Prescription medications for dry eye disease: patient-centered treatment selection

By Douglas Katsev, MD

The contents of this article are informational only and are not intended to be a substitute for professional medical advice, diagnosis, or treatment recommendations. This editorial presents the views and experiences of the author and does not reflect the opinions or recommendations of the publisher of Ophthalmology 360.

Dry eye disease (DED) is a highly prevalent disorder of the ocular surface that often leads patients to seek treatment from eye care professionals.^1,2 Disease etiology and patient characteristics are important factors that inform treatment decisions when prescribing DED therapies.

Supportive Care Provides Inadequate Relief for Many Patients With DED

DED is characterized by signs observed by the evaluating clinician (eg, increased corneal staining, decreased Schirmer test score) and symptoms reported by patients.^3,4 In addition to dryness, DED symptoms can include burning, stinging, grittiness, foreign body sensation, light sensitivity, ocular pain, and blurred vision.⁴ DED symptoms negatively affect many aspects of patients’ lives, including visual function, work productivity, and participation in daily activities.^5-7 In patients who fail to obtain adequate relief from home care routines and over-the-counter ocular lubricants, prescription DED therapies should be considered.⁸ Due to the chronic nature of DED, many patients will require long-term treatment.

Prescription Options for the Treatment of DED

Although the etiology of DED can be broadly classified as aqueous-deficient, evaporative, or mixed, excess tear film evaporation due to meibomian gland dysfunction is the leading cause of DED.⁸ Approximately 9 in 10 people with DED have tear evaporation as a contributing factor.^9,10 Other factors that contribute to the cycle of desiccation that characterizes DED include insufficient tear production and ocular surface inflammation.¹¹

Prescription treatments focus on addressing the inflammatory pathways or excessive evaporation that contribute to the vicious cycle of DED. Cyclosporine-based products (RESTASIS^®, CEQUA^®, and VEVYE^®) act by targeting the calcineurin-phosphate pathway to inhibit the activation of T cells resulting in increased tear production.^12-14 Cyclosporine may also prevent the death of goblet cells within the conjunctival epithelium.^13,14 After the introduction of RESTASIS, subsequent products were designed to facilitate the ocular delivery of cyclosporine by using a nanomicellar technology in the case of CEQUA¹³ and by using the semifluorinated alkane (SFA) perfluorobutylpentane (PFBP or F4H5) as a vehicle in the case of VEVYE.¹⁵

XIIDRA^® (lifitegrast) targets ocular inflammation and has a mechanism of action distinct from cyclosporine.¹⁴ Lifitegrast disrupts inflammatory processes involved in DED via several mechanisms including preventing T-cell activation, blocking recruitment of activated T cells to the ocular surface, preventing secondary activation of T cells at the ocular surface, and inhibiting the secretion of inflammatory cytokines.^14,16 Specifically, lifitegrast acts by binding to lymphocyte function-associated antigen-1 (LFA-1; a protein found on the surface of leukocytes) and blocks the interaction of LFA-1 with its ligand (intercellular adhesion molecule-1 [ICAM-1]).^14,16

MIEBO^® is a novel ophthalmic drop that targets the evaporative component of DED.^17,18 MIEBO is composed entirely of the SFA perfluorohexyloctane (PFHO or F6H8) with no additives, excipients, or preservatives. PFHO forms a monolayer at the air-liquid interface of the tear film and thus prevents tear evaporation.¹⁷ In doing so, PFHO may serve to compensate for deficiencies in naturally occurring meibum, which forms the outer lipid layer of the tear film.¹⁷ Although both MIEBO and VEVYE contain an SFA (chemically inert molecules composed of a fluorocarbon segment and a hydrocarbon segment),¹⁹ there are important physiochemical differences that affect how they function. The SFA in the VEVYE formulation (PFBP) functions as a vehicle to solubilize cyclosporine.¹⁵ MIEBO (PFHO) has anti-evaporative properties because of its chemical structure.¹⁷ The longer chain length of PFHO facilitates the formation of a stable monolayer at air-liquid interfaces.²⁰ PFHO also has a higher boiling point (lower volatility) than PFBP,²¹ which means that it evaporates much more slowly and has a longer ocular surface residence time.^17,22 In addition, in contrast to PFBP, PFHO was demonstrated to stabilize the tear film lipid layer in a 7-day study in rabbits.²³

Distinct from these ophthalmic drops that are administered to the ocular surface, TYRVAYA^® (varenicline solution) is formulated as a nasal spray and designed to stimulate tear production.²⁴ Varenicline is a nicotinic acetylcholine receptor agonist that, when administered intranasally, activates the trigeminal parasympathetic pathway that innervates the lacrimal function unit.²⁴

Symptom Reduction as a Differentiating Feature Among Prescription DED Treatments

Key clinical trials of cyclosporine-based DED treatments include randomized, vehicle-controlled studies of RESTASIS,²⁵ CEQUA,²⁶ and VEVYE.^27,28 In all of these studies, cyclosporine-based eye drops demonstrated significantly greater improvements in signs of DED (eg, corneal staining, Schirmer test) compared with vehicle control.^25-28 Reduction in DED symptoms, however, tended to be similar in the active treatment and control groups.^25-28 For RESTASIS, changes in eye dryness, sandy/gritty feeling, burning, stinging, itching, and pain did not differ between the treated and control groups, although a significantly greater reduction in blurred vision was observed with treatment.²⁵ For CEQUA, compared with vehicle, change in the global symptom score was similar.²⁶ For VEVYE, the primary symptom endpoint (Ocular Surface Disease Index score in ESSENCE-1, eye dryness in ESSENCE-2) was not met in either study, although reduction in eye dryness (as a secondary endpoint) was significantly greater with VEVYE versus vehicle in ESSENCE-1.^27,28

XIIDRA (lifitegrast) was evaluated in 4 randomized, placebo-controlled trials (phase 2, OPUS-1, OPUS-2, OPUS-3).^29-32 Aggregated results show that lifitegrast was effective for addressing both prespecified signs endpoint (corneal staining) and symptoms endpoint (eye dryness, eye discomfort) of DED.^29-32

MIEBO (PFHO) was shown to provide rapid and sustained improvement in both signs (corneal staining) and symptoms (eye dryness, burning/stinging) of DED, with significantly greater effects relative to a hypotonic saline (0.6%) control obtained consistently in 2 randomized, controlled trials (GOBI, MOJAVE).^33,34

In randomized, vehicle-controlled studies (ONSET-1, ONSET-2), TYRVAYA (varenicline nasal spray) was superior to vehicle for improving Schirmer test scores (consistent with its intended mechanism of action), and significantly greater reduction in eye dryness was also observed at most assessments in ONSET-1.^35,36

Clinical Implications

Considerations in the selection of prescription medications for patients with DED should include disease etiology, symptomatology, and patient preferences. Cyclosporine-based products or TYRVAYA (varenicline nasal spray), which increase tear production, could be targeted treatment for patients with primarily aqueous-deficient DED, with product selection taking into account patient preference for an eye drop or nasal spray. MIEBO (PFHO) is most appropriate for patients with evaporative DED, due to its demonstrated ability to reduce tear evaporation. When indicators of inflammation are present, consideration should be given to lifitegrast, which disrupts the inflammatory processes involved in DED via several mechanisms. For patients who are particularly bothered by dryness or other DED symptoms, products that have demonstrated effectiveness for symptom reduction (lifitegrast, PFHO) may be preferable. Taking these patient-specific characteristics into account can improve treatment selection for people with DED. See TABLE below for a snapshot of the DED treatments previously described.

Douglas Katsev, MD, is a board-certified ophthalmologist who performs more than 2500 cataract and refractive surgeries a year. He is the founder and surgical director of Santa Barbara Eyecare in Santa Barbara, California. Disclosures: Dr. Katsev is a consultant and speaker for Bausch + Lomb.

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