

Related: Dry eye strategies from lab to clinic 

Earlier this year, the company announced the OC-02 PEARL study met both sign and symptom primary endpoints by showing a statistically significant improvement in each compared with a vehicle control.

The OC-02 RAINIER study was a randomized, double-masked, vehicle-controlled, phase IIb clinical trial that evaluated the safety and efficacy of 2.0% OC-02 nasal spray in 53 subjects (2:1 randomization) with DED in the United States.

The company began trading more than 5 million of its common stock on The Nasdaq Global Select Market on Oct. 31, 2019 under the symbol “OYST.” 

Most recently, the company announced positive topline results in Nov. 2019 from a phase I “ZEN” study of Its lead nicotinic agonist nasal spray in development for the treatment of DED.

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

RGN-259 eye drops contain an active small protein, thymosin beta 4, which is naturally occurring in tears and other body fluids. 

Related: Reeling in the shark: How to take the fear out of dry eye diagnosis and treatment 

The eye drops have demonstrated wide-ranging and multifunctional activities. Such activities underlie the efficacy of RGN-259 eye drops seen to date in alleviating both the signs and symptoms of dry eye. 

According to the company, both ARISE-1 and ARISE-2 patients reported minimal ocular discomfort similar to that of the placebo.

ARISE-3 is designed to compare 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.

Related: Zeroing in on the presence of dry eye 

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. 

Related: Lid hygiene device improves meibomian gland dysfunction, blepharitis 

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 had 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 IIb/III 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 is expected by the end of the year. 

Read more dry eye content 

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.