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Cataract surgery is one of the most commonly performed medical procedures and the leading diagnosis for outpatient surgery visits (3 million) in the U.S. In the past decade, the introductions of presbyopic and toric intraocular lenses (IOLs) have elevated cataract surgery into a refractive procedure. The latest introduction of femtosecond laser-assisted cataract surgery may further improve the predictability and safety of refractive cataract surgery and enhance refractive outcomes.

Comparing laser-assisted vs. conventional refractive cataract surgery

Semifluorinated alkanes (SFAs) seem to be all the rage since the launch of perfluorohexyloctane (PFHO) (Miebo; Bausch+Lomb) and cyclosporine 0.1% dissolved in perfluorobutylpentane (PFBP) (Vevye; Harrow). Both are indicated to treat the signs and symptoms of 

 (DED)—contrary to popular belief, there are no FDA-approved products with an indication for evaporative dry eye disease or meibomian gland dysfunction (MGD). Many of us have gladly adopted these two SFA-containing drops into our armamentarium of dry eye treatments and happily received whatever story the sales representative wants to tell us. The current DED treatment landscape is very crowded, and there is not 1 magic bullet that works for all our patients with DED. As doctors, we are continually searching for better treatment options for DED. This article aims to dive deeper into the preclinical and clinical studies around some of the science of these SFAs and help us better understand how SFAs work in the eyes of our patients seeking relief. 

SFAs are not a new development in the ophthalmic space. They have been used for decades in retinal surgeries. PFHO has been available as an over-the-counter artificial tear in Europe, Australia, and New Zealand since 2015 under trade names such as EvoTears, NovaTears, and Optase, among others, establishing a safety record. Much of the science for both PFHO and PFBP is buried within preclinical studies. I will quickly summarize findings from various studies used in the clinical claims we regularly hear today in hopes of clearing up muddy waters around these drops.

Vittitow et al evaluated PFHO to distinguish the evaporation rate of buffered saline vs harvested human meibum in an in vitro setting.

 The rate of evaporation was measured gravimetrically (weight based). The researchers found almost a 4 times difference in evaporation favoring PFHO vs meibum alone. Although these findings are statistically significant, investigators point out major study design concerns in the discussion section: “A major finding of the current study…in relative agreement with yet other studies that show that, in vitro, meibum lipid does not inhibit evaporation of saline significantly.” Furthermore, “PFHO on evaporation was not measured in vivo, in an environment where blinking and tear film composition is more complex.” The investigators point out that the control group does not mimic real-world dynamics, as harvest meibum does not inhibit evaporation well.

Agarwal et al evaluated the clearance rates of both SFAs in an ex vivo pig eye model. Evaporation was again measured gravimetrically, in a controlled environment that did not simulate tear turnover or blink shear rates; researchers found that 50% of PFBP had evaporated within 0.5 hours and 100% had gone within 2 hours.

 More than 50% of PFHO was still unevaporated at 24 hours. This model was repeated using a perfusion chamber to simulate tear turnover at 1 hour and found similar but less dramatic results. PFBP’s clearance rate vs cyclosporine 0.05% ophthalmic emulsion (Restasis; Abbvie) was 5.1 times slower, whereas PFHO’s clearance rate vs 0.05% cyclosporine was 11 times slower.

Spencer et al evaluated radiolabeled PFHO in an ex vivo model and found that PFHO was detectable in tears for up to 6 hours.

 In a separate study, Spencer et al evaluated radiolabeled PFBP and found that PFBP was detectable in tears for up to 8 hours.

Agarwal et al evaluated ocular surface tear dynamics in an in vivo animal model using live rabbits. Investigators found that both SFAs improved lipid layer grading (LLG) immediately upon instillation of a single drop while decreasing in the saline arm.

 In repeated dosing over 7 days, PFHO did see statistical significance starting at day 5 vs baseline in LLG improvement. However, the study did not show a statistically significant improvement in tear evaporation rate, tear volume, or osmolarity from baseline for either SFA or between SFAs. In a post-hoc analysis by the investigator, PFBP also showed a statistically significant improvement in LLG with no statistically significant difference vs PFHO.

Cyclosporine’s dose-ranging phase 2 study (NCT02617667), conducted by Wirta et al, included a PFBP vehicle arm, PFBP+0.05% cyclosporine, PFBP+0.1% cyclosporine, and cyclosporine 0.05% ophthalmic emulsion.

 Primary efficacy end points evaluated change from baseline in total corneal fluorescein staining (tCFS) and visual analog scale (VAS) dryness at days 15, 29, 85, and 113. PFBP alone showed no statistically significant difference in reduction in tCFS vs 0.05% cyclosporine ophthalmic emulsion, with results numerically favoring PFBP at all measured time points. There were also no statistically significant findings for PFBP in symptom differences vs 0.05% cyclosporine.

Sheppard et al and Tauber et al evaluated PFHO vs saline as PFHO’s pivotal phase 3 studies and found PFHO demonstrated statistically significant improvement in tCFS and VAS dryness scores over 8 weeks vs saline.

 The study enrolled patients with a history of MGD and low tear film breakup time (TFBUT); however, TFBUT results were not reported after 8 weeks of treatment. Perhaps the lack of TFBUT data led to PFHO’s mechanism of action on the package insert as follows: “PFHO forms a monolayer at the air-liquid interface of the tear film [that] can be expected to reduce evaporation. The exact mechanism of PFHO in DED is not known.”

In summary of these findings, do SFAs work in DED? Doctors and patients seem to think so, and the data seem to support it. Do SFAs demonstrate an entirely new mechanism of action for treating DED? That is unclear. Neither SFA showed improvement in tear evaporation rates nor osmolarity in preclinical studies. Although many anecdotal reports show improvement in clinical markers, no well-controlled clinical studies have demonstrated improvement in TFBUT, osmolarity, meibography, meibomian expression, or any measures of MGD or evaporative DED. Finally, the preclinical study evaluating PFHO vs harvested human meibum was not conducted in an ideal environment mimicking a real-world environment. Do our patients really care about mechanism of action? I do not believe so. If they are feeling better, the mechanism of action is irrelevant.

is the president of Omni Eye Specialists, headquartered in Wilmington, North Carolina, and a founding partner of Keplr Vision. Schmidt is president of the Optometric Glaucoma Society and was recently named one of the Top 250 Innovators in Optometry by 

. He is an adjunct professor at various schools of optometry and is a frequent contributor to optometric journals. He is the author of 

Lids and Nasolacrimal System: Clinical Procedures

 and lectures internationally on glaucoma and other ocular diseases.

In the past 24 months Schmidt has received honoraria or compensation from the following companies as an advisor of speaker: Allergan, Bausch & Lomb, Lumenis, Sydnexis, Topcon, Thea Pharmaceuticals, Eyenovia, Sight Science, Harrow, M&S Technologies, Carl Zeiss

Vittitow J, Kissling R, DeCory H, Borchman D. In vitro inhibition of evaporation with perfluorohexyloctane, an eye drop for dry eye disease. 

 2023;98:100704. doi:10.1016/j.curtheres.2023.100704

Agarwal P, Scherer D, Günther B, Rupenthal ID. Semifluorinated alkane based systems for enhanced corneal penetration of poorly soluble drugs. 

. 2018;538(1-2):119-129. doi:10.1016/j.ijpharm.2018.01.019

Krösser S, Spencer E, Grillenberger R, Struble CB, Fischer K. Ocular and systemic distribution of 14C- perfluorohexyloctane following topical ocular administration to rabbits. I

Krösser S, Korward J, Tauber J. Pharmacokinetics and distribution of perfluoroputylpentane, a novel eye drop vehicle, in rabbits after topical administration. Presented at: Tear Film and Ocular Surface Society Congress; October 30-November 2, 2024; Venice, Italy.

Agarwal P, Khun D, Krösser S, et al. Preclinical studies evaluating the effect of semifluorinated alkanes on ocular surface and tear fluid dynamics

. 2019;17(2):241-249. doi:10.1016/j.jtos.2019.02.010

Wirta DL, Torkildsen GL, Moreira HR, et al. A clinical phase II study to assess efficacy, safety, and tolerability of waterfree cyclosporine formulation for treatment of dry eye disease. 

 2019;126(6):792-800. doi:10.1016/j.ophtha.2019.01.024

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. 

. 2023;252:265-274. doi:10.1016/j.ajo.2023.03.008

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. 

. 2023;130(5):516-524. doi:10.1016/j.ophtha.2022.12.021

What we know and what we do not know…yet.

Semifluorinated alkanes in dry eye disease

The FDA has granted Breakthrough Device designation for SightGlass Vision's Diffusion Optics Technology (DOT) spectacles lenses, which are under investigation for the slowing of myopia in children.

 DOT is the first design to leverage contrast management mechanism of action, which gently scatters light across the retina. If approved by the FDA, DOT spectacle lenses will be the first non-contact lens myopia control tactic available to the US market.

“The FDA Breakthrough Device designation for Diffusion Optics Technology (DOT) spectacle lenses is a milestone for our organization—and for the broader fight against the pediatric myopia epidemic. Recent studies

 illustrate that about half of U.S. children are myopic, yet most are not receiving treatments proven to slow myopia progression,” Andrew Sedgwick, CEO of SightGlass Vision, said in a press release. “We are enthusiastic about more closely collaborating with the FDA as we pursue US market clearance.”

DOT technology has a rich history of positive results in clinical trials. The CYPRESS study is in its 5th year, with the most recent data presented in September 2023 at the Congress of the Chinese Ophthalmological Society in Changsha.

 The full 4-year outcomes showed statistically significant slowing of axial length progression and cycloplegic spherical equivalent refraction (cSER) in patients aged 6-10 who used DOT spectacle lenses.

Prior to this, SightGlass Vision presented positive outcomes at ARVO 2023 in New Orleans, Louisiana. The 42-month data from the CYPRESS study extension indicated positive safety and efficacy in children aged 6-10 (at the start of the study).

 The extension re-enrolled 98 patients from the original multi-site clinical trial, which had previously reported improvements in axial length and cSER.

SightGlass Vision, which is a joint venture of CooperCompanies and EssilorLuxottica, has set its sights on developing innovative technologies to combat the global myopia crisis. DOT spectacle lenses are already on the market in China, the Netherlands, and Israel, and the technology is in preliminary market trials in other countries.

1. SightGlass Vision receives breakthrough device designation from US Food and Drug Administration. Press release. February 14, 2024. Accessed February 15, 2024.

Current Trends in Pediatric Eye Examinations and Contact Lens Prescribing in the U.S.

 Poster presentation at the Global Specialty Lens Symposium, January 2024.

3. Myopia Management 2024 Report, Jobson Optical Research, January 2024. 

https://reviewofmm.com/2024-myopia-report/

4. SightGlass presents four-year results of CYPRESS trial at CCOS. Review of Myopia Management. September 5, 2023. Accessed February 15, 2024. https://reviewofmm.com/sightglass-presents-four-year-results-of-cypress-trial-at-ccos/

5. Chalberg T, et al. Control of myopia using diffusion optics spectacle lenses: efficacy and safety study (CYPRESS) 42-month results. ARVO 2023 Annual Meeting presentation. 27 April 2023.

Diffusion Optics Technology (DOT) spectacle lenses are intended to slow myopia progression in children via contrast management mechanism of action.

Pipeline

FDA grants SightGlass Vision Breakthrough Device designation for DOT spectacle lenses

Patient Case 2: Reversal of Contact Lens Intolerance in a Young Patient Following Demodex Blepharitis Treatment

A panelist discusses how treating Demodex blepharitis led to successful reversal of contact lens intolerance in a young patient, highlighting the importance of addressing underlying ocular surface conditions.

Video Series

Patient Case 1: Delaying Cataract Surgery to Prioritize Aggressive Treatment of Ocular Surface Disease, Including Demodex Blepharitis

A panelist discusses how prioritizing aggressive treatment of ocular surface disease, particularly Demodex blepharitis, before proceeding with cataract surgery can lead to better surgical outcomes and patient satisfaction.

Preoperative Ocular Surface Disease Algorithm Overview

A panelist discusses how evaluating and treating ocular surface disease before cataract or refractive surgery through a systematic algorithm improves surgical outcomes and patient satisfaction.

This poll is for optometrists and eyecare professionals, only. It will close on Friday, November 5, 2021.

Andrew L. Nguyen, PhD

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