A Review of the First Anti-Evaporative Prescription Treatment for Dry Eye Disease: Perfluorohexyloctane Ophthalmic Solution

ABSTRACT

Dry eye disease (DED) is one of the most common ocular surface disorders. All DED involves an imbalance between tear production and evaporation. Most cases of DED are driven by excessive evaporation, which is often associated with meibomian gland dysfunction (MGD). In evaporative DED, a deficient tear film lipid layer is believed to lead to increased tear evaporation, inflammation, and ocular surface damage. Most prescription treatments for DED address signs and symptoms by targeting tear production and/or inflammation, but they do not address excessive evaporation. Perfluorohexyloctane (PFHO) ophthalmic solution (MIEBO™; Bausch + Lomb) is a water-free, single-ingredient, preservative-free prescription eye drop that directly targets tear evaporation and is approved by the FDA to treat the signs and symptoms of DED. Results from preclinical studies indicate that PFHO has a high oxygen carrying capacity, may reduce friction on blinking, and spreads quickly over the tear film surface to form a monolayer that inhibits evaporation. These effects can lead to stabilization of the tear film to promote ocular surface healing. Further, PFHO was detected in tears for at least 6 hours in a rabbit pharmacokinetic study, and results indicate that it may improve lipid layer thickness and quality. In 2 pivotal phase 3 trials in patients with DED and clinical signs of MGD (GOBI [NCT04139798] and MOJAVE [NCT04567329]), treatment with PFHO consistently met primary efficacy end points related to DED signs and symptoms (total corneal fluorescein staining and eye dryness, respectively) and was well tolerated. Compared with use of hypotonic saline solution, instillation of PFHO led to significant improvements in signs and symptoms in as early as 2 weeks. In a long-term, open-label safety extension study, efficacy of PFHO was sustained over 12 months, and the safety profile was consistent with those of previous studies. Clinical trial results indicate that treatment with PFHO effectively and consistently reduces the signs and symptoms of DED.

Am J Manag Care. 2023;29(suppl 14):S251-S257. https://doi.org/10.37765/ajmc.2023.89464

For author information and disclosures, see end of text.

Introduction

Dry eye disease (DED) is one of the most common ocular surface conditions reported in the United States, with over 18 million US adults estimated to have a diagnosis of DED in 2023.^1-4 An imbalance between aqueous tear production and evaporation commonly drives the development and continuation of DED.^1,5 DED is characterized by signs of ocular surface damage due to tear film instability and excessive evaporation associated with deficient lipid or aqueous tear film components and by symptoms of ocular pain and discomfort.^1,5 Up to 90% of DED is associated with meibomian gland dysfunction (MGD), in which meibomian gland blockage and dropout contributes to a dysfunctional tear film lipid layer and consequent excessive evaporation.^6-9

Most prescription eye drops for DED address signs and symptoms of disease by increasing tear production or decreasing inflammation, but they do not target the excessive evaporation that occurs in the majority of patients.^1,10-15 Perfluorohexyloctane (PFHO) ophthalmic solution (MIEBO™; Bausch + Lomb) is the first and only FDA-approved treatment for DED that directly targets tear evaporation by supplementing the tear film lipid layer in patients whose tear evaporation exceeds tear production.^16,17 PFHO is a water-free, preservative-free, single-ingredient prescription eye drop approved to treat the signs and symptoms of DED.¹⁸ Approval of PFHO was based on the results of 2 pivotal phase 3, multicenter, randomized clinical trials (RCTs), GOBI (NCT04139798) and MOJAVE (NCT04567329).^18-20 This article reviews preclinical data on the mechanism of action for PFHO and clinical data on its efficacy and safety in patients with DED.

Excessive Tear Evaporation and DED

The tear film is comprised of an inner, nutrient-rich mucoaqueous gradient layer that forms the bulk of the tear film and a thin outer lipid layer (Figure 1).^21,22 Aqueous basal tear production largely occurs in the lacrimal glands, whereas most tear film mucins are synthesized by conjunctival goblet cells.^1,21

The meibomian glands, located within the tarsal plate of the upper and lower eyelids, produce the meibum that comprises the lipid layer.²¹ In a healthy tear film, the lipid layer resists tear evaporation and provides protection against foreign matter, stability to prevent thinning and rapid breakup of tears, and a smooth surface for light refraction into the visual system.^21,23 The lipid layer also contributes to lowering the healthy tear film’s surface tension, resulting in its easy spreading across the eye and limiting irritation from blinking friction.^21,23

A deficiency in any layer of the tear film can cause a loss of tear film homeostasis. Most commonly, the outermost layer of the tear film is dysfunctional, resulting in increased tear evaporation.^7,24 Increased tear evaporation, in turn, can lead to a cycle of hyperosmolarity, ocular surface desiccation and friction, inflammation and epithelial damage, and loss of goblet cells and meibomian glands, further driving aqueous tear evaporation and tear film instability.^1,24,25 This damaging cycle can lead to the development and continuation of DED.²⁴

The imbalance between aqueous tear production and evaporation drives all forms of DED, including aqueous-deficient DED (driven by insufficient aqueous tear production), evaporative DED (associated with increased evaporation due to low levels or poor spreading of meibum), or some combination of these pathologies.^1,7 However, most DED involves some level of excessive evaporation.^1,7 A contributing factor to development of evaporative DED is meibomian gland dysfunction (MGD), in which dysfunction and dropout of the meibomian glands and changes in the composition and viscosity of meibum compromise the tear film lipid layer.^7,24 Up to an estimated 86% of patients with DED show signs of MGD, highlighting the pathophysiologic importance of a dysfunctional tear film lipid layer.^6-8

Current Treatment Approaches

Appropriate treatment of DED should be guided by disease etiology and should address the underlying mechanisms of disease (eg, excessive evaporation, aqueous deficiency) to restore tear film stability and ocular surface homeostasis.^1,26 Diagnosis involves investigation of clinical signs of DED, including low tear production, tear film instability, and ocular surface damage, which may be assessed via Schirmer testing, tear film breakup time, and ocular surface staining, respectively.^9,10 Sustained care and management is frequently required to address the lingering effects of this chronic disease.¹

Recommended first-line treatments include tear replacement approaches, such as topical OTC ocular lubricants, as well as treatments aimed to decrease evaporation, including lipid-containing eye drops and therapies that encourage improved meibum flow and unblocking of affected glands (eg, eyelid hygiene, warm compresses).^1,11,27 Patients for whom current first-line therapies prove to be inadequate may benefit from more advanced treatments, such as prescription medications or office-based procedures.^1,10 Those with aqueous deficiency may benefit from placement of temporary or permanent punctal plugs to block tear drainage and improve tear supply.¹¹ To restore meibomian gland function and improve meibum flow in those with evaporative DED, procedural options include manual expression of meibomian glands, intraductal probing with a microcannula, and thermal pulsation or intense pulsed light therapies.^10,11,27

Prescription treatments approved for DED include those indicated to increase tear production or improve signs (eg, ocular surface damage) and/or symptoms (eg, eye dryness) of the disease.^{10,12-15,18,28,29} These treatments include a tear-film stabilizing ophthalmic insert, a cholinergic agonist nasal spray, eye drops with agents that have immunomodulatory or anti-inflammatory action (eg, calcineurin inhibitors, LFA-1 antagonists, corticosteroids), and, most recently, an eye drop that decreases tear-film evaporation.1,10,18,28,29

The preservative-free hydroxypropyl cellulose ophthalmic insert (Lacrisert^®; Bausch + Lomb) stabilizes and thickens the tear film to prevent rapid breakup of tears and lubricates and protects the ocular surface to relieve symptoms of DED.²⁸ Some patients may require twice-daily insertion for sufficient symptom relief, and satisfactory improvement may not occur for several weeks. Mostly mild and transient instances of vision blurring or photophobia, hypersensitivity, eyelid edema, and discomfort of the eyes or eyelashes have been reported with its use; in addition, corneal abrasion or foreign body sensation may occur if the insert is improperly placed.²⁸ Another prescription treatment for DED is varenicline nasal spray (Tyrvaya; Viatris), which contains a nicotinic acetylcholine receptor agonist that increases basal tear production by activating the trigeminal parasympathetic pathway.²⁹ In clinical trials, patients commonly experienced sneezing, cough, and throat or nose irritation upon instillation; adverse events (AEs) led to treatment discontinuation in approximately 3% or fewer of patients.^29-31 A precise and multistep process of priming the bottle and delivering the varenicline spray is required²⁹; therefore, appropriate dosing may be a challenge for some patients.

Prescription Eye Drops and Unmet Needs

Most prescription eye drops indicated for treatment of DED reduce inflammation or stimulate tear production to address signs and symptoms of disease, although the exact mechanism of action in DED is rarely known.^10-15,32

Cyclosporine is a calcineurin inhibitor immunosuppressant; it is available as a 0.05% emulsion (Restasis; Allergan), a 0.09% nanomicellar solution (Cequa; Sun Ophthalmics), and a 0.1% water-free solution (Vevye; Novaliq). It acts as a partial immunomodulator to increase tear production in patients whose tear production is presumed to be suppressed consequent to ocular inflammation.^10,12,14,32 However, patients treated with the emulsion may not experience full clinical benefit for several months.^11,33 Furthermore, patients with DED who are already being treated with topical anti-inflammatory drugs or punctal plugs may not experience increased tear production with use of cyclosporine ophthalmic emulsion, 0.05%.¹² Lifitegrast ophthalmic solution, 5.0% (Xiidra; Novartis), is an LFA-1 antagonist indicated for the treatment of signs and symptoms of DED; the results of in vitro studies suggest that it can inhibit certain inflammatory processes in corneal and conjunctival tissues.^10,13

Cyclosporine- and lifitegrast-containing eye drops are formulated without preservatives; they may be packaged in single-use vials, which are associated with increased costs.^10,12-14,32

Long-term treatment with cyclosporin- and lifitegrast-containing eye drops is often required to address DED; however, real-world use of these medications may be associated with low adherence and high rates of discontinuation.^1,33 The most common AEs seen in clinical trials with cyclosporine were instillation-site pain, ocular burning, and conjunctival hyperemia.^12,14,32 AEs associated with lifitegrast treatment in clinical trials included instillation site irritation, dysgeusia, and reduced visual acuity.¹³

Loteprednol etabonate ophthalmic suspension, 0.25% (Eysuvis; Kala Pharmaceuticals), contains a corticosteroid that inhibits inflammation to address signs and symptoms of DED.¹⁵ Treatment carries a lower risk of intraocular pressure (IOP) elevation than does treatment with other ocular steroids; however, this agent is intended for short-term use (maximum, 2 weeks) and carries the potential for steroid-associated AEs (eg, increased IOP; infection, cataracts, and delayed ocular surface healing).^10,15,34 Instillation site pain was the most common AE in clinical trials with loteprednol etabonate, 0.25%.¹⁵ Loteprednol etabonate ophthalmic suspension is formulated with benzalkonium chloride, a preservative that can be associated with ocular surface toxicity.^11,25

These agents target different pathophysiologic pathways to disrupt the cycle of DED, yet until now topical prescription eye drops did not directly target the excessive evaporation present in most DED.^1,10-15 PFHO—the first and only single-ingredient, preservative-free prescription eye drop approved for DED in the United States—was developed to target excessive evaporation.¹⁸

PFHO Mechanism of Action—Preclinical Study Results

Results from preclinical studies evaluating PFHO suggest that it can supplement the tear film lipid layer in patients with DED by rapidly spreading on instillation to form an anti-evaporative layer that remains on the eye for at least 6 hours and does not block the diffusion of oxygen to the corneal surface. These results indicate PFHO’s potential to stabilize the tear film, reduce friction, and promote ocular surface healing.^16,17,35-40

PFHO is a physiologically inert, semifluorinated alkane consisting of 6 perfluorinated and 8 hydrogenated carbons; it therefore has amphiphilic properties, allowing it to form a monolayer at the tear film air-liquid interface when applied topically (Figure 2^35,41).^16-18 PFHO is a liquid at temperatures above –7.1 °C, and it does not scatter or absorb visible light; with a refractive index similar to water, PFHO is associated with minimal blurred vision.^16,19,35,42

The anti-evaporative effect of PFHO was demonstrated in a series of in vitro gravimetric assays.¹⁶ Results of a preclinical study comparing the evaporation rate (R_evap) of saline alone to that of saline following layered application with common OTC artificial tear formulations (100 µL) or with PFHO showed that OTC eye drops did not significantly change the R_evap of saline, but layering different amounts of PFHO (range, 50-200 µL) on top of saline inhibited the R_evap by approximately 80% (all P < .0001). Additionally, when meibum collected from a healthy volunteer was layered on top of saline, the R_evap was inhibited by only 8%. However, layering an 11-µL or 100-µL drop of PFHO on top of saline and meibum inhibited the R_evap of saline by 34% and 83%, respectively (both P < .0001 vs saline alone). These results suggest that treatment with topical PFHO could address the excessive evaporation seen in most patients with DED.¹⁶

Results from another preclinical study support the potential of PFHO to spread quickly on the ocular surface and improve the tear film lipid layer.¹⁷ Compared with a drop of saline, a drop of PFHO exhibited faster spreading on the surface of ex vivo porcine eyes due to its lower surface tension. To examine PFHO’s potential to stabilize the tear film lipid layer in vivo, the study also examined the effects of PFHO vs saline instillation into healthy rabbit eyes. When instilled twice daily (bid) over 7 days, lipid layer grade—which is associated with the quality and thickness of the tear film lipid layer—improved significantly with PFHO treatment compared with saline treatment from day 5 onwards (P < .05).¹⁷ PFHO may help spread ocular surface lipids to reduce friction on blinking, stabilize the tear film lipid layer, and improve the lipid layer grade to increase evaporation resistance.^17,39

Results from a third preclinical study showed that PFHO has a long-lasting presence in tears.35 In a study with rabbits given a single topical ocular dose of PFHO (target dose, 45.6 mg/eye), the concentration of PFHO in tears was maintained for at least 6 hours. Exposure and distribution was highest in the tears and meibomian glands, with much lower exposure in conjunctival and corneal tissues; systemic absorption was minimal.³⁵ In addition, PFHO was present at 24 hours in the meibomian glands, indicating that the glands may function as a depot of the drug.^10,35

Finally, in another in vitro study, the oxygen concentration in PFHO was evaluated and determined to be high. The cornea is avascular; thus, tears are a crucial source of the oxygen necessary for corneal health and epithelial healing after injury. The high oxygen solubility of PFHO indicates that it will allow oxygen transport from air to tears for corneal oxygenation to facilitate ocular surface healing.³⁶

Together, these preclinical study results suggest the potential of PFHO for DED treatment.^16,17,35,36 The safety and efficacy of PFHO treatment also was examined across several clinical trials in patients with DED and clinical signs of MGD.

Clinical Evidence Supporting Use of PFHO

The efficacy and safety of PFHO for the treatment of DED was assessed in 2 pivotal phase 3 clinical trials, GOBI and MOJAVE (Table^18-20,43,44). Results indicated that treatment with PFHO was well tolerated and associated with statistically significant improvement vs control for both primary and key secondary sign and symptom end points, confirming efficacy and safety results from a previous phase 2 trial (SEECASE; NCT03333057).^19,20,43 Furthermore, in an open-label safety extension trial (KALAHARI; NCT04140227) including a subset of patients from the GOBI study, treatment with PFHO remained safe and effective over the course of 52 weeks.⁴⁴

The SEECASE, GOBI, and MOJAVE trials compared topical treatment of PFHO to treatment with saline as a control in patients with DED and clinical signs of MGD.^19,20,43 Typically, a vehicle control is used in DED clinical trials, but this was not viable, as the ophthalmic drop is composed of 100% PFHO.¹⁹ Therefore, SEECASE used isotonic (0.9%) saline as a control, whereas GOBI and MOJAVE used hypotonic (0.6%) saline as the control.^19,20,43 Saline is a common ingredient in artificial tears, and the use of hypotonic saline solution as a control comparator in the trials provided additional rigor, as this solution can reduce tear film hyperosmolarity to effectively treat DED.¹⁹

To assess the ocular surface damage associated with DED, the trials measured corneal fluorescein staining (CFS) using the National Eye Institute scale. Investigators rated staining with scores ranging from 0 (no staining) to 3 (heavy staining) in each of 5 areas of the cornea (ie, inferior, superior, central, nasal, and temporal); the maximum total CFS (tCFS) score was 15. Symptom assessment was completed using the visual analog scale (VAS), with scores ranging from 0 (no discomfort) to 100 (maximal discomfort).¹⁹

SEECASE

The phase 2, multicenter, double-masked SEECASE study evaluated the efficacy, safety, and tolerability of bid or 4 times daily (qid) PFHO instillation compared with isotonic saline instillation for signs and symptoms of DED (Table^18-20,43,44). The study population was mostly female and had a mean age of 53 years.⁴³ Change from baseline (CFB) in mean tCFS and mean VAS eye dryness scores at 8 weeks were significantly greater for both PFHO dosing arms than for the isotonic saline (0.9%) arm, with greater improvements seen in the qid dosing arm; further, both signs and symptoms showed significant improvements with as little as 2 weeks of treatment. Treatment with PFHO was well tolerated at both dosing regimens, with low rates of ocular AEs (eg, blurred vision, eye irritation, eye pain).⁴³

GOBI Pivotal Trial

GOBI was a phase 3, multicenter, double-masked RCT conducted to evaluate the efficacy and safety of treatment with PFHO compared with a hypotonic (0.6%) saline control for the treatment of signs and symptoms of disease in 597 patients with DED and clinical signs of MGD after 2, 4, and 8 weeks of treatment (Table^18-20,43,44). The study population was mostly female, with approximately half of patients aged 65 years or older.¹⁹ Both primary end points in GOBI were met, with significantly greater improvement from baseline in tCFS and VAS dryness score seen in patients who were treated with PFHO compared with those given hypotonic saline treatment at 8 weeks (Figure 3^19,20). Mean improvement from baseline with PFHO treatment was significantly greater across all key secondary end points, including CFB in VAS dryness and tCFS scores at week 2 and CFB in VAS burning or stinging score and central CFS (cCFS) score at week 8.¹⁹ In addition, compared with results in the hypotonic saline arm, the CFB in mean VAS dryness score in the PFHO arm was significant at week 2 and week 8, although the treatment difference at week 4 did not reach statistical significance (Figure 4^19,20).

Significantly more patients in the PFHO arm (41.2%) were tCFS responders (defined as showing ≥ 3-step tCFS score improvement) compared with those in the hypotonic saline arm (27.2%). Similarly, 57.4% of patients in the PFHO arm were eye dryness responders (defined as showing ≥ 30% reduction in VAS dryness score), whereas 46.6% of those in the hypotonic saline arm were considered eye dryness responders.¹⁹

In general, PFHO treatment was found to be safe and well tolerated. Among reported ocular AEs in both arms, none were serious, and most were mild in severity. Ocular AEs were considered to be related to treatment in 6.3% of patients in the PFHO arm and 3.1% of patients in the hypotonic saline arm. One patient discontinued PFHO treatment due to an ocular AE (eye irritation; severe), and 3 patients discontinued hypotonic saline treatment (conjunctivitis, dry eye, punctate keratitis); no serious ocular AEs were reported in either arm. The most common ocular AEs, reported in 1% or more of patients treated with PFHO, were blurred vision (3.0%; mostly mild and transient) and instillation site pain and eye discharge (both 1.0%).¹⁹

Results from the GOBI trial support the safety and tolerability of PFHO and its efficacy in treating the signs and symptoms of DED as early as 2 weeks and through 8 weeks of treatment.¹⁹

MOJAVE Pivotal Trial

Efficacy and safety of PFHO treatment was further assessed in the similarly designed phase 3 MOJAVE RCT, in which 620 patients with DED and clinical signs of MGD were randomly assigned to either PFHO or 0.6% hypotonic saline treatment instilled qid for 8 weeks (Table^18-20,43,44). The study population was mostly female, with approximately a third of patients aged 65 years or older.²⁰ Consistent with results from the GOBI trial, significantly greater improvements from baseline in both tCFS and VAS dryness scores were seen with PFHO treatment versus use of hypotonic saline beginning at week 2 and continuing through week 8 (Figures 3 and 4).^19,20 Significant improvement in other secondary efficacy outcomes (eg, central CFS, VAS burning/stinging scores) was seen as early as week 2. Additionally, 50.0% of patients in the PFHO arm were tCFS responders and 65.6% were eye dryness responders at week 8 compared with 30.7% and 45.3%, respectively, among those in the hypotonic saline arm.²⁰

Both treatment arms had similarly low rates of ocular AEs, which were mostly mild in severity, confirming the findings from SEECASE and GOBI and indicating that PFHO treatment was well tolerated.^19,20,43 One patient in the hypotonic saline arm experienced a severe ocular AE of eye irritation, but no patients in either arm discontinued treatment due to AEs.²⁰ Ocular AEs deemed related to treatment were seen in 6.4% of patients in the PFHO arm and 6.8% of patients in the hypotonic saline arm. The most common ocular AEs (incidence, ≥ 1%) reported in patients treated with PFHO included blepharitis (1.6%); conjunctival or ocular hyperemia, conjunctival papillae, and blurred vision (1.3% each); and visual acuity reduction and hordeolum (1.0% each).²⁰ Consistent with results from the GOBI study, PFHO achieved statistical superiority compared with hypotonic saline for all key end points, demonstrating improvements over hypotonic saline in treating both DED signs and symptoms across the length of the 8-week study.^19,20 Furthermore, PFHO was similarly well tolerated and effective over 8 weeks of treatment, with a similar safety profile to the hypotonic saline control.20

KALAHARI Extension Trial

The KALAHARI trial was an open-label extension of GOBI, in which a subset of patients from both the PFHO and hypotonic saline arms in GOBI were treated with PFHO qid for 52 weeks. Results from the KALAHARI trial supported the long-term efficacy and safety of PFHO treatment in patients with DED and clinical signs of MGD.⁴⁴

After 52 weeks of PFHO treatment, 13.9% of patients experienced an ocular AE, of which most were mild in severity. The most common ocular AEs were vitreous detachment (1.9% of patients, none considered treatment-related), allergic conjunctivitis (1.4%), blurred vision (1.4%), and increased lacrimation (1.4%); in 2.4% of patients, ocular AEs (eg, blurred vision, chalazion, dry eye, increased lacrimation, and increased IOP [each in 1 patient]) led to treatment discontinuation. Improvements in tCFS and VAS dryness score seen in GOBI among the active arm were maintained; in those who switched from the hypotonic saline control to PFHO at the start of the study, improvement in these measures was seen by week 4 and was maintained for the remainder of the study.⁴⁴

Conclusions

Results from multiple clinical trials showed the consistent efficacy and favorable safety profile of PFHO in treating the signs and symptoms of disease in patients with DED and clinical signs of MGD. PFHO recently received FDA approval for treatment of the signs and symptoms of DED, and it may address unmet needs in the prescription treatment of DED. Excessive evaporation is a major contributor to disease pathogenesis and the continuing cycle of DED progression. There are estimated to be over 18 million patients in the United States with a DED diagnosis, most of whom experience excess tear evaporation. PFHO is the first and only FDA-approved prescription eye drop that directly targets excessive evaporation in patients with DED, thereby promoting ocular surface healing and symptomatic relief.

Authorship affiliation: Eastern Virginia Medical School (JDS); Total Eye Care, PA (DGE); Seidenberg Protzko Eye Associates (EEP)

Funding source: Financial support for this article was provided by
Bausch + Lomb.

Author disclosure: Dr Sheppard reports serving on a consultancy or paid advisor board for AbbVie, Alcon, Aldeyra, Bausch + Lomb, Novaliq, Oyster Point, and Viatris. Dr Sheppard also reports receiving lecture fees for speaking at the invitation of a commercial sponsor from AbbVie, Alcon, Aldeyra, Bausch + Lomb, Novaliq, Oyster Point, and Viatris. Dr Evans reports serving on a consultancy or paid advisor board for Visus. Dr Protzko reports no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this supplement.

Authorship information: Concept and design (JDS); acquisition of data (EEP); analysis and interpretation of data (JDS, DGE, EEP); drafting of the manuscript (JDS, DGE); critical revision of the manuscript for important intellectual content (JDS, DGE); provision of study materials or patients (EEP); administrative, technical, or logistic support (JDS); supervision (JDS, EEP).

Address correspondence to: John D. Sheppard MD, MMSc, FACS. Virginia Eye Consultants, 241 Corporate Boulevard. Norfolk, VA 23502. mmarino@cvphealth.com

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