April 2020


Pharmaceutical Focus
The dry eye pharmacologic zone

by Maxine Lipner Senior Contributing Writer

Fluorescein negative staining with recurrent paracentral corneal epithelial erosion
Source: John Sheppard, MD

When it comes to dry eye treatment, physicians have three FDA-approved prescription medications, but a variety of other possibilities are in development.
The three FDA-approved drugs are Restasis (cyclosporine, Allergan), Xiidra (lifitegrast, Novartis), and Cequa (cyclosporine, Sun Pharmaceutical). Technically, Cequa and Restasis are approved for increased tear production and, therefore, directly for patients with aqueous tear deficiency, said John Sheppard, MD. Xiidra is the first, and currently the only, dry eye medication approved for both signs and symptoms, specifically for eye dryness as well as punctate keratopathy, Dr. Sheppard said.
While both Restasis and Cequa have a cyclosporine component, the lifitegrast molecule in Xiidra was computer modeled and designed in a test tube to inhibit the immunologic handshake between LFA-1 and ICAM-1, Dr. Sheppard explained. “That cell surface interaction causes T cells to activate, proliferate, and secrete cytokines,” he said. Cyclosporine prevents the activation of T cells, which can then take up to 6 weeks to die off.
One of the big differences among the three drugs is the vehicle used. “Restasis has an emulsion vehicle, Cequa a nanoparticle vehicle, and Xiidra a saline vehicle,” Dr. Sheppard said. With the nanoparticle vehicle, attaining a higher concentration of cyclosporine is possible, and there seems to be less burning and stinging with Cequa than with the other two, according to Dr. Sheppard.

Autologous products

The dry eye treatment arsenal also includes products made from the patient’s own blood, like autologous serum eye drops and platelet-enriched plasma drops. Anat Galor, MD, said these are currently not regulated by the FDA because “there’s no pathway to do so for autologous products.”
Still, she finds that autologous serum eye drops are useful in certain dry eye patients. “Specifically, the ones I use them for are people who have immune-mediated dry eye,” she said, including patients with Sjögren’s disease and graft-versus-host disease for whom FDA-approved products have failed. “I generally use autologous serum tears in a concentration from 20–50%. If they don’t do well, I switch them to platelet-enriched plasma.” Platelet-enriched plasma is like autologous serum tears but at a 100% concentration instead of 20–50%, Dr. Galor said.

Off-label possibilities

Some medications used off-label, like steroids, could be used short term to reduce both aqueous and evaporative dry eye as well as manage blepharitis initially, Dr. Galor said.
She also uses antibiotics, such as doxycycline, minocycline, and azithromycin, orally and topically in patients with evaporative dry eye when trying to improve meibomian gland function. “We think that the antibiotics have an effect on the meibocytes,” she said, explaining that the goal is to make overall oil quality better.
One downside of azithromycin drops is that they have preservatives, and they’re thick without much product in the bottle, Dr. Sheppard said. Still, he said he’s been able to use the oral antibiotics successfully, capitalizing on their anti-microbial, anti-inflammatory, and meibomian-regenerative activity. Doxycycline supports corneal epithelial adhesion by downregulating MMP-9 as well as collagenases. There’s also a minocycline gel for ocular surface disease and meibomian gland disease in clinical trials, Dr. Sheppard said.
Demodex, mites that live at the base of the lashes, are also correlated with dry eye symptoms. For these, Dr. Galor finds tea tree oil a useful strategy. Dr. Sheppard finds hypochlorous acid preparations useful for Demodex.

Emerging agents

Dr. Sheppard estimates there are nearly three dozen different companies working on other medical therapies for dry eye conditions. “The nearest to approval is CyclASol from Novaliq, which is a cyclosporine preparation in a truly unique vehicle,” Dr. Sheppard said. CyclASol is a water-free, semi-fluorinated alkane that produces a 20-microliter drop. As a water-free preparation, it requires no preservative with a lower risk of infection, Dr. Sheppard said. “Also, it turns out that the semi-fluorinated alkanes alone in a higher molecular weight preparation have a direct effect on meibomian glands that can alleviate meibomian gland-related ocular surface lid disease,” he said.
There is also promise for hyaluronic acid.
It is approved as a prescription topical agent for dry eye in Japan, Dr. Sheppard noted. However, repeated failures have occurred in trying to obtain approval in the U.S. Other ophthalmic lubricating preparations that include hyaluronic acid are Oasis Tears (Oasis Medical), Blink (Johnson & Johnson Vision), and Refresh Relieva (Allergan), Dr. Sheppard said.
Another avenue is a uniquely delivered compound being explored by Oyster Point Pharma. This product, a nicotinic agonist nasal spray, targets the upregulation of natural tear production, similar to the TrueTear (Allergan) approach, but the latter relies on intranasal electrical stimulation. “It’s based on a common pathway feeding these trigeminal neuroreceptors that induce the production of normal tears,” Dr. Sheppard said. “The final jury is not in yet, but the data are becoming more and more promising.”
Dr. Sheppard said he is hopeful that one or more of these options may eventually expand the pharmacologic arsenal available to eyecare providers with truly synergistic modalities.

About the doctors

Anat Galor, MD
Associate professor
of ophthalmology
Bascom Palmer Eye Institute
Miami, Florida

John Sheppard, MD
Professor of ophthalmology,
microbiology, and molecular biology
Eastern Virginia Medical School
Norfolk, Virginia

Relevant disclosures

: Allergan, Novaliq, Shire
Sheppard: AbbVie, Aldeyra, Allergan, Bausch + Lomb, Novaliq, Noveome, Oasis Medical, Oyster Point Pharma, Novartis, Sun Pharmaceutical


: AGalor@med.miami.edu
Sheppard: jsheppard@vec2020.com

The dry eye pharmacologic zone The dry eye pharmacologic zone
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