Perfluorohexyloctane
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Overview
Perfluorohexyloctane ophthalmic solution (MIEBO; Bausch + Lomb) was approved in 2023 in the United States as a treatment for dry eye disease (DED) signs and symptoms. This prescription eye drop is the first FDA-approved eye drop targeting tear evaporation in DED.
Background
Dry eye disease (DED) affects over 16 million individuals in the United States.[1] DED can be subdivided into evaporative and aqueous-deficient etiologies. Evaporative DED refers to excessive tear evaporation in the setting of otherwise sufficient tear production - this may be caused by intrinsic (e.g., meibomian gland deficiency, improper blink reflex) or extrinsic (e.g., vitamin A deficiency, low environmental humidity) sources. Aqueous-deficient DED refers to insufficient tear production, which may be either lacrimal or conjunctival in origin.[2] Affected patients often experience a wide spectrum of symptoms including dryness, burning, tearing, gritty sensation, photophobia, and/or transient blurriness.[3] Initial treatment options include therapies such as warm compresses, artificial tear analogs, topical antibiotic/steroid combinations, immunomodulators, neurostimulation, and/or secretagogues amongst others. For more advanced cases, punctal occlusion, specialty contact lenses, oral antibiotics, and/or other medical and procedural / surgical interventions can be utilized.[4] In May 2023, the FDA approved perfluorohexyloctane ophthalmic solution (MIEBO) for the treatment of signs and symptoms of DED by reducing tear film evaporation.
Existing FDA-approved prescription treatments for DED include cyclosporine (Restasis, Cequa), lifitegrast (Xiidra), loteprednol (Eysuvis), and varenicline solution (Tyrvaya).[5] Cyclosporine and lifitegrast have anti-inflammatory effects via their inhibition of cytokine production and T-cell activation.[6] Loteprednol, a topical steroid, exerts anti-inflammatory effects.[7] Varenicline nasal spray targets the parasympathetic pathway to stimulate tear secretion.[8]
Disease Entity
The pre-corneal tear film is comprised of lipid and mucoaqueous components. Sensory neurons on the corneal surface stimulate autonomic nerves to promote tear secretion. Damage to the ocular surface can result in decreased stimulation of the sensory neurons and thus decreased tear film secretions. Further, factors altering the ocular surface, the blink reflex, and eyelid function can impact the effectiveness of the tear film by altering its distribution across the corneal surface.[4][9]
Deficiency in any of the tear film layers can lead to hyperosmolarity and tear film instability, resulting in ocular surface inflammation and eventual epithelial damage.[10] Initially, inflammation leads to increased sensitization and excitation of channels resulting in stimulation of the lacrimal gland and reflex tearing. If persistent, the inflammation can lead to decreased corneal sensation and secretory dysfunction of the lacrimal gland.[2][9]
Mechanism of Action
Although the exact mechanism of action is not yet known, perfluorohexyloctane is an amphiphilic semifluorinated alkane, which possesses properties that allow for miscibility in aqueous solutions. These amphiphilic properties theoretically allow perfluorohexyloctane to stabilize the tear film by forming an anti-evaporative layer on the tearfilm while allowing for diffusion of oxygen.[11][12]
Clinical Trials
Two phase 3 trials (GOBI and MOJAVE) were conducted with a total of 1,217 patients to evaluate the safety and efficacy of perfluorohexyloctane in treating DED signs and symptoms. Both trials were multicenter, randomized, double-masked, saline-controlled studies where patients were randomized in a 1:1 fashion into a perfluorohexyloctane treatment group or a saline 0.6% control group. Both groups received drops four times a day in each eye for 8 weeks.[13][14]
The efficacy of perfluorohexyloctane in treating signs of DED was measured by a change in total corneal fluorescein staining (tCFS) from day 0 to week 8 as well as by a change in eye dryness score (0-100 visual analogue scale [VAS]) at week 8 (Table 1).[13][14] tCFS was recorded using a 0-3 grading system for the inferior, superior, central, nasal, and temporal regions of the cornea (Table 1). VAS was measured on a scale of 0-100 with 0 being no discomfort and 100 being maximal discomfort. Points were given for dryness, burning/stinging, sticky feeling, foreign body sensation, itching, blurred vision, sensitivity to light, pain, awareness of dry eye symptoms, and frequency of dryness.[13][14]
| tCFS | VAS | |
| MOJAVE | -1.2 | -10.2 |
| GOBI | -0.97 | -7.6 |
Table 1: Least-squares (LS) mean change from baseline to week 8 between perfluorohexyloctane group and saline control group (p < 0.001)
The results of the GOBI and MOJAVE trials demonstrate that, by week 8, patients treated with perfluorohexyloctane had significantly decreased fluorescein staining and a significant improvement in eye dryness score. Significant improvement in tCFS and VAS scores were observed between the perfluorohexyloctane and control groups as early as week 2 in both the GOBI and MOJAVE trials. Determination of longer-term efficacy will require further investigation.
KALAHARI, a phase 3, multicenter, single-arm, open-label extension study of the GOBI trial followed 208 patients who completed the GOBI trial. Patients in the perfluorohexyloctane arm of the GOBI study continued to receive perfluorohexyloctane drops 4 times a day in each eye while patients in the saline arm of the GOBI study were converted to receiving perfluorohexyloctane drops 4 times a day in each eye for the subsequent 52 weeks. Efficacy was determined by a change in tCFS and VAS scores from baseline GOBI scores. At 52 weeks, the mean change in tCFS from GOBI baseline was -2.1 and the mean change in VAS from GOBI baseline was -33.7. Mean tCFS and VAS dryness scores were improved as early as 4 weeks in patients who were converted from the GOBI saline arm. In sum, these results demonstrate a sustained efficacy at 60 weeks of perfluorohexyloctane in improving signs and symptoms of DED.[15]
Contraindications and Adverse Events
No absolute contraindications currently exist for use of perfluorohexyloctane for DED. However, perfluorohexyloctane has not been studied in pregnant, breastfeeding, or pediatric populations. The most commonly observed adverse reaction in the GOBI and MOJAVE trials was blurred vision reported by 1.3%-3.0% of patients. The most commonly observed adverse event noted in the KALAHARI trial was vitreous detachment in 1.9% of patients, but this was considered unrelated to treatment. Other adverse events observed less frequently included instillation site pain, subconjunctival hemorrhage, punctate keratitis, eye discharge, blepharitis, conjunctival hyperemia, conjunctival papillae, visual acuity reduction, hordeolum, eye pruritis, and eye pain. No clinically significant concerns were observed in best-corrected visual acuity, slit-lamp examination, intraocular pressure, or dilated fundoscopy exam.[13][14] Further investigations are needed to assess longer-term adverse effects.
| Percentage of Patients Experiencing Adverse Event (%) | ||
| Adverse Effect | Perfluorohexyloctane Group | Saline Control Group |
| Blepharitis | 1.6 | 0.3 |
| Conjunctival hyperemia | 1.3 | 1.9 |
| Conjunctival papillae | 1.3 | 1.6 |
| Ocular hyperemia | 1.3 | 0.3 |
| Blurred vision | 1.3 | 0.3 |
| Visual acuity reduction | 1.0 | 1.0 |
| Hordeolum | 1.0 | 0.6 |
| Eye pruritis | 0.6 | 1.0 |
| Eye discharge | 0.3 | 1.3 |
| Eye pain | 0.3 | 1.3 |
Table 2: Adverse effects from MOJAVE Trial
Dosing, Administration, and Preparation
Perfluorohexyloctane is formulated as a preservative and excipient-free ophthalmic solution containing 100% perfluorohexyloctane. Current dosage recommendations suggest one drop of perfluorohexyloctane be administered four times daily into each affected eye. Contact lenses should be removed prior to administration of perfluorohexyloctane and should not be reinserted for at least 30 minutes after administration.[12]
Patient Selection
Controlled studies with perfluorohexyloctane use in pregnant women have not been performed. In murine studies, oral administration of perfluorohexyloctane at doses 162 times the recommended ophthalmic dose did not elicit adverse maternal or fetal developmental effects. However, in rabbits, at 41 times the recommended human ophthalmic dose and beyond, maternal toxicity, miscarriage and reduced fetal weight were observed at all doses tested. No fetal mortality or malformation were noted in this study.[12] As such, when deciding whether to prescribe perfluorohexyloctane to pregnant or breast-feeding women, the necessity of treatment should be weighed against the potential risks.
Safety and efficacy in patients younger than 18 years have not been established.[12]
Conclusions
Perfluorohexyloctane ophthalmic solution (MIEBO) was FDA approved in 2023 for the treatment of signs and symptoms of DED. The clinical trials only enrolled patients with clinical signs of MGD and it is the first prescription eye drop specifically targeting evaporative DED. Three phase 3 clinical trials have supported perfluorohexyloctane to be efficacious and safe in treating DED signs and symptoms. Further studies are needed to determine efficacy and adverse effects beyond one year.
References
- ↑ Farrand KF, Fridman M, Stillman IÖ, Schaumberg DA. Prevalence of Diagnosed Dry Eye Disease in the United States Among Adults Aged 18 Years and Older. Am J Ophthalmol. 2017;182:90-98.
- ↑ 2.0 2.1 The definition and classification of dry eye disease: Report of the definition and classification subcommittee of the International Dry Eye Workshop. Ocul Surf. 2007.
- ↑ Zeev MS, Miller DD, Latkany R. Diagnosis of dry eye disease and emerging technologies. Clin Ophthalmol. 2014;20:581-90.
- ↑ 4.0 4.1 Rolando M, Merayo-Lloves J. (2022) Management Strategies for Evaporative Dry Eye Disease and Future Perspective. Curr Eye Res. 2022;47(6):813-823.
- ↑ Cui D, Saldanha IJ, Li G, Mathews PM, Lin MX, Akpek EK. United States Regulatory Approval of Topical Treatments for Dry Eye. Am J Ophthalmol. 2023
- ↑ Pflugfelder SC, de Paiva CS. The Pathophysiology of Dry Eye Disease: What We Know and Future Directions for Research. Ophthalmology. 2017;124(11S):S4-S13.
- ↑ Venkateswaran N, Bian Y, Gupta PK. Practical Guidance for the Use of Loteprednol Etabonate Ophthalmic Suspension 0.25% in the Management of Dry Eye Disease. Clin Ophthalmol. 2022;16:349-355.
- ↑ Frampton JE. Varenicline Solution Nasal Spray: A Review in Dry Eye Disease. Drugs. 2022;82(14):1481-1488.
- ↑ 9.0 9.1 Huang R, Su C, Fang L, Lu J, Chen J, Ding Y. Dry eye syndrome: comprehensive etiologies and recent clinical trials. Int Ophthalmol. 2022;42(10):3253-3272.
- ↑ Aragona P, Giannaccare G, Mencucci R, et al. Br J Ophthalmol. 2021;105:446–453.
- ↑ Vittitow J, Kissing R, DeCory H, Borchman D. In vitro inhibition of evaporation with perfluorohexyloctane, an eye drop for dry eye disease. Curr Ther Res Clin Exp. 2023;98:100704.
- ↑ 12.0 12.1 12.2 12.3 Miebo. Prescribing information. Bausch + Lomb; 2023. https://www.bausch.com/globalassets/pdf/packageinserts/pharma/miebo-package-insert.pdf
- ↑ 13.0 13.1 13.2 13.3 Tauber J, Berdy GJ, Wirta DL, Krösser S, Vittitow JL, GOBI Study Group. NOV03 for Dry Eye Disease Associated with Meibomian Gland Dysfunction: Results of the Randomized Phase 3 GOBI Study. Ophthalmology. 2023;130(5):516-524.
- ↑ 14.0 14.1 14.2 14.3 Sheppard JD, Kurata F, Epitropoulos AT, Krösser S, Vittitow JL, MOJAVE Study Group. NOV03 for Signs and Symptoms of Dry Eye Disease Associated With Meibomian Gland Dysfunction: The Randomized Phase 3 MOJAVE Study. Am J Ophthalmol. 2023;252:265-274.
- ↑ Protzko EE, Segal BA, Korenfeld MS, Krösser S, Vittitow JL. Long-Term Safety and Efficacy of Perfluorohexyloctane Ophthalmic Solution for the Treatment of Patients With Dry Eye Disease: The KALAHARI Study. Cornea. 2023.
