The Most Promising Treatments in the OSD Pipeline

Eyes On Dry Eye 2023 provided eyecare professionals with the latest research and education, live sessions, and interactive Q&As with renowned specialists. Attendees could earn up to 7 hours of free COPE-accredited CE on topics directly related to patient care, including how to get started with a dry eye practice, learning about the most promising treatments in the pipeline, and many more.

Enjoy this presentation from Cecelia Koetting, OD, FAAO, Dipl. ABO, and don't forget to check out our list of future events!

Please note these videos are provided for review only.

With the cornea playing such a vital role in our overall vision—by shielding the eye, filtering out the most harmful UV rays, and contributing up to 75% of the eye’s refractive power—ocular surface health is imperative.

Overview of dry eye disease

One of the biggest culprits in compromising the cornea is dry eye disease (DED), which is defined by the DEWS report as “a multifactorial disease of the ocular surface characterized by a loss of the homeostasis of that tear film and accompanied by ocular symptoms in which the tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities play etiological roles.”

A key aspect of dry eye’s multifactorial nature is that it can be both evaporative and aqueous deficient, with many patients possessing some component of both. In addition, ocular disease comprises a true cycle that involves irritants (i.e., environment, medications, contact lenses, ocular surgery, screen time), inflammation from systemic diseases, and tear deficiency/instability that can result from hormonal changes or meibomian gland dysfunction (MGD).

The multifactorial nature of DED makes diagnosis and treatment complicated. Luckily, there are continuing innovations on both fronts.

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Watch the full lecture on the ocular surface disease pharmaceutical pipeline!

Diagnosis of dry eye disease

Diagnosis starts with an understanding of the patient, their lifestyle, and their condition. This can best be gained through questionnaires, such as SPEED and OSDI, and an in-depth conversation that covers environmental and lifestyle factors, systemic diseases (i.e., Graves’ disease, thyroid eye disease, sleep apnea, diabetes, Crohn's disease, rosacea, eczema, and allergies), and any medications.

Follow up the interview with general observation to assess blink rate, incomplete lid closure, and ptosis. The cornerstone of accurate diagnosis is a thorough slit lamp examination that adheres to the mantra of “look-lift-push-pull.”

Key components of the slit lamp exam include:

Grading the lids and the glands, based on pitting, capping, and lid structure abnormality.
Checking lid laxity.
Assessing meibomian gland quality for ease of expression and oil quality.
Checking for blepharitis and Demodex with a focus on saponification, lid margin debris, lid margin biofilm, collarettes, telangiectasia, and lid margin thickening.
Vital dye corneal staining to best analyze the pattern, location, severity, and tear breakup time.
Lissamine green staining to assess sub-clinical DED and conjunctival involvement.

In addition, tear osmolarity (to check for increased evaporation rate or reduction in tear secretion), MMP-9 testing (to detect elevated inflammatory levels), and meibography (to grade the structure of the glands and atrophy) are in my diagnostic arsenal.

New and emerging treatments for DED

There is currently a broad range of exciting therapies that are newly available or near release to treat four of the main contributors to DED: Demodex blepharitis, keratoconjunctivitis sicca, meibomian gland dysfunction, and neurotrophic keratitis.

Here are a few of the most promising pharmaceuticals.

Treatments for Demodex blepharitis

Though not entirely new, products containing Manuka honey (Blephadex) are worth examining more deeply. Along with honey’s anti-inflammatory and antimicrobial properties, the Manuka variety boasts the highest concentration of methyl glycosyl (MGO). A 2020 study incorporating 53 participants with blepharitis and demodex found a topical overnight application of manuka honey-based eye cream produced a significant improvement in ocular surface symptomology, tear film stability, lipid layer thickness, and reduced lid margin staining.
Okra extract (Zocular) exerts antioxidative and anti-inflammatory effects by suppressing the specific mediators that serve an important role in dry eye and blepharitis. A study comparing an okra eyelid patch to tea tree oil found it to be just as effective but with much less irritation.
TP-O3 ophthalmic solution (Tarsus) is a potent, non-competitive antagonist that targets the insect and arachnid GABA CI channels, paralyzing and killing them. The solution is lipophilic in nature, allowing it to easily migrate to the lash follicles where Demodex lives. The dosage is twice a day for patients for 6 weeks. Saturn-1 results showed that 33% of patients had mite eradication (i.e., 0 mites) at 18 days, 40% at day 22, and 68% at day 43. Phase III trials are complete, and an FDA PDUFA is coming in 2023.

Treatments for keratoconjunctivitis sicca (aqueous deficient DED)

Reproxalap (Aldeyra) is a first-in-class reactive aldehyde species (RASP), which is defined as a pre-cytokine systems-based mediator of inflammation that covalently binds to cellular biomolecules on receptors and kinases. They are believed to work at the top of the inflammatory cascade and improve everything beneath. Data shows Reproxalap has a positive effect on OSDI score, redness, and in Schirmer's.
INV102 (Invirsa) addresses the naturally occurring DNA damage linked to inflammation and dysfunction by mitigating that damage by modifying the naturally occurring compound that regulates DNA response. Preclinical trials are promising and showed potent healing activity and an excellent safety profile. Currently, Inversa is enrolling INV102 in Phase I and II clinical trials.
ALY688 (Allysta Pharmaceuticals) is a sterile and preservative-free drop that reduces levels of pro-inflammatory cytokines and activates T cells on the ocular surface to reduce corneal damage and improve tear film integrity. ALY688 is a peptide with multi-modal mechanisms of action, including anti-inflammatory activity as well as enhancement of corneal and conjunctival regeneration. ALY688 is entering Phase IIb/III clinical trials.
TearSolutions (Lacriprep) addresses the deficiency of lacritin, which is a common facet in all dry eye disease. Insufficient lacritin negatively impacts tear film homeostasis as well as neuronal and epithelial cell repair and regrowth. Early trials have found impressive improvement among dry eye patients. Lacriprep is set to enter Phase II trials in 2023.
SURF 100 and SURF 200 (Surface Ophthalmics), which both contain their proprietary vehicle Klarity. This vehicle reduces cellular oxidative stress while enhancing viscosity and surface lubrication. SURF 100 combines Klarity with the corticosteroid, betamethasone, and mycophenolate, which inhibits T-cell and B-cell lymphocytes to treat chronic DED. SURF 200 is composed of Klarity and low-dose betamethasone to target acute dry eye flares. Studies of SURF 100 show superior results in improving dry eye symptoms and tear production when compared to lifitegrast and cyclosporine.

Treatments for meibomian gland dysfunction and evaporative DED

NOVO3 (B&L/Novaliq) is a 100% perfluorohexyloctane; this means it has no vehicle, making it water-free and preservative-free and giving it enhanced surface adhesion. Week 8 data showed a statistically significantly improved VAS score. With Phase III trials complete and an FDA filed, the PDUFA date is set for June 28, 2023.
AZR-MD-001 (Azura Ophthalmics) is an ophthalmic ointment, applied directly to the meibomian glands twice a week, that harnesses the power of selenium disulfide. It employs a multi-modal mechanism of action using keratolytic to loosen meibomian gland blockage combined with keratostatic to decrease hyperkeratinization and lipogenesis to increase meibum secretion and promote healthy function. AZR-MD-001 is finishing Phase III.
CBT-008 (Cloudbreak Therapeutic) is methyl-beta-cyclodextrin applied topically in repeat dosing with the aim of dissolving potential cholesterol crystal deposits in the orifice of the meibomian gland to improve tear film stability.

Neurotrophic keratitis (NK)

CSB-001(Claris Bio) is a five amino-acid-deleted hepatocyte growth factor (HGF) that offers a range of therapeutic benefits in regard to NK. By exposing the cornea to HGF, CSB-001 restarts the function of the nerve endings. Early clinical trials show very promising results.
Oyster Point has two offerings on this front. First, they are investigating the use of varenicline nasal spray, which is already on-label for dry eye disease, for use in NK. Additionally, they are looking at Enriched Tear Film (ETF) Gene Therapy, which in preclinical models has been shown to deliver target genes to cells and harness the lacrimal gland’s power to secrete selected proteins, peptides, and enzymes to treat ocular surface diseases.

In closing

As understanding continues to grow around the individual issues that figure into the DED cycle, such as Demodex blepharitis and meibomian gland dysfunction, companies are developing products that pinpoint and more accurately target the specific condition.

It is incredibly exciting to see the array of treatments in the pipeline to address the ever-growing problem of dry eye disease and to anticipate how they will improve the lives of our patients.