Semifluorinated alkanes in dry eye disease

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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 dry eye disease (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.¹ 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.² 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.³ In a separate study, Spencer et al evaluated radiolabeled PFBP and found that PFBP was detectable in tears for up to 8 hours.⁴

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.⁵ 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.⁶ 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.^7,8 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.

References:

1. Vittitow J, Kissling 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. doi:10.1016/j.curtheres.2023.100704

2. Agarwal P, Scherer D, Günther B, Rupenthal ID. Semifluorinated alkane based systems for enhanced corneal penetration of poorly soluble drugs. Int J Pharm. 2018;538(1-2):119-129. doi:10.1016/j.ijpharm.2018.01.019

3. Krösser S, Spencer E, Grillenberger R, Struble CB, Fischer K. Ocular and systemic distribution of 14C- perfluorohexyloctane following topical ocular administration to rabbits. Invest Ophthalmol Vis Sci. 2018;59(9):2656.

4. 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.

5. Agarwal P, Khun D, Krösser S, et al. Preclinical studies evaluating the effect of semifluorinated alkanes on ocular surface and tear fluid dynamics. Ocul Surf. 2019;17(2):241-249. doi:10.1016/j.jtos.2019.02.010

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

7. 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. doi:10.1016/j.ajo.2023.03.008

8. 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. doi:10.1016/j.ophtha.2022.12.021