Published in Ocular Surface

Exploring the Dry Eye Pipeline

This is editorially independent content
11 min read

In this session from Eyes On 2023, Damon Dierker, OD, FAAO, and Walter O. Whitley, OD, MBA, FAAO, discuss the pharmaceutical pipeline for dry eye disease.

Exploring the Dry Eye Pipeline

From November 18 to 20, 2022, eyecare practitioners (ECPs) from around the world gathered online for Eyes On 2023, a 3 day educational summit offering up to 9 hours of COPE-accredited CE and CME providing the latest innovations in the ophthalmic industry.

Enjoy this presentation from Damon Dierker, OD, FAAO, and Walter Whitley, OD, MBA, FAAO, and don't forget to check out our list of future events!

Please note these videos are provided for review only.

The main challenge that many ECPs who manage and treat ocular surface disease have to face is understanding the clinical data collected from patient history, point-of-care diagnostics, and clinical exams to obtain an accurate diagnosis for dry eye disease (DED) patients. By analyzing this information, this lecture aimed to review the richness of the dry eye pipeline as well as treatments on the horizon.

Watch the full lecture on the DED pharmaceutical pipeline!

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Current available treatments for DED

Recently approved treatment options address challenges and unmet needs through:

  • Novel mechanism of action
    • Xiidra (lifitegrast ophthalmic solution 5%) indicated for the signs and symptoms of DED
    • Tyrvaya (varenicline solution 0.3mg/spray) intranasal delivery for the treatment of the signs and symptoms of DED
  • Increase in concentrations of effective dose
    • Cequa (cyclosporine ophthalmic solution 0.9%) indicated to increase tear production in patients with DED
  • Molecular design and formulation science—increased lipophilicity, solubility, and ocular tissue penetration
    • Cequa (cyclosporine ophthalmic solution 0.9%)
    • Eysuvis (Loteprednol etabonate ophthalmic suspension 0.25%) for the short-term (up to 2 weeks) treatment of the signs and symptoms of DED
    • Dextenza (dexamethasone ophthalmic insert 0.4mg) intracanalicular insert for the treatment of ocular itching associated with allergic conjunctivitis
Additionally, in-office procedures such as photobiomodulation therapies, nutritional supplementations, extranasal neurostimulation, and pulsed steroids for flare-ups work well for patients struggling to manage DED. For patients with persistent nocturnal lagophthalmos, the eyelid tape product SleepTite/SleepRite has proven helpful for protecting the lid seal overnight.

Stepping into the future for 2023

The spectrum of ocular surface drug discovery continues to be a therapeutic space full of innovation heading into 2023. While there have been many chemical entities unable to cross the finish line, these novel agents display the greatest potential for FDA approval and commercialization.

NOV03 to treat meibomian gland dysfunction

For patients with evaporative dry eye due to meibomian gland dysfunction (MGD), NOV03 (100% perfluorohexyloctane), developed by Novaliq, could be a significant advance.
NOV03 features two mechanisms of action: stabilization of the lipid layer for hours to protect the tear film and penetration into the meibomian glands to improve secretions. A single drop of NOV03 can last up to 4 hours on the ocular surface, and the smaller drop size (<12μL) prevents vision blurring and the blink reflex from being activated.

Results from clinical trials

In both Phase 3 studies, GOBI and MOJAVE, NOV03 was well-tolerated, and the studies achieved their primary outcomes of improvements in both total corneal fluorescein staining and in visual analog scale (VAS) reporting on dryness. The 12-month extension trial, KALAHARI, will release results later in 2023.
Bausch + Lomb acquired this chemical entity in 2019 with the intent to commercialize in the US and Canada in 2023. If approved by the FDA, this will be the first product for the treatment of DED to need only two Phase 3 studies to demonstrate efficacy on signs and symptoms.

TP-03 to treat Demodex blepharitis

An underserved market in DED is patients with Demodex blepharitis, with prevalence ranging from 9 to 25 million in the US. A pathognomonic sign of a Demodex infestation would be the presentation of collarettes on the eyelashes.

While there are methods to control the Demodex population, there is currently nothing on the market to actually eradicate the problem.

To address this issue, TP-03 (lotilaner ophthalmic solution 0.25%) was designed to treat the root cause of Demodex blepharitis by eradicating Demodex mites and collarettes. The mechanism of action for TP-03 is the paralysis and death of Demodex mites, achieved by using the drops twice a day for 6 weeks. Of note, over time, these mites will come back after treatment, meaning it is prudent to see patients for a follow-up examination roughly 6 months after completing the course of treatment.

Results from clinical trials

Two pivotal studies (Phase 2b/3 SATURN-1 and Phase 3 SATURN-2) evaluated the efficacy and safety of TP-03 in patients with Demodex blepharitis. The primary endpoint of complete collarette cure was achieved by 56% of patients on TP-03 at day 43, and 89% of patients achieved a significant, clinically meaningful collarette cure.
SATURN-2 trial results demonstrated that TP-03 was well-tolerated with a safety profile similar to the vehicle group. There were no serious treatment-related adverse effects, and 91% of patients reported that the drop comfort was neutral to very comfortable.

Reproxalap to treat DED

Reactive aldehyde species (RASP) are pre-cytokine and pro-inflammatory mediators that are elevated in the tears of patients with DED. Reproxalap (0.25% ophthalmic solution), by Aldeyra, binds and modulates RASP to treat inflammation at the top of the inflammatory cascade without the side effects noted with corticosteroids.

In the past, the treatment methods for inflammation addressed more downstream processes like cytokines, T-cell activation, and the cyclooxygenase pathway.

Additionally, RASP inhibitors have been shown not to raise intraocular pressure (IOP) or cause cataracts. Aldeyra submitted data for review to the FDA for reproxalap in 2022, with a potential commercial launch by late 2023.

Results from clinical trials

In the Phase 3 study TRANQUILITY 2, reproxalap showed superior efficacy compared to the vehicle in both prespecified primary endpoints of the Schirmer test (p=0.0001) and >10mm Schirmer Test Responder Proportions (p<0.0001) for acute signs of dry eye. In addition, reproxalap met the secondary endpoints, having noted improvements in dryness, discomfort, grittiness, stinging, burning, and itching. Many study participants noticed symptom relief within 5 or 10 minutes from the first dose of medication.
During the Phase 3 RENEW-Part 1 study, the co-primary endpoint of the Ocular Dryness Symptom Score (p=.0004) was measured with the use of a visual analog scale (VAS) over a 12-week period to illustrate potential relief for those suffering chronically from DED.

If approved, reproxalap would be the first dry eye disease drug to potentially contain at least two labeled objective signs. Furthermore, it could be the only topical ocular drug with evidence of symptomatic improvement within minutes of dosing.

CyclASol to treat DED

Novaliq is developing CyclASol (cyclosporine ophthalmic solution 0.1%), a water-free excipient treatment that is soluble in the EyeSol technology (excipient perfluorobutylpentane). The compound has the potential to allow for improved bioavailability and residence time which might facilitate enhanced penetration in the target tissue. Additional clinical benefits for patients suggest improved tolerability and decreased visual disturbances.

Results from clinical trials

In both the Phase 2b/3 study ESSENCE-1 and Phase 3 study ESSENCE-2, there was a statistically significant reduction in the total corneal fluorescein staining score, which favored CyclASol compared to vehicle at days 15 and 29.
Up to 71.6% of patients responded within 4 weeks with a clinically meaningful improvement for >3 grades in total corneal staining. The most common adverse reaction observed was instillation site reactions, which were reported in 8.1% of patients in the pooled studies.

Dry eye pipeline for 2024 and beyond

As mentioned before, the future of DED treatments is rich with innovation with a myriad of companies seeking to address signs and symptoms with new formulations and platform techniques for drug delivery.
A model example would be ophthalmic keratolytics, which would be a new therapeutic class for DED that uses a dermatological approach to hyperkeratinization. Keratolytics are used to break up the disulfide bonds in the meibomian glands that lead to the obstruction and poor release of the meibum to the ocular surface.

Upcoming treatments for DED include:

  1. AZR-MD-001 (selenium sulfide 0.5% ointment) by Azura Ophthalmics for the treatment of MGD.
  2. OTX-CSI (cyclosporine intracanalicular insert) is being studied by Ocular Therapeutix, which will be preservative-free and designed to potentially deliver sustained release therapy for up to 12 weeks when treating chronic dry eye.
  3. AR-15512 (0.003% ophthalmic solution) is a transient receptor potential melastatin (TRPM8), which is a cold thermoreceptor selective agonist by Aerie Pharmaceuticals* for DED.
  4. SURF-100 (mycophenolic acid 0.3% and betamethasone 0.01% ophthalmic suspension) by Surface Ophthalmics is a combination therapy targeted to treat chronic dry eye, while SURF-200 (betamethasone 0.2% ophthalmic suspension) looks to address acute flares of DED. Both contain the Klarity delivery vehicle which was developed by Richard L. Lindstrom, MD with a design intent to protect and rehabilitate the ocular surface.
  5. RGN-259 (Tβ4 0.1% ophthalmic solution) is in development by RegeneRx Biopharmaceuticals and has been shown to promote corneal rehabilitation through various cellular mechanisms (migration, cell-cell/cell-matrix communication via boosted levels of laminin-5) and anti-inflammatory properties. Therapeutic targets include both DED and neurotrophic keratitis.
*Aerie Pharmaceuticals was acquired by Alcon in the late summer of 2022.

Conclusion: What do we do now?

There have been exciting innovations in dry eye with reformulated and novel molecules that can be used for the ocular surface. While this may bring tremendous enthusiasm, the next logical step is addressing patient access. The challenge for established and fledgling companies that develop these medications has been to make these treatments as easily accessible as possible for patients.
In essence, getting these therapies into the hands of ECPs could be considered of paramount importance for both patient care along with the thirst for financial and scientific reinvestment in dry eye disease therapeutics by the industry, depending on the quality of future launches.
Damon Dierker, OD, FAAO
About Damon Dierker, OD, FAAO

Dr. Dierker is Director of Optometric Services at Eye Surgeons of Indiana, an adjunct faculty member at the Indiana University School of Optometry, and Immediate Past President of the Indiana Optometric Association. Dr. Dierker is the Co-Founder and Program Chair of Eyes On Dry Eye, the largest event for eyecare professionals in the industry. He has made significant contributions to raising awareness of dry eye and ocular surface disease in the eyecare community, including the development of Dry Eye Boot Camp and other content resources across dozens of publications.

Damon Dierker, OD, FAAO
Walter O. Whitley, OD, MBA, FAAO
About Walter O. Whitley, OD, MBA, FAAO

Dr. Whitley serves as the Director of Optometric Services and Residency Program Supervisor at Virginia Eye Consultants in Norfolk, Virginia where his practice encompasses ocular surface disease, glaucoma, surgical co-management, clinical research and the supervision of an extensive referral network. Dr. Whitley is a nationally recognized lecturer on topics ranging from ocular disease, surgical co-management, pharmaceuticals and practice management topics. He serves as Co-Chief Medical Editor for Advanced Ocular Care and contributing editor for the Review of Optometry and Optometry Times.

Walter O. Whitley, OD, MBA, FAAO
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