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Purpose: Changes in meibum composition and quantity in meibomian gland dysfunction (MGD) result in tear film instability and dry eye. This exploratory study aimed to identify changes in (O-acyl)-ω-hydroxy fatty acid (OAHFA) and hydrocarbon chain (HC) unsaturation levels in meibum related to the presence and severity of MGD. Methods: Meibum samples were collected from 3 cohorts of adults with no MGD, mild-to-moderate MGD, and severe MGD in a noninterventional clinical trial (NCT01979887). OAHFAs, cholesterol esters (CE), HC unsaturation, and HC length in the meibum samples were quantified with 1 H-nuclear magnetic resonance spectroscopy using 2 methods of normalization. Results: Meibum samples from 62 subjects were analyzed: 21 non-MGD, 21 mild-to-moderate MGD, and 20 severe MGD. Meibum OAHFA and CE levels and HC unsaturation were reduced with increasing severity of MGD, with most pairwise comparisons significant ( P < 0.05, t -tests), following the order non-MGD > mild-to-moderate MGD > severe MGD. Regardless of the resonances used for normalization, each pairwise comparison of OAHFA, CE, and HC unsaturation levels in MGD (combined severities) versus non-MGD samples was significant ( P < 0.01, t -test). Analysis using various normalization equations showed reductions of 20%-22% for OAHFAs, 51%-57% for CE, and 36%-66% for HC unsaturation in MGD (combined severities) compared with non-MGD. HC length was not altered in MGD (combined severities) compared with non-MGD samples ( t -test). Conclusions: Meibum OAHFA, CE, and HC unsaturation levels were reduced in MGD and were lowest in the severe MGD cohort. These findings may contribute to the understanding of the pathophysiology of MGD.

Purpose: To investigate gel stent implantation with and without intraoperative sustained-release mitomycin C (MMC SR) in a rabbit model for gel stent implantation, and to examine aqueous humor outflow (AHO) postimplantation. Methods: Four groups of rabbits were included. Group 1 was untreated (control). Groups 2, 3, and 4 received the gel stent without MMC, with MMC solution (subconjunctival injection), and with MMC SR (subconjunctival injection), respectively. Intraocular pressure (IOP) and AHO were assessed via tonometry and indocyanine green-based angiography, respectively. The main efficacy measure was change in IOP from baseline. Results: Following gel stent implantation, Groups 2, 3, and 4 maintained ≥20% IOP reduction (response) for a median duration of 1 week, 6.5 weeks, and 30 weeks, respectively. Angiography showed normal aqueous humor drainage (Group 1) beginning at the perilimbal trabecular plexus and continuing posteriorly to episcleral outflow vessels. Following implantation, drainage occurred preferentially and directly into the subconjunctival bleb. Conclusions: Gel stent implantation with MMC SR was most effective in achieving sustained, long-term IOP reduction in the rabbit model, compared with implantation with or without MMC solution. Bleb presence and the postimplantation aqueous angiography results indicated redirection of the AHO to the subconjunctival vasculature and presumed lymphatics, suggesting efficient glaucoma filtration to lower IOP in this model. This rabbit model and aqueous angiography may help refine understanding of the mechanism of action of minimally invasive glaucoma surgeries and ultimately translate to improved surgical devices and procedures for patients with glaucoma.

Purpose: This study was intended to characterize the impact of meibomian gland dysfunction (MGD) on patients' quality of life. Methods: In this prospective, multicenter, noninterventional clinical study (NCT01979887), eligible individuals (age ≥40 years; absence of uncontrolled ocular/systemic disease) were categorized, based on composite grading of ocular symptoms, Schirmer score, and meibum quality, into (1) non-MGD, (2) mild/moderate MGD, or (3) severe MGD cohorts. The MGD Impact Questionnaire (MGD IQ), a 10-item patient-reported outcome measure, was self-administered at clinic visit on day 1, and readministered on day 22 to assess intervisit agreement regarding MGD IQ responses. Results: In total, 75 subjects were assigned to the study cohorts (25 per cohort). Across cohorts, MGD IQ item scores rose incrementally with increasing MGD severity. The severe MGD cohort experienced greater difficulty with reading and performance of leisure activities, greater time on eye care, and greater bother with eye care and eye appearance than the mild/moderate MGD cohort (all P  < 0.05). Compared with the non-MGD cohort, the mild/moderate MGD cohort had greater difficulty working on computer, whereas the severe MGD cohort had greater difficulty reading, driving, and performing leisure activities, more frequent difficulty with outdoor activities, more time on eye care, and greater bother with eye care (all P  < 0.05). Intervisit agreement between MGD IQ responses was fair to moderate (weighted kappa statistic 0.33‒0.58). Conclusions: Vision-related activities are negatively impacted by increasing severity of MGD. The MGD IQ instrument can help characterize disease severity and amplify the patient's voice in patient-centric clinical research. ClinicalTrials.gov NCT01979887.

Purpose: Dry eye disease is attributed to impaired tear production and/or evaporative dry eye. Evaporative dry eye is frequently associated with meibomian gland dysfunction (MGD). The objective of this study was to identify clinical study endpoints related to MGD. Methods: This 22-day, noninterventional, case-control clinical study involved three cohorts with increasing MGD severity: no MGD, mild/moderate MGD, and severe MGD. Symptoms were assessed with an ocular symptom questionnaire grading blurred vision, eye burning, eye dryness, eye pain, light sensitivity, eye itching, eye foreign body sensation, and overall ocular discomfort. Sign assessments included the maximum meibum quality score (MMQS), tear breakup time, Schirmer tear tests, biomicroscopy, and corneal staining. Signs and symptoms were compared between cohorts and study visits. Results: Seventy-five study participants were assigned to the cohorts (25 per cohort). MMQS scores increased with increasing MGD severity, reflecting the selection criteria for the cohorts. Between-visit scores showed a weighted kappa statistic of 0.72 indicating substantial agreement. Mean scores of all assessed symptoms increased with increasing MGD severity. Scores for symptoms showed moderate (κ = 0.41-0.60) to substantial (κ = 0.61-0.80) agreement between visits. Overall ocular discomfort demonstrated the strongest correlation with the MMQS. Conclusion: The MMQS was a reproducible sign of MGD showing good agreement with ocular symptoms. Overall ocular discomfort was well correlated with typical dry eye symptoms and could potentially be used as a single measure of MGD symptoms. The findings from this observational study may inform endpoints for future clinical trials. ClinicalTrials.gov NCT01979887.

Purpose: To evaluate the time course of biodegradation of an intracameral, biodegradable, sustained-release bimatoprost implant that lowers intraocular pressure without the need for daily eye drops. Methods: In 2 identically designed, randomized, phase 3 clinical trials, adults with open-angle glaucoma or ocular hypertension and open iridocorneal angles inferiorly in the study eye were administered 10- or 15-μg bimatoprost implant (day 1 and weeks 16 and 32) or twice-daily topical timolol 0.5%. Implants were assessed on gonioscopy throughout the studies. Investigators reported whether implants were visible, estimated the size of visible implants relative to their initial size at implantation, and reported the implant location. Data for 10-μg implant placed on day 1 were pooled from both studies for analysis. Results: A total of 372 patients received the 10-μg bimatoprost implant. The degree of implant biodegradation at each follow-up time point was variable among patients. The implant frequently swelled during the initial phase of biodegradation from 6 to 28 weeks. Accelerated biodegradation occurred between 31 and 52 weeks, resulting in 82% of implants absent or ≤25% of initial size by 52 weeks. By month 20, 95% of implants had biodegraded to absent or ≤25% of initial size. The implant was predominantly located inferiorly in the iridocorneal angle. Conclusions: Bimatoprost implant biodegradation in phase 3 studies showed some degree of variability among patients. Clinically significant implant biodegradation was observed in the majority of patients by 12 months. Clinical studies are in progress to further understand implant biodegradation and the ideal timing for implant re-administration. ClinicalTrials.gov NCT02247804; ClinicalTrials.gov NCT02250651.

Purpose: To assess the intraocular pressure (IOP)-lowering effect of a biodegradable bimatoprost implant following selective laser trabeculoplasty (SLT) in a canine model. Methods: Unilateral SLT was performed in 11 normotensive, treatment-naive beagle dogs. IOP was measured at baseline (pre-SLT) and weekly post-SLT (≤10 weeks). After IOP returned to baseline or at 10 weeks (whichever occurred first), a sustained-release bimatoprost implant was administered bilaterally in the anterior chamber of each animal. IOP was measured weekly for 4 weeks and then every 2 weeks up to week 42. Results: The main outcomes included the IOP change (%) from baseline, calculated in both eyes in the overall population, SLT responder subgroup (defined by peak IOP reduction from baseline ≥3 mmHg or ≥15% for >1 week post-SLT), and SLT nonresponder subgroup (defined by peak IOP reduction from baseline <3 mmHg or <15%). The bimatoprost implant lowered IOP similarly in both the SLT-treated and fellow SLT-naive eyes. Following bimatoprost implant administration, the mean (standard deviation [SD]) peak IOP reduction from baseline was 34.4% (8.5%) in SLT-treated eyes and 35.7% (5.9%) in fellow SLT-naive eyes. The bimatoprost implant lowered IOP comparably ( P  > 0.17) in eyes that responded to SLT (mean [SD] peak IOP reduction, 34.6% [10.7%]; n  = 6) and those that did not (mean [SD] peak IOP reduction, 34.1% [6.1%]; n  = 5). Conclusion: The bimatoprost implant effectively lowered IOP in eyes pretreated with SLT, regardless of response to SLT. The current data suggest that eyes previously treated with SLT can still benefit from the intracameral bimatoprost implant.

Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes that degrade extracellular matrix (ECM) components such as collagen and have important roles in multiple biological processes, including development and tissue remodeling, both in health and disease. The activity of MMPs is influenced by the expression of MMPs and tissue inhibitors of metalloproteinase (TIMPs). In the eye, MMP-mediated ECM turnover in the juxtacanalicular region of the trabecular meshwork (TM) reduces outflow resistance in the conventional outflow pathway and helps maintain intraocular pressure (IOP) homeostasis. An imbalance in the MMP/TIMP ratio may be involved in the elevated IOP often associated with glaucoma. The prostaglandin analog/prostamide (PGA) class of topical ocular hypotensive medications used in glaucoma treatment reduces IOP by increasing outflow through both conventional and unconventional (uveoscleral) outflow pathways. Evidence from in vivo and in vitro studies using animal models and anterior segment explant and cell cultures indicates that the mechanism of IOP lowering by PGAs involves increased MMP expression in the TM and ciliary body, leading to tissue remodeling that enhances conventional and unconventional outflow. PGA effects on MMP expression are dependent on the identity and concentration of the PGA. An intracameral sustained-release PGA implant (Bimatoprost SR) in development for glaucoma treatment can reduce IOP for many months after expected intraocular drug bioavailability. We hypothesize that the higher concentrations of bimatoprost achieved in ocular outflow tissues with the implant produce greater MMP upregulation and more extensive, sustained MMP-mediated target tissue remodeling, providing an extended duration of effect.

Purpose: To compare the dose-response profiles of bimatoprost sustained-release implant (Bimatoprost SR) and topical bimatoprost in lowering intraocular pressure (IOP) in normotensive beagle dogs., Methods: In 1 study, topical bimatoprost 0.001%, 0.01%, or 0.1% was administered twice daily in the study eye for 5 days. IOP was measured at baseline and up to hour 6 each day. Other studies evaluated the IOP response to a single administration of Bimatoprost SR at dose strengths ranging from 8 to 120 μg. IOP was measured before implant administration and during 3 months of follow-up; IOP in response to topical bimatoprost 0.03% was measured prestudy as an internal control., Results: Mean percentage decrease in IOP from baseline at hour 6 (peak effect) across study days was 15.7%, 36.1%, and 24.8% (2.8, 7.0, and 4.0 mmHg) in animals treated with topical bimatoprost 0.001%, 0.01%, and 0.1%, respectively. After Bimatoprost SR administration, mean percentage decrease in IOP from baseline across 3 months consistently increased with increasing dose strength and was 38.7% (7.2 mmHg) with Bimatoprost SR 120 μg. Mean percentage IOP decrease with topical bimatoprost 0.03% was 27.6% (5.9 mmHg)., Conclusions: Topical bimatoprost demonstrated a U-shaped dose-response curve; increasing the bimatoprost concentration to 0.1% resulted in reduced IOP-lowering efficacy. In contrast, the dose-response curve for Bimatoprost SR showed consistently greater IOP lowering as the dose strength increased, with the dose strength producing maximum IOP lowering not yet determined. At 60- and 120-μg dose strengths, Bimatoprost SR produced greater IOP reductions than were achieved with topical dosing.

Purpose: To explore the ocular distribution of bimatoprost after intracameral administration of a biodegradable sustained-release bimatoprost implant (Bimatoprost SR) versus repeated topical administration of bimatoprost 0.03% ophthalmic solution in dogs. Bimatoprost SR and topical bimatoprost 0.03% previously were shown to have similar intraocular pressure-lowering effects in humans in a phase 1/2 clinical trial., Methods: Twenty-four beagle dogs received either once-daily topical bimatoprost 0.03% for 7 days or a bilateral intracameral administration of Bimatoprost SR (15 μg). At predetermined time points, ocular tissues were collected and concentrations of bimatoprost and bimatoprost acid were quantified using liquid chromatography-tandem mass spectrometry., Results: Bimatoprost SR administration enhanced delivery of study drug to a site of action [iris-ciliary body (ICB)] compared with topical bimatoprost (C max [bimatoprost+bimatoprost acid] = 18,200 and 4.13 ng/g, respectively). However, distribution of drug to tissues associated with prostaglandin analog (PGA)-related side effects (i.e., bulbar conjunctiva, eyelid margins, and periorbital fat) was limited following Bimatoprost SR administration (C max [bimatoprost+bimatoprost acid] = BLQ [beneath the limit of quantitation] to 0.354 ng/g) compared with topical dosing (C max [bimatoprost+bimatoprost acid] = 36.6-2,110 ng/g)., Conclusions: Bimatoprost SR administration in dogs selectively delivered drug to the ICB with low or undetectable drug levels in ocular surface and extraocular tissues. Use of Bimatoprost SR for glaucoma treatment may reduce the incidence of adverse events typically associated with topical PGAs by targeting bimatoprost delivery to the key site of action of the PGA class and reducing exposure to off-target tissues.