Water-Free Cyclosporine Ophthalmic Solution vs Vehicle for Dry Eye Disease: A Randomized Clinical Trial.

Importance: Dry eye disease (DED) is a prevalent eye disorder. Cyclosporine is an effective immunomodulator that is widely used in DED; however, due to its highly hydrophobic nature, delivery of cyclosporine to the ocular surface is challenging. Objective: To evaluate the efficacy and safety of SHR8028, a water-free cyclosporine ophthalmic solution, 0.1%, compared with vehicle in Chinese participants with DED. Design, Setting, and Participants: This was a multicenter, double-blind, vehicle-controlled, phase 3 randomized clinical trial conducted from March 4, 2021, to July 22, 2022. Adult participants with moderate to severe DED were recruited from 12 hospitals in China. Study data were analyzed April 2, 2022, for the primary analysis. Interventions: Following a 14-day run-in period with an artificial tear, participants were randomly assigned (1:1) to receive water-free cyclosporine or vehicle (1 eye drop in each eye twice daily). After a 29-day treatment, participants of both groups were given the option to receive water-free cyclosporine for an additional 12 weeks for longer-term safety assessment. Main Outcomes and Measures: The primary end points were changes from baseline in total corneal fluorescein staining (tCFS) using the National Eye Institute scale and in dryness score on a visual analog scale at day 29. Results: A total of 206 participants (mean [SD] age, 47.8 [14.2] years; 185 female [90%]) were enrolled, with 103 each in the cyclosporine group and the vehicle group. At day 29, the cyclosporine group experienced improved tCFS compared with vehicle (change [Δ] = -1.8; 95% CI, -2.7 to -1.0; P < .001), with a tCFS score decrease from baseline of -4.8 in the cyclosporine group and -3.0 in the vehicle group. Dryness score decreased from baseline in both groups (-19.2 vs -15.4; Δ = -3.8; 95% CI, -9.2 to 1.6; P = .17). During the 29-day treatment, treatment-related adverse events were reported in 15 participants (14.6%) in the cyclosporine group and 11 participants (10.7%) in the vehicle group. Conclusions And Relevance: Results demonstrated superiority of a water-free cyclosporine, 0.1%, eye solution over vehicle in improving tCFS score at day 29 in Chinese participants with DED. However, dryness score (VAS) was not improved at day 29. Trial Registration: ClinicalTrials.gov Identifier: NCT05841043.

Efficacy of a Novel Water-Free Topical Cyclosporine 0.1 % Solution for Optimizing the Ocular Surface in Patients with Dry Eye and Cataract.

This is a pooled analysis from two phase III clinical trials investigating a water-free topical cyclosporine 0.1% for the treatment of moderate to severe dry eye. The analyses included 1162 patients: 35% with cataract, 20% with pseudophakia and 45% without cataract. Demographics or baseline characteristics were comparable across groups except for age and vision. The cyclosporine treated patients achieved large mean improvements from baseline by day 15: -3.7 in patients without cataract, -3.2 in patients with cataract and -3.1 in pseudophakic patients. These improvements were statistically significantly higher compared to the respective vehicle groups. In the cataract subgroup, 59% of patients treated with cyclosporine achieved ≥3 grade improvements in corneal staining score, as early as day 15. The magnitude of the effect and early onset of action make this novel cyclosporine solution a promising candidate for pre-operative management of ocular surface in patients undergoing cataract surgery.

Long-Term Safety and Efficacy of Perfluorohexyloctane Ophthalmic Solution for the Treatment of Patients With Dry Eye Disease: The KALAHARI Study.

PURPOSE: The aim of this study was to assess the long-term safety and efficacy of perfluorohexyloctane (PFHO) ophthalmic drop (formerly NOV03) for treatment of dry eye disease (DED). METHODS: KALAHARI was a phase 3, multicenter, single-arm, open-label extension study in patients aged 18 years or older with DED associated with Meibomian gland dysfunction who completed the randomized, double-masked, hypotonic saline-controlled GOBI study. Patients instilled 1 drop of PFHO (MIEBO, Bausch + Lomb) 4 times daily in both eyes for 52 weeks. Safety assessments included adverse events, best-corrected visual acuity, slit-lamp biomicroscopy, intraocular pressure, and dilated fundoscopy. Efficacy end points included change from GOBI study baseline in total corneal fluorescein staining and eye dryness score (0-100 visual analog scale). RESULTS: Overall, 208 patients from GOBI (PFHO [n = 97]; saline [n = 111]) were rolled over into KALAHARI. Twenty-nine patients (13.9%) had ≥1 ocular adverse event, with most being mild or moderate in severity; the most common ocular adverse events were vitreous detachment (1.9%), allergic conjunctivitis (1.4%), blurred vision (1.4%), and increased lacrimation (1.4%). Other safety end points were unremarkable. For patients continuing PFHO from GOBI, improvements in total corneal fluorescein staining and visual analog scale dryness scores observed in GOBI were maintained throughout KALAHARI. Patients treated with saline in GOBI and switched to PFHO in KALAHARI showed improvements in total corneal fluorescein staining and visual analog scale scores by week 4 that were maintained for the rest of the study. CONCLUSIONS: PFHO was safe and well tolerated and maintained efficacy for improving signs and symptoms of DED in this year-long study of patients with DED associated with Meibomian gland dysfunction.

Preclinical characterization of water-free cyclosporine eye drops - Factors impacting ocular penetration ex vivo and in vivo.

Although the efficacy of Cyclosporine A (CsA) in the management of ocular inflammation is well-demonstrated, ocular delivery remains challenging due to its hydrophobic nature. The semifluorinated alkane, perfluorobutylpentane (F4H5) has previously been suggested as an efficient vehicle for preparation of CsA eyedrops. Here we evaluated the influence of drop volume and the formulation aid, ethanol (EtOH), on ocular penetration of CsA and compared it to that of the commercial eyedrop, Ikervis, ex vivo and in vivo. Moreover, conjunctival and corneal tolerability after EtOH addition were evaluated ex vivo. The F4H5/EtOH vehicle was well tolerated and resulted in better corneal CsA penetration (AUC(0-4h): 63,008 ± 3,946 ng.h.g-1) than Ikervis (AUC(0-4h): 10,328 ± 1,462 ng.h.g-1) or F4H5 alone (AUC(0-4h): 50,734 ± 3,472 ng.h.g-1) ex vivo. Interestingly, in vivo the CsA concentration in cornea, conjunctiva and lacrimal glands observed after administration of the F4H5 formulation (AUC(0.133-24h): 7,741 ± 1,334 ng.h.g-1, 1,313 ± 291 ng.h.g-1, 48.2 ± 26.3 ng.h.g-1) and F4H5/EtOH, both at a reduced dose of 11 µl (AUC(0.133-24h): 9,552 ± 1,738 ng.h.g-1, 1,679 ± 285 ng.h.g-1, 50.3 ± 21.1 ng.h.g-1) was similar or even greater than that observed on administration of 50 µl Ikervis (AUC(0.133-24h): 9,943 ± 1,413 ng.h.g-1, 2,069 ± 263 ng.h.g-1, 30.6 ± 18.4 ng.h.g-1). Thus, F4H5-based eyedrops were shown to deliver CsA more efficiently to anterior ocular tissues at a reduced dose in comparison to Ikervis, reducing dose wastage and minimizing any potential systemic side effects.

Efficacy and Safety of a Water-Free Topical Cyclosporine, 0.1%, Solution for the Treatment of Moderate to Severe Dry Eye Disease: The ESSENCE-2 Randomized Clinical Trial.

Importance: Dry eye disease (DED) is a common public health problem with significant impact on vision-related quality of life and well-being of patients. Medications with rapid onset of action and a good tolerability profile remain an unmet need. Objective: To assess efficacy, safety, and tolerability of a water-free cyclosporine ophthalmic solution, 0.1% (CyclASol [Novaliq GmbH]), applied twice daily in DED compared with vehicle. Design, Setting, and Participants: CyclASol for the Treatment of Signs and Symptoms of Dry Eye Disease (ESSENCE-2) was a phase 3, multicenter, randomized, double-masked, vehicle-controlled clinical study conducted from December 5, 2020, to October 8, 2021. Following a 14-day run-in period with an artificial tear administered 2 times per day, eligible participants were randomly assigned 1:1 to the treatment groups. Patients with moderate to severe DED were included in the study. Interventions: Cyclosporine solution vs vehicle administered 2 times per day for 29 days. Main Outcomes and Measures: The primary end points were changes from baseline in total corneal fluorescein staining (tCFS; 0-15 National Eye Institute scale) and in dryness score (0-100 visual analog scale) at day 29. Conjunctival staining, central corneal fluorescein staining, and tCFS responders were also assessed. Results: A total of 834 study participants were randomly assigned to cyclosporine (423 [50.7%]) or vehicle (411 [49.3%]) groups at 27 sites. Participants had a mean (SD) age of 57.1 (15.8) years, and 609 (73.0%) were female individuals. The majority of participants self-identified in the following race categories: 79 Asian (9.5 %), 108 Black (12.9%), and 635 White (76.1%). Participants treated with cyclosporine solution had greater improvement in tCFS (-4.0 grades) than the vehicle group (-3.6 grades) at day 29 (change [∆] = -0.4; 95% CI, -0.8 to 0; P = .03). The dryness score showed treatment benefits from baseline in both groups: -12.2 points for cyclosporine and -13.6 points for vehicle (∆ = 1.4; 95% CI, -1.8 to 4.6; P = .38). In the cyclosporine group, 293 participants (71.6%) achieved clinically meaningful reductions of 3 grades or higher in tCFS vs 236 (59.7%) in the vehicle group (∆ = 12.6%; 95% CI, 6.0%-19.3%; P < .001). These responders showed greater improvement in symptoms at day 29 including dryness (∆ = -4.6; 95% CI, -8.0 to -1.2; P = .007) and blurred vision (Δ = -3.5; 95% CI, -6.6 to -4.0; P = .03) compared with nonresponders. Conclusions and Relevance: The ESSENCE-2 trial confirmed that treatment with a water-free cyclosporine solution, 0.1%, results in early therapeutic effects on the ocular surface compared with vehicle. The responder analyses suggest that the effect is clinically meaningful in 71.6% of participants in the cyclosporine group. Trial Registration: ClinicalTrials.gov Identifier: NCT04523129.

Perfluorohexyloctane Eye Drops for Dry Eye Disease Associated With Meibomian Gland Dysfunction in Chinese Patients: A Randomized Clinical Trial.

Importance: Meibomian gland dysfunction (MGD) is a leading cause of evaporative dry eye disease (DED). Medical and surgical management for DED is limited; therefore, new treatment options are sought. Objective: To evaluate the efficacy and safety of SHR8058 (perfluorohexyloctane) eye drops in Chinese patients with DED associated with MGD through 57 days. Design, Setting, and Participants: This was a randomized, multicenter, double-masked, saline-controlled, phase 3 clinical trial conducted from February 4, 2021, to September 7, 2022. Patients were recruited from the departments of ophthalmology in 15 hospitals in China. Patients with DED associated with MGD were enrolled between February 4 and July 1, 2021. The diagnosis was based on patient complaint of DED symptoms, an ocular surface disease index of 25 or higher, tear film break-up time of 5 seconds or less, Schirmer I test without anesthesia results of 5 mm or more at 5 minutes, total corneal fluorescein staining (tCFS) score of 4 to 11, and an MGD score of 3 or higher. Interventions: Eligible participants were randomly assigned 1:1 to receive perfluorohexyloctane eye drops or 0.6% sodium chloride [NaCl]) 4 times per day. Main Outcomes and Measures: The primary end points were the changes from baseline in tCFS and eye dryness scores at day 57. Results: A total of 312 participants were included in the analysis: 156 (mean [SD] age, 45.4 [15.2] years; 118 female [75.6%]) in the perfluorohexyloctane group and 156 (mean [SD] age, 43.7 [15.1] years; 127 female [81.4%]) in the NaCl group. Both primary end points were achieved, ie, changes from baseline at day 57 of tCFS score (mean [SD], -3.8 [2.7] vs -2.7 [2.8]) and eye dryness score (mean [SD], -38.6 [21.9] vs -28.3 [20.8]) in the perfluorohexyloctane group were superior to the control group, with estimated mean differences of -1.14 (95% CI, -1.70 to -0.57; P < .001) and -12.74 (95% CI, -17.20 to -8.28, P < .001), respectively. Improvements on both end points appeared to be noted on day 29 and day 15, respectively, and maintained through day 57. Compared with the control, perfluorohexyloctane eye drops also alleviated symptoms including pain (mean [SD] tCFS score, 26.7 [23.7] vs -18.7 [22.5]; P = .003), awareness of DED symptoms (mean [SD] tCFS score, -38.1 [25.1] vs -23.7 [27.6]; P < .001), and frequency of dryness (mean [SD] tCFS score, -43.3 [23.8] vs -29.1 [24.8]; P < .001). Treatment-emergent adverse events occurred in 34 participants (21.8%) and 40 participants (25.6%) in the perfluorohexyloctane and control groups, respectively. Conclusions and Relevance: Results of this randomized clinical trial demonstrate that perfluorohexyloctane eye drops significantly ameliorated the signs and symptoms of DED associated with MGD with a rapid efficacy as well as satisfactory tolerability and safety through 57 days. Findings support the use of these eye drops if results can be confirmed independently and over longer time periods. Trial Registration: ClinicalTrials.gov Identifier: NCT05515471.

NOV03 for Signs and Symptoms of Dry Eye Disease Associated With Meibomian Gland Dysfunction: The Randomized Phase 3 MOJAVE Study.

PURPOSE: To evaluate the efficacy and safety of NOV03 (perfluorohexyloctane) ophthalmic drop for the treatment of signs and symptoms of dry eye disease (DED) associated with meibomian gland dysfunction (MGD). DESIGN: Randomized, double-masked, controlled trial. METHODS: Patients ≥18 years of age with a history of DED and signs of MGD were randomly assigned 1:1 to treatment with NOV03 or hypotonic saline (0.6%) 4 times daily for 8 weeks. The primary sign and symptom endpoints were change from baseline to week 8 in total corneal fluorescein staining (tCFS; National Eye Institute scale) and eye dryness score (0-100 visual analog scale), respectively. RESULTS: A total of 620 patients (NOV03, n = 311; saline, n = 309) were randomized and treated. Least-squares (LS) mean change from baseline to week 8 was statistically significantly greater for NOV03 compared with saline for both tCFS (-2.3 vs -1.1; LS mean treatment difference, -1.2 [95% confidence interval -1.7 to -0.8]; P < .001) and visual analog scale dryness score (-29.4 vs -19.2; LS mean treatment difference, -10.2 [95% CI -14.4 to -6.1]; P < .001), with statistically significant between-group differences observed as early as week 2. The incidence of ocular adverse events was similar for NOV03 (12.9%) and saline (12.3%). There were no serious adverse events and no adverse events leading to treatment discontinuation. CONCLUSIONS: In this randomized controlled trial of patients with DED associated with MGD, NOV03 significantly reduced both signs and symptoms of DED compared with hypotonic saline control. NOV03 was well tolerated, with an adverse event profile similar to that of saline.

NOV03 for Dry Eye Disease Associated with Meibomian Gland Dysfunction: Results of the Randomized Phase 3 GOBI Study.

PURPOSE: To evaluate the efficacy and safety of NOV03 (perfluorohexyloctane) ophthalmic drop in patients with dry eye disease (DED) associated with meibomian gland dysfunction (MGD). DESIGN: Eight-week, phase 3, multicenter, randomized, double-masked, saline-controlled study. PARTICIPANTS: Adults ≥ 18 years with a history of DED for ≥ 6 months, tear film breakup time of ≤ 5 seconds, Schirmer I test (without anesthesia) score ≥ 5 mm, MGD score ≥ 3 (0-15 scale), and total corneal fluorescein staining (tCFS) score ≥ 4 and ≤ 11 (0-15 National Eye Institute [NEI] scale). METHODS: Patients were randomized 1:1 to NOV03 or hypotonic (0.6%) saline 4 times daily. MAIN OUTCOME MEASURES: The primary sign and symptom end points were change from baseline in tCFS and eye dryness score (0-100 visual analog scale [VAS]) at week 8. Key secondary end points were change from baseline in eye dryness score at week 2, tCFS at week 2, eye burning or stinging score (0-100 VAS) at week 8, and central corneal fluorescein staining (cCFS; 0-3 NEI scale) at week 8. RESULTS: Of the 599 patients randomized, 597 were treated (NOV03, n = 303; saline, n = 294). At week 8, improvement from baseline was significantly greater (P < 0.001) with NOV03 versus saline for tCFS (least square [LS] mean treatment difference, -0.97; 95% confidence interval [CI]: -1.40, -0.55) and VAS dryness score (-7.6; 95% CI: -11.8, -3.4). Improvement from baseline also significantly (P < 0.01) favored NOV03 on all key secondary end points: LS mean treatment difference (95% CI) was -4.7 (-8.2, -1.2) for VAS dryness score at week 2, -0.6 (-0.9, -0.2) for tCFS at week 2, -5.5 (-9.5, -1.6) for VAS burning or stinging score at week 8, and -0.2 (-0.4, -0.1) for cCFS at week 8. Most ocular adverse events (AEs) were mild in severity; no serious ocular AEs occurred. One patient discontinued NOV03 because of an AE (eye irritation). CONCLUSIONS: In patients with DED associated with MGD, NOV03 demonstrated statistically significant and clinically meaningful improvements versus hypotonic saline in signs and symptoms of DED and was well tolerated. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

A Water-free 0.1% Cyclosporine A Solution for Treatment of Dry Eye Disease: Results of the Randomized Phase 2B/3 ESSENCE Study.

PURPOSE: To assess the efficacy, safety, and tolerability of a topical water-free cyclosporine A formulation (CyclASol 0.1% ophthalmic solution) in comparison with vehicle for the treatment of dry eye disease (DED). METHODS: Three hundred twenty-eight patients were enrolled in this prospective, 12-week, multicenter, randomized, double-masked, confirmatory, vehicle-controlled clinical study. After a 2-week run-in period, eligible DED patients were randomized 1:1 to either CyclASol 0.1% or vehicle twice daily. The primary efficacy endpoint was change from baseline in total corneal fluorescein staining (National Eye Institute scale), and the second hierarchical primary efficacy endpoint was change from baseline in the Ocular Surface Disease Index score, both at 4 weeks. Secondary efficacy and safety assessments included conjunctival lissamine green staining (Oxford scale), visual analog scales for dry eye symptoms, and adverse event. RESULTS: Treatment with CyclASol 0.1% was superior to vehicle in the primary endpoint: total corneal fluorescein staining at week 4 (Δ -0.8; 95% confidence interval, -1.3 to -0.4; P = 0.0002, analysis of covariance). This difference had already reached statistical significance after 2 weeks and was maintained throughout the study. The study did not statistically meet its second hierarchically tested primary endpoint: Ocular Surface Disease Index score (P = 0.2634). However, CyclASol 0.1% treatment showed statistically significant improvement compared with that of vehicle in the eye dryness score at week 4 (Δ -4.783; 95% confidence interval, -9.129 to -0.438; P = 0.0311). CONCLUSIONS: CyclASol 0.1% was effective in treating signs and symptoms of DED. It significantly reduced corneal and conjunctival staining and improved ocular dryness compared with vehicle. CyclASol 0.1% was safe and showed excellent tolerability.

A Randomized Clinical Study (SEECASE) to Assess Efficacy, Safety, and Tolerability of NOV03 for Treatment of Dry Eye Disease.

PURPOSE: NOV03 has a unique dual mode of action to address dry eye disease (DED) associated with meibomian gland dysfunction. SEECASE evaluated the efficacy, safety, and tolerability of NOV03 at 2 dosing regimens compared with a saline comparator in patients with DED. METHODS: SEECASE was a prospective, multicenter, randomized, double-masked, saline-controlled clinical study. A total of 336 DED patients [tear film breakup time ≤5 seconds, abnormal meibum secretion, total corneal fluorescein staining (tCFS) score of 4 ≤ X ≤ 11 (National Eye Institute scale), Schirmer of ≥5 mm] were randomized in a 2:2:1:1 manner to NOV03 4 times daily (QID), NOV03 twice daily (BID), saline BID, and saline QID, respectively. The primary efficacy endpoint was tCFS staining at 8 weeks for both regimens. Secondary endpoints included visual analog scales and the Ocular Surface Disease Index questionnaire for symptom assessment. RESULTS: The study met its primary endpoint, change from baseline of tCFS over control, for both dosing regimens QID and BID (P < 0.001 and P = 0.009, respectively). NOV03 also showed pronounced improvement in various symptoms. For the Eye Dryness Score, changes from baseline were statistically significant compared with those of the control at week 8 [P < 0.001 (QID) and P = 0.002 (BID)]. Benefits on tCFS and symptoms started at 2 weeks after start of treatment and were maintained over the study duration. The effects were dosing schedule dependent. NOV03 was well tolerated with instillation site reactions below 3% in both treatment regimes. CONCLUSIONS: The SEECASE study demonstrated that NOV03 improves signs and symptoms in patients with highly symptomatic evaporative dry eye disease.

Influence of Perfluorohexyloctane Eye Drops on Tear Film Thickness in Patients with Mild to Moderate Dry Eye Disease: A Randomized Controlled Clinical Trial.

Purpose: The aim of this mechanistic clinical study was to explore the effect of water-free perfluorohexyloctane eye drops on tear film thickness (TFT) in patients with dry eye disease (DED). Methods: Forty-eight patients with mild to moderate DED participated in this randomized, single-masked, observer-blinded parallel group study in a 1:1 ratio to receive either perfluorohexyloctane or unpreserved 0.9% saline solution (Hydrabak®, Thea, France) eye drops 4 times daily in both eyes for 4 weeks. A custom-built ultrahigh-resolution optical coherence tomography system was used to measure TFT. Furthermore, evaluation of lipid layer thickness (LLT) and noninvasive tear film breakup time, as well as standard clinical tests for signs and symptoms of DED were performed. Results: Mean TFT and LLT at baseline were comparable between the 2 treatment groups. After a single drop instillation, perfluorohexyloctane eye drops temporarily increased TFT immediately. After multiple dosing, perfluorohexyloctane eye drops gradually increased TFT over time with a maximum effect at the end of the study (least square mean difference: 6.42%; P = 0.0142 at week 4). LLT values measured before drop instillation showed a more prominent increase in LLT for perfluorohexyloctane eye drops (13.36% ± 26.33% vs. 3.21% ± 28.65%). All other parameters got better in both treatment groups with no statistical difference between groups. Conclusions: These results demonstrate that perfluorohexyloctane eye drops increase TFT as well as LLT over time. These tear film reestablishing attributes are in line with the mode of action of perfluorohexyloctane eye drops to avoid evaporation through stabilization of the lipid layer.

Semifluorinated Alkane Eye Drops in Chronic Ocular Graft-versus-Host Disease: A Prospective, Multicenter, Noninterventional Study.

PURPOSE: Ocular graft-versus-host disease (oGvHD) following allogeneic hematopoietic stem cell transplantation develops as severe dry eye disease (DED) and is initially treated with lubricants, although no clinical trials are available using artificial tears in oGvHD. This trial was set up to test perfluorohexyloctane (NovaTears®) as nonpreserved layer-forming agent for the treatment of DED in oGvHD. METHODS: 25 patients with severe DED due to oGvHD received 1 drop perfluorohexyloctane 4 times daily during a prospective, multicenter, observational 12-week study on top of established topical therapy. Clinical parameters included Schirmer test, tear film breakup time, corneal staining, meibum secretion and ocular surface disease index. Adverse events, visual acuity and intraocular pressure were key safety parameters. RESULTS: From 25 patients recruited, 23 presented for the second visit. Perfluorohexyloctane treatment did not lead to any changes in clinical or safety parameters but led to fast relief in symptoms in 57% of the patients. One adverse reaction occurred. CONCLUSIONS: This study showed no change in clinical signs in severe DED due to oGvHD, which was not unexpected due to the underlying pathomechanisms. However, the study showed improvement of symptoms in individual patients allowing application of perfluorohexyloctane as an additional symptomatic therapy in oGvHD.

Topical semifluorinated alkane-based azithromycin suspension for the management of ocular infections.

The management of ocular infections is challenging due to poor drug bioavailability and vehicle related adverse effects associated with current antibiotic eye drops. Semifluorinated alkanes (SFAs) are reportedly well-tolerated on the ocular surface and can enhance ocular drug bioavailability. Therefore, an SFA-based azithromycin suspension (SFA-AZM) was prepared and its antibacterial efficacy was compared to that of marketed azithromycin eye drops by monitoring the growth of bioluminescent Staphylococcus aureus in ex vivo ocular tissues. Corneal and conjunctival distribution of hydrophobic fluorescent dye particles from an SFA suspension (SFA-BODIPY) resulted in preferential dye localisation in the epithelial layers of both tissues. However, corneal dye absorption was significantly lower than conjunctival absorption, likely due to limited adhesion of suspended dye particles to the corneal compared to the conjunctival epithelium. In line with the dye distribution results, bacterial colonisation in the conjunctiva reduced significantly upon application of SFA-AZM with the efficacy being greater than or at least equal to the marketed azithromycin eye drops. In the cornea, all tested azithromycin eye drops reduced the rate of bacterial growth with similar efficacy. Overall, the SFA-AZM suspension tested here may provide a safe and effective alternative for the management of ocular infections by enhancing conjunctival drug absorption and thus drug efficacy.

Preclinical studies evaluating the effect of semifluorinated alkanes on ocular surface and tear fluid dynamics.

PURPOSE: Dry eye disease (DED) is one of the most prevalent ocular surface disorders that presents clinically. Recently, the semifluorinated alkane (SFA) perfluorohexyloctane (NovaTears®; EvoTears®) entered the market for the management of evaporative DED, while perfluorobutylpentane has been used as a vehicle to enhance ocular drug delivery. This study evaluated the mechanisms by which SFAs might improve therapeutic outcomes in DED. METHODS: Interactions of both SFAs with the corneal surface were evaluated ex vivo using high-speed photography. The in vivo influence of SFAs on tear fluid dynamics was evaluated in healthy rabbit eyes observing changes in lipid layer grade, tear evaporation rate, tear volume and tear osmolarity. Furthermore, ocular tolerability was confirmed by clinical scoring and sodium fluorescein staining. RESULTS: Ex vivo studies demonstrated that both SFAs rapidly spread on the ocular surface with their contact angle on the cornea being virtually zero. A significant improvement in lipid layer grade was observed immediately after instillation of both SFAs in vivo, although the improvement was more sustained upon instillation of perfluorohexyloctane with a statistically significant difference compared to saline instillation evident from day five onwards. No significant changes in tear evaporation rate, volume or osmolarity, nor any signs of ocular irritation were observed after application of either SFA over the seven-day study period. CONCLUSION: Both SFAs showed excellent spreading on the ocular surface. Perfluorohexyloctane improved the lipid layer grade significantly after topical application supporting its potential to stabilise the tear film lipid layer and thus provide symptomatic relief in evaporative DED.

A Clinical Phase II Study to Assess Efficacy, Safety, and Tolerability of Waterfree Cyclosporine Formulation for Treatment of Dry Eye Disease.

PURPOSE: To compare the efficacy, safety, and tolerability of waterfree cyclosporine formulation (CyclASol) at 2 concentrations (0.1% and 0.05% of cyclosporine [CsA]) to vehicle when applied twice daily for 16 weeks in patients with dry eye disease (DED). An open-label Restasis (Allergan, Irvine, CA) arm was included to allow a direct comparison with an approved therapy. DESIGN: An exploratory phase II, multicenter, randomized, vehicle-controlled clinical trial, double-masked between CyclASol and vehicle with an open-label comparator. PARTICIPANTS: Two hundred and seven eligible patients with a history of dry eye disease were randomized 1:1:1:1 to 1 of 4 treatment arms (CyclASol 0.05%, n = 51; CyclASol 0.1%, n = 51; vehicle, n = 52, and Restasis, n = 53). METHODS: After a 2-week run-in period with twice-daily dosing of Systane Balance (Alcon, Fort Worth, TX), patients were randomized to the respective treatment arm and dosed twice daily for 16 weeks. MAIN OUTCOME MEASURES: The study was set up to explore efficacy on a number of sign and symptom end points including total and subregion corneal fluorescein staining, conjunctival staining, visual analog scale (VAS) for dry eye symptoms VAS severity, and Ocular Surface Disease Index (OSDI) questionnaire. RESULTS: CyclASol showed a consistent reduction in corneal and conjunctival staining compared with both vehicle and Restasis over the 16-week treatment period, with an early onset of effect (at day 14). A mixed-effects model-based approach demonstrated that the CyclASol drug effect was statistically significant over vehicle (total corneal staining P < 0.1, central corneal staining P < 0.001, conjunctival staining P < 0.01). This model-based analysis suggests a significant CyclASol effect for OSDI as symptom parameter (P < 0.01). The numbers of ocular adverse events were low in all treatment groups. CONCLUSIONS: CyclASol showed efficacy, safety, and tolerability at 2 concentrations in moderate-to-severe DED. In a direct head-to-head against open-label Restasis, CyclASol was found to have an earlier onset of action, as early as after 2 weeks of treatment, in relieving the signs of DED, as measured by corneal and conjunctival staining. The central region of the cornea, an important area for visual function in dry eye sufferers, was shown to have the most benefit from treatment. Excellent safety, tolerability, and comfort profile supports this new CsA formulation as having a positive benefit-to-risk ratio.

Semifluorinated Alkane Eye Drops for Treatment of Dry Eye Disease Due to Meibomian Gland Disease.

PURPOSE: Meibomian gland disease is generally accepted as the leading cause for evaporative dry eye disease (DED). In a previous study, perfluorohexyloctane, a semifluorinated alkane, has been demonstrated to significantly increase tear film breakup time and to reduce corneal fluorescein staining in patients with evaporative DED, thereby vastly reducing dry eye-related symptoms. This study was set up to evaluate perfluorohexyloctane in a larger population of patients with Meibomian gland dysfunction. METHODS: Seventy-two patients with Meibomian gland disease and associated dry eye received 1 drop of perfluorohexyloctane 4 times daily during an observational, prospective, multicenter, 6-8-week study. Clinical assessment included best-corrected visual acuity, intraocular pressure, Schirmer test I, tear film breakup time, anterior and posterior blepharitis assessment, number of expressible Meibomian glands, meibum quality and quantity, ocular surface fluorescein staining, lid margin and symptom assessment, and Ocular Surface Disease Index (OSDI©). RESULTS: From the 72 patients recruited, 61 completed the trial per protocol. Nine patients did not apply the medication as recommended and 2 patients were lost to follow-up. Tear film breakup time, corneal and conjunctival fluorescein staining, number of expressible Meibomian glands, and severity of anterior and posterior blepharitis significantly improved after 6-8 weeks of perfluorohexyloctane application. In addition, symptoms improved as demonstrated by a significant decrease of OSDI-values from 37 (±13) to 26 (±16). CONCLUSIONS: In concordance with previous findings, 6-8 weeks of topical application of perfluorohexyloctane significantly improves clinical signs of Meibomian gland disease and associated mild to moderate DED.

[Influence of Aging on Severity and Anti-Inflammatory Treatment of Experimental Dry Eye Disease]. / Einfluss von Alterung auf Schweregrad und antientzündliche Therapie des experimentellen Trockenen Auges.

Purpose Aging is an important factor in dry-eye disease that has not been studied in the context of therapeutic measures. Aging-associated modifications of the ocular immune system implicate that anti-inflammatory therapies may act differently among younger individuals in terms of onset and effect of different substances. The goal of this study was to determine differences in clinical phenotype and topical anti-inflammatory therapy using a desiccating stress mouse model. Methods An experimental dry-eye disease (desiccating stress model) was induced in 12-week and 12-month-old female BALB/c mice. Topical therapy included 0.05% cyclosporine/F4H5 (Novaliq), F4H5, 0.05% cyclosporine (Restasis®, Allergan) and dexamethasone (Monodex®, Thea Pharma) for 3 consecutive weeks. A control group received no therapy whatsoever. Readout parameters included tear secretion, corneal fluorescein staining at 5 timepoints and histological analysis of goblet cell count at the end of the experiments. Results The older mice demonstrated a significantly stronger dry eye phenotype than the younger mice. Following therapy, the older mice responded to topical anti-inflammatory therapy significantly later than the younger individuals. Regarding the different substances used, cyclosporine/F4H5 showed a significantly faster decrease in corneal fluoresceine staining after only 1 week of therapy in comparison to all other groups. This substance was also superior regarding tear secretion and goblet cell count in age matched groups and in comparison to younger mice. Conclusions These experimental data support the implication that aging should be considered as an important factor in daily clinical practice. Furthermore, the differences found between substance classes, such as calcineurin antagonists and steroids, as well as different drug formulations, should be considered in future pre-clinical and clinical trials.

A semifluorinated alkane (F4H5) as novel carrier for cyclosporine A: a promising therapeutic and prophylactic option for topical treatment of dry eye.

PURPOSE: Cyclosporine A (Cs) has been used as effective topical therapy for inflammatory dry eye disease since more than a decade. However, due to its lipophilic character, Cs is formulated as emulsions or oily solutions for topical application. This experimental study aimed to test if the use of semifluorinated alkanes (SFAs) as a preservative-free, well-tolerated non-stinging or burning vehicle maintains or even improves the benefits of Cs in the topical therapy of dry-eye disease. METHODS: Desiccating stress was applied to C57BL/6 mice for 14 consecutive days to induce experimental dry-eye. Cs dissolved in SFA (perfluorobutylpentane = F4H5with 0.5% Ethanol), F4H5 with 0.5% ethanol only, 0.05% Cs (Restasis®), and dexamethasone (Monodex®) were applied three times daily beginning either at day 4 or day 11 of desiccating stress for up to 3 weeks after end of dry-eye induction. RESULTS: In comparison to other groups, Cs/F4H5 demonstrated high efficacy and earlier reduction of corneal staining. In this study, Cs/F4H5 had the ability to maintain conjunctival goblet cell density once applied on day 4. Flow cytometry analysis from cervical lymphnodes demonstrated a significantly lower CD4+ and CD8+ T-cells in the Cs/F4H5 group following 3 weeks of therapy than at baseline, but no difference in regulatory T cells from regional lymphnodes were seen. CONCLUSIONS: Overall, compared to a commercially available Cs formulation (Restasis®) and dexamethasone, Cs/F4H5 was shown to be equally effective but with a significantly faster therapeutic response in reducing signs of dry-eye disease in an experimental mouse model.

Semifluorinated Alkane Eye Drops for Treatment of Dry Eye Disease--A Prospective, Multicenter Noninterventional Study.

PURPOSE: Evaporation of the tear film is heavily discussed as one core reason for dry eye disease (DED). Subsequently, new artificial tear products are developed that specifically target this pathomechanism. Perfluorohexyloctane (F6H8, NovaTears(®)) from the family of semifluorinated alkanes is a novel substance that has been approved as a medical device, as a nonblurring wetting agent for the ocular surface. METHODS: Thirty patients with hyperevaporative dry eye received F6H8 during a prospective, multicenter, observational 6-week study. Patients were advised to apply 1 drop 4 times daily in both eyes. Parameters assessed included best corrected visual acuity, intraocular pressure, Schirmer I test, tear fluid, tear film breakup time (TFBUT), corneal staining, meibum secretion, and Ocular Surface Disease Index (OSDI(©)). RESULTS: From the 30 patients recruited, 25 completed the trial per protocol. Four patients discontinued F6H8 and 1 patient did not present for follow-up. F6H8 treatment led to significant reduction of corneal staining and significant increase of Schirmer I and TFBUT. In addition, OSDI score dropped significantly from a mean of 55 (± 23.0) to 34 (± 22.4). Visual acuity and ocular pressure did not change. CONCLUSIONS: This prospective observational study shows significant beneficial effects in patients suffering from evaporative DED, using F6H8 in all the relevant parameters tested. The decrease of the OSDI by a mean of 21 points was particularly remarkable and clearly exceeds minimal, clinical important differences for mild or moderate and severe disease. Overall, F6H8 (NovaTears) seems to be safe and effective in treating mild to moderate hyperevaporative DED.

Effect of ceralifimod (ONO-4641) on lymphocytes and cardiac function: Randomized, double-blind, placebo-controlled trial with an open-label fingolimod arm.

This randomized, double-blind, placebo-controlled, 6-arm, parallel-design study investigated cardiac and hematological pharmacodynamic effects of ceralifimod (ONO-4641), a selective sphingosine-1-phosphate (S1P) receptor modulator, over a broad dose range in direct comparison with the nonselective S1P modulator fingolimod. Healthy subjects were assigned to ceralifimod (0.01, 0.025, 0.05, or 0.10 mg), fingolimod (0.5 mg), or placebo once daily for 14 days (n = 24 per group). After 14 days of treatment, mean absolute lymphocyte count percentage change from baseline was greatest in the fingolimod (-62%) and ceralifimod 0.10 mg (-56%) groups. On treatment cessation, lymphocyte recovery was faster in the ceralifimod versus the fingolimod group. Ceralifimod showed dose- and concentration-dependent chronotropic effect. Cardiac effects in the fingolimod group were dependent on fingolimod-P concentrations. Maximum mean heart rate (HR) effect on day 1 was larger with fingolimod (placebo-adjusted change from time-matched baseline HR [ΔΔHR], -14.9 beats per minute [bpm]) versus ceralifimod (ΔΔHR, -6.2 and -12.0 bpm for the 0.05- and 0.10-mg doses, respectively). Ceralifimod's effect on the PR interval was minor. Safety biomarker results suggest that potential therapeutic doses of ceralifimod, in particular the 0.05-mg dose, might result in reduced occurrence of bradycardia, atrioventricular block absolute lymphocyte count and grade 3/4 lymphopenia compared with fingolimod 0.5 mg.