Phase 3 Randomized Clinical Trial of the Safety and Efficacy of Travoprost Intraocular Implant in Patients with Open-Angle Glaucoma or Ocular Hypertension.

PURPOSE: To evaluate the safety and intraocular pressure (IOP)-lowering efficacy of 2 models of the travoprost intraocular implant (fast-eluting [FE] and slow-eluting [SE] types) from 1 of 2 phase 3 trials (the GC-010 trial). DESIGN: Multicenter, randomized, double-masked, sham-controlled, noninferiority trial. PARTICIPANTS: Patients with open-angle glaucoma or ocular hypertension having an unmedicated baseline mean diurnal IOP (average of 8 am, 10 am, and 4 pm time points) of ≥ 21 mmHg, and IOP of ≤ 36 mmHg at each of the 8 am, 10 am, and 4 pm timepoints at baseline. METHODS: Study eyes were randomized to the travoprost intraocular implant (FE implant [n = 200] or SE implant [n = 197] model) or to timolol ophthalmic solution 0.5% twice daily (n = 193). MAIN OUTCOME MEASURES: The primary outcome was mean change from baseline IOP in the study eye at 8 am and 10 am, at each of day 10, week 6, and month 3. Safety outcomes included adverse events (AEs) and ophthalmic assessments. RESULTS: Mean IOP reduction from baseline over the 6 time points ranged from 6.6 to 8.4 mmHg for the FE implant group, from 6.6 to 8.5 mmHg for the SE implant group, and from 6.5 to 7.7 mmHg for the timolol group. The primary efficacy end point was met; the upper limit of the 95% confidence interval of the difference between the implant groups and the timolol group was < 1 mmHg at all 6 time points. Study eye AEs, most of mild or moderate severity, were reported in 21.5%, 27.2%, and 10.8% of patients in the FE implant, SE implant, and timolol groups, respectively. The most common AEs included iritis (FE implant, 0.5%; SE implant, 5.1%), ocular hyperemia (FE implant, 3.0%; SE implant, 2.6%), reduced visual acuity (FE implant, 1.0%; SE implant, 4.1%; timolol, 0.5%), and IOP increased (FE implant, 3.5%; SE implant, 2.6%; timolol, 2.1%). One serious study eye AE occurred (endophthalmitis). CONCLUSIONS: The travoprost intraocular implant demonstrated robust IOP reduction over the 3-month primary efficacy evaluation period after a single administration. The IOP-lowering efficacy in both implant groups was statistically and clinically noninferior to that in the timolol group, with a favorable safety profile. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

The Impact of Baseline Intraocular Pressure on Initial Treatment Response in the LiGHT Trial: Selective Laser Trabeculoplasty versus Medication.

PURPOSE: The Laser in Glaucoma and Ocular Hypertension Trial demonstrated the efficacy and safety of selective laser trabeculoplasty (SLT) compared with topical hypotensive medication as first-line therapy for ocular hypertension and open-angle glaucoma. This substudy explored the impact of pretreatment (baseline) intraocular pressure (IOP) on treatment response. DESIGN: Post hoc analysis of randomized control trial data. PARTICIPANTS: A total of 1146 eyes from 662 patients were included in this analysis: 559 eyes in the SLT group and 587 in the medication group. METHODS: Intraocular pressure reduction at 8 weeks after treatment with either SLT or prostaglandin analog (PGA) eye drops was assessed at different levels of baseline IOP, and the groups were compared. Differences in absolute and percentage IOP lowering between SLT and PGA groups were tested with a linear mixed-effects model. Differences in the probability of achieving ≥ 20% IOP lowering between SLT and PGA groups, at different levels of baseline IOP, were estimated using a logistic mixed-effects model. MAIN OUTCOME MEASURE: Intraocular pressure-lowering response to SLT versus PGA eye drops. RESULTS: Mean IOP was not significantly different between the groups at baseline or 8 weeks after treatment initiation. Both treatments showed greater IOP lowering at higher baseline IOP and less IOP lowering at lower baseline IOP. Selective laser trabeculoplasty tended to achieve more IOP lowering than PGA drops at higher baseline IOP. Prostaglandin analog drops performed better at lower baseline IOP, and the difference compared with SLT, in terms of percentage IOP reduction, was significant at baseline IOP of ≤ 17 mmHg. A significant difference was found in the relationship between baseline IOP and probability of ≥ 20% IOP lowering between the two treatments (P = 0.01), with SLT being more successful than PGA at baseline IOP of more than 22.5 mmHg. CONCLUSIONS: We confirm previous reports of greater IOP lowering with higher baseline IOP for both SLT and PGA drops. In treatment-naïve eyes, at higher baseline IOP, SLT was more successful at achieving ≥ 20% IOP lowering than PGA drops. At lower baseline IOP, a statistically greater percentage, but not absolute, IOP lowering was seen with PGA drops compared with SLT, although the clinical significance of this is uncertain. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Bimatoprost sustained-release intracameral implant reduces episcleral venous pressure in dogs.

OBJECTIVE: To determine the effect of a bimatoprost sustained-release intracameral implant (Bimatoprost SR) on episcleral venous pressure (EVP) in normal dogs. METHODS: Normotensive beagle dogs were randomized to receive Bimatoprost SR 30 µg (n = 7) or sham injection (needle insertion only, n = 7) in one eye on day 1. EVP was measured with an episcleral venomanometer through day 65. Episcleral aqueous outflow vessels were identified using fluorescence imaging following intracameral injection of indocyanine green in one additional animal. A separate cohort of dogs that had been trained for conscious intraocular pressure (IOP) measurements received Bimatoprost SR 30 µg (n = 8) in one eye; IOP was evaluated through day 66. RESULTS: Baseline mean EVP was 10.0 mmHg in the Bimatoprost SR group and 10.4 mmHg in the sham group. Eyes treated with Bimatoprost SR exhibited a transient increase in mean EVP that peaked at day 8, followed by a decrease to levels below baseline. From day 29 to day 65, the change in mean EVP from baseline ranged from -2.4 to -3.9 mmHg (P < 0.05 vs. sham). Baseline mean IOP in eyes treated with Bimatoprost SR was 14.9 mmHg, and a steady IOP reduction was maintained through day 66. Bimatoprost SR-treated eyes exhibited a selective, sustained dilation of aqueous outflow vessels that was not observed in sham-treated eyes. CONCLUSIONS: In normal dogs, Bimatoprost SR was associated with a transient increase in EVP followed by a sustained decrease. Changes in EVP were accompanied by a sustained dilation of aqueous outflow vessels.

Periorbital changes associated with prostaglandin analogs in Korean patients.

BACKGROUND: Prostaglandin analogs (PGAs) are commonly used to treat glaucoma because of their powerful intraocular pressure lowering effect. However, various periorbital changes associated with the use of PGAs have been reported. We investigated the incidence of periorbital changes in Korean patients who were treated with PGAs, and analyzed clinical factors associated with superior sulcus deepening. METHODS: This study included 58 glaucoma patients who were treated with latanoprost, travoprost, or bimatoprost unilaterally. Face photographs were collected, and periorbital changes such as superior sulcus deepening, eyelid pigmentation, ptosis, lid retraction, dermatochalasis, and redness were evaluated by two oculoplastic specialists. For each patient, the contralateral eye served as a control. The frequency of ptosis, dermatochalasis, pigmentation, erythema, and superior sulcus deepening were analyzed. Demographic and ocular factors were compared between patients who showed superior sulcus deepening and those who did not. RESULTS: Thirty-one patients (53.4%) showed one or more periorbital changes associated with PGAs. The most common change was superior sulcus deepening (24.1%), followed by eyelid pigmentation (19.0%), eyelid erythema (19.0%), dermatochalasis (10.3%), eyelid retraction (5.2%), and ptosis (3.4%). The age of the patient and the duration of PGA administration was significantly correlated with superior sulcus deepening (p = 0.007, p = 0.002, respectively). CONCLUSIONS: Periorbital changes are frequently seen in patients who use PGAs, and superior sulcus deepening is the most common change in Korean patients. Long-term use of PGAs and old age were associated with superior sulcus deepening.

Periocular mexametric melanin and erythema indexes in adult glaucoma patients treated with topical prostaglandin analogs.

CONTEXT: Although topical prostaglandin analogs (PGAs) have been previously associated with periocular skin hyperpigmentation, studies using objective clinical methods are lacking. Furthermore changes in periocular skin erythema indexes associated with topical PGAs have not been reported previously. OBJECTIVE: The purpose of the present study was to evaluate periocular melanin and erythema indexes in patients treated with topical PGA using an objective clinical method - Mexameter. METHODS: About 45 glaucoma patients treated with topical PGA therapy, and 30 age-, and sex-matched controls were enrolled in the study. Demographic data, medical history including duration of therapy, PGA type, involved eye (unilateral, bilateral) were noted, and skin phototypes were evaluated. Melanin and erythema indexes on medial and lateral upper and lower eyelids, and normal skin from the upper cheeks were measured using Mexameter MX-18. The index of difference for lower/upper eyelid was calculated. Reading results of patients and controls were compared. RESULTS: Melanin and erythema indexes of upper/lower eyelids, and the index of differences for upper/lower eyelids were significantly higher in patients despite similar clinical findings (p < 0.05). Duration of therapy and type of PGA were not associated with skin changes (p > 0.05). CONCLUSIONS: Both periocular melanin and erythema indexes increased in both upper and lower eyelids due to PGA therapy compared to controls, despite similar clinical findings. Mexametric evaluation is more sensitive than clinical evaluation, and may be used as an objective, sensitive clinical method to evaluate periocular skin changes, even smallest changes, in such patients.

Tolerability and efficacy of bimatoprost 0.01 % in patients with open-angle glaucoma or ocular hypertension evaluated in the Taiwanese clinical setting: the Asia Pacific Patterns from Early Access of Lumigan 0.01 % (APPEAL Taiwan) study.

BACKGROUND: In randomized, controlled trials of open-angle glaucoma (OAG) or ocular hypertension (OHT), bimatoprost 0.01 % improved tolerability while retaining the intraocular pressure (IOP)-lowering efficacy of bimatoprost 0.03 %. Given geographic/racial differences in glaucoma presentation, the APPEAL study assessed the occurrence and severity of hyperemia produced by bimatoprost 0.01 %, and its efficacy, in the Taiwanese clinical setting. METHODS: In this multicenter, open-label, observational study, treatment-naïve and previously treated patients with OHT or OAG received once-daily bimatoprost 0.01 % for 12 weeks. Hyperemia (primary endpoint) was graded at baseline, week 6, and week 12 using a photonumeric scale (0, +0.5, +1, +2, +3), grouped (≤ +1, none to mild; ≥ +2, moderate to severe), and reported as unchanged from baseline, improved, or worsened. IOP assessments followed the same schedule. Supplemental efficacy analyses were conducted based on previous therapies. RESULTS: The intent-to-treat population (N = 312) included treatment-naïve (13.5 %) and previously treated (86.5 %) patients; mean age was 53.3 years. At baseline, 46.3 % of previously treated patients were receiving prostaglandin analog (PGA) monotherapy. At week 12, 91.2 %, 5.9 %, and 2.9 % of treatment-naïve patients exhibited unchanged, worsened, and improved hyperemia from baseline, respectively; 77.9 %, 12.9 %, and 9.2 % of previously treated patients showed no change, worsening, and improvement, respectively. There were no statistically significant shifts in hyperemia severity in either group, or in subgroups based on previous use of any PGA, any non-PGA, latanoprost, or travoprost monotherapies. In treatment-naïve patients, mean IOP reduction from baseline (18.0 ± 3.8 mm Hg) was 3.6 mm Hg at week 12 (P < 0.0001); 83.3 % had baseline IOP ≤ 21 mm Hg. In previously treated patients, mean additional IOP reduction from baseline (17.8 ± 3.9 mm Hg) was 2.6 mm Hg (P < 0.0001); similar results were observed in patient subgroups based on previous therapies. CONCLUSIONS: In the Taiwanese clinical setting, bimatoprost 0.01 % provided significant IOP lowering in treatment-naïve patients (regardless of baseline IOP) and previously treated patients (even those with relatively low IOP on other therapies), while causing no significant changes in hyperemia from baseline. TRIAL REGISTRATION: Clinicaltrials.gov NCT01814761 . Registered 18 March 2013.

Real-World Study of the Effectiveness and Safety of Intracameral Bimatoprost Implant in a Clinical Setting in the United States.

Purpose: A sustained-release, biodegradable, intracameral 10-µg bimatoprost implant (Durysta) is approved for single administration per eye to lower intraocular pressure (IOP) in open-angle glaucoma (OAG) and ocular hypertension (OHT). The purpose of this study was to evaluate the IOP-lowering effectiveness and safety of a single implant administration per eye in patients with OAG or OHT in a real-world clinical setting. Methods: This was a retrospective, single-site study involving 105 consecutive adult patients with OAG or OHT treated with the bimatoprost implant in 1 or both eyes in routine clinical practice. Available medical records of the patients for 12 months or longer after the initial implant administration were reviewed, and data including IOP, IOP-lowering medication and procedure use, and safety outcomes were collected and analyzed. The analysis used ranges of follow-up because of the real-world setting. Results: The study included 197 eyes (85.3% diagnosed with OAG, 94.9% pseudophakic, and 83.8% with angle grade 4). IOP reduction was observed through 1 year after the bimatoprost implant administration. Mean IOP was 16.6 mmHg at baseline and 13.3 mmHg at 11-13 months, with the mean number of topical IOP-lowering medications used reduced from 1.4 at baseline to 0.2 at 11-13 months. IOP and IOP-lowering medication use were similarly reduced in eyes treated with both selective laser trabeculoplasty (SLT) and bimatoprost implant (including 66 eyes with their last SLT before implant administration and 28 eyes with their last SLT after implant administration). There were no cases of treatment-emergent corneal edema after bimatoprost implant administration, and no eye required implant removal. Conclusion: A single bimatoprost implant administration safely and effectively reduced IOP for up to 1 year and decreased the need for topical IOP-lowering medications in eyes with OAG or OHT with or without previous or subsequent SLT.

Travoprost Intracameral Implant Demonstrates Superior IOP Lowering Versus Topical Prostaglandin Analog Monotherapy in Patients with Open-Angle Glaucoma or Ocular Hypertension.

INTRODUCTION: This study was conducted to analyze and compare the intraocular pressure (IOP) treatment effect of the slow-eluting (SE) travoprost intracameral implant to the IOP treatment effect of topical prostaglandin analog (PGA) monotherapy in a subgroup of subjects who were on pre-study PGA monotherapy prior to enrollment in the two pivotal phase 3 trials of the travoprost intracameral implant. METHODS: A combined study population of 133 subjects from two phase 3 trials, who were on topical PGA monotherapy at screening, subsequently underwent a washout period from their topical PGA, and then were randomized and administered an SE travoprost intracameral implant. The subjects were analyzed for the IOP treatment effects of the pre-study topical PGA monotherapy and the in-study SE travoprost intracameral implant. Paired t-tests were used to compare the difference in screening minus post-washout baseline IOP versus month 3 minus post-washout baseline IOP. The IOP-lowering efficacy in eyes administered an SE travoprost intracameral implant was compared to the IOP lowering in the same eyes while on a topical PGA monotherapy prior to study entry. RESULTS: Pre-study topical PGA monotherapy and the SE travoprost intracameral implant demonstrated IOP treatment effects of -5.76 mmHg and -7.07 mmHg, respectively. The IOP-lowering treatment effect was significantly greater by 1.31 mmHg for the SE travoprost intracameral implant relative to pre-study PGA monotherapy (95% confidence interval: -2.01, -0.60; P = 0.0003). CONCLUSIONS: The SE travoprost intracameral implant demonstrated superior IOP-lowering treatment effect versus pre-study topical PGA monotherapy with a superiority margin that was both statistically significant and clinically meaningful. The greater IOP reduction from baseline while on the SE implant versus pre-study topical PGA monotherapy may be a reflection of the optimized adherence and continuous elution of PGA therapy into the anterior chamber achieved with the SE travoprost intracameral implant. TRIAL REGISTRATION: ClinicalTrials.gov identifiers, NCT03519386 and NCT03868124.

Real-World Analysis of the Efficacy of Bimatoprost Sustained-Release Glaucoma Implant Where American Indians Comprise the Largest Minority Population.

Purpose: To assess the effectiveness and safety of bimatoprost sustained release (SR) glaucoma implant as a treatment for open-angle glaucoma and ocular hypertension in a real-world private practice setting with a significant American Indian population. Methods: This retrospective study included 156 eyes from adult patients who received a single injection of bimatoprost implant between June 2020 and May 2022 at the Oklahoma Eye Surgeons. Patients were stratified by baseline intraocular pressure (IOP) (≥21 mmHg versus IOP<21 mmHg). The co-primary endpoints were changes in the mean IOP and the number of topical IOP-lowering medications from baseline to Month 6. Results: At 6 months, eyes with baseline IOP≥21 mmHg had a significantly lower mean IOP (19.85±8.01 versus 26.25±4.84 mmHg; p<0.0001) and the mean number of IOP-lowering medications (1.04±1.44 versus 1.38±1.50; p=0.048) compared with baseline. One year after implantation, 73.58% of eyes had a ≥20% reduction in IOP, 41.51% were medication-free and 30.19% were receiving at least one fewer medication. Among eyes with baseline IOP<21 mmHg, there was a significant reduction in the mean number of IOP-lowering medicines by Month 6 (0.61±1.03 versus 1.93±1.21 at baseline; p<0.0001), with no change in IOP. At 12 months, 24.27% of eyes had a ≥20% decrease in IOP, 43.69% of eyes did not require any medications and 63.11% had at least one fewer medication compared with baseline. An analysis using Welch's two-sample t-test showed no significant differences in the outcomes between the overall population and the American Indian population (number of eyes, 23). Conclusion: Bimatoprost SR glaucoma implant lowered IOP in eyes with high, uncontrolled baseline IOP, while it reduced the number of medications in eyes with a controlled baseline IOP. No clinically meaningful and statistically significant differences in the efficacy of bimatoprost were observed in patients of American Indian descent.

Latanoprostene Bunod 0.024% in Patients with Open-Angle Glaucoma Switched from Prior Pharmacotherapy: A Retrospective Chart Review.

Introduction: Latanoprostene bunod 0.024% (LBN, Vyzulta®) is a nitric oxide-donating prostaglandin analog (PGA). We investigated the real-world efficacy and safety of LBN in patients with open-angle glaucoma (OAG) or ocular hypertension (OHT) who switched their existing intraocular pressure (IOP)-lowering treatment(s) to LBN. Methods: This non-interventional, multicenter (United States), retrospective chart review included patients aged ≥18 years with OHT and/or mild-to-moderate OAG diagnoses taking 1-2 IOP-lowering treatments at the time of switch to LBN (index visit). Chart-extracted data included demographics, diagnoses, IOP and ocular assessments, other IOP-lowering treatments, adverse events (AEs), and reasons for discontinuation. The main study outcome was IOP change from the index visit to each of the next 2 chart-recorded follow-up visits. Analysis groups included the overall dataset and 2 subgroups of patients switched from PGA therapy to LBN: "PGA-all" subgroup [all patients previously on a PGA with/without another IOP-lowering product] and "PGA-monotherapy" subgroup [patients previously on a PGA alone]). Additional ocular outcomes (eg, visual acuity) were examined, if available. Results: The overall dataset included 49 patients (46 had OAD alone, 2 had OHT alone, and 1 had both). The PGA-all subgroup and PGA-monotherapy subgroups had 41 and 32 patients, respectively. Switching to LBN led to a ~25% IOP reduction from the index visit to Visit 1 that was sustained at Visit 2. IOP findings in the PGA-all and PGA-monotherapy subgroups were consistent with the overall dataset. No meaningful changes in other ocular outcomes were found. Of 14 ocular AEs, 3 were recorded as such (mild in severity, considered unrelated to treatment), and 11 were identified through review of interval ocular histories (no severity/relatedness information); none led to discontinuation. Conclusion: In this short-term retrospective chart review of mild-to-moderate OAG/OHT, switching prior IOP-lowering therapy to LBN produced an additional ~25% IOP reduction and appeared to be well tolerated.

Single Administration of Bimatoprost Implant: Effects on 24-Hour Intraocular Pressure and 1-Year Outcomes.

PURPOSE: To evaluate the effects of a single bimatoprost implant administration on 24-hour intraocular pressure (IOP) lowering at 8 weeks, and 1-year IOP-lowering efficacy and safety outcomes. DESIGN: Multicenter, open-label, 12-month, phase 3b study (NCT04285580). PARTICIPANTS: Adults with open-angle glaucoma or ocular hypertension. METHODS: Participants (n = 31) received 10-µg bimatoprost implant in the study eye on day 1; IOP (sitting and/or supine) was measured with pneumatonometry every 2 hours throughout a 24-hour period at baseline and week 8. IOP was measured by Goldmann applanation tonometry (GAT) at hour 0 (8 am ± 1 hour) at baseline, weeks 8 and 16, and months 6, 9, and 12. MAIN OUTCOME MEASURES: The primary endpoint was the week-8 hour-matched change from baseline in habitual position IOP over 24 hours assessed with pneumatonometry. Hour 0 IOP change from baseline measured with GAT in study eyes that received no additional (rescue) IOP-lowering treatment, treatment-emergent adverse events (TEAEs), and central corneal endothelial cell density (CECD) were evaluated through 12 months. RESULTS: The mean (standard deviation [SD]) baseline IOP at hour 0 was 24.2 (2.70) mmHg and 25.3 (7.15) mmHg by GAT and pneumatonometry, respectively. Pneumatonometer measurements of IOP taken over 24 hours at week 8 with the participant in habitual position (sitting from 8 am to 10 pm, supine from 12 am to 6 am) showed consistent IOP lowering through the day and night and reduced fluctuation in IOP. The range in IOP measurements over 24 hours was reduced from baseline by a mean (SD) of -1.6 (2.98) mmHg. All 31 bimatoprost implant-treated participants completed the 12-month study; 23 (74%) required no rescue IOP-lowering treatment. The mean (SD) IOP reduction from baseline at month 12 in nonrescued eyes was -4.3 (3.35) mmHg. The most common TEAE was conjunctival hyperemia (incidence 35.5%, 11/31). No implant-treated eye had a ≥ 15% loss in CECD from baseline. CONCLUSIONS: A single intracameral administration of the bimatoprost implant lowered IOP in the habitual position consistently throughout the day and night at week 8. The majority of participants continued to have reduced IOP for 1 year without additional therapy. The 1-year safety profile was favorable. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

The efficacy of topical prostaglandin analogs for hair loss: A systematic review and meta-analysis.

Background: Prostaglandin analogs have been found to have more versatile uses: treatment of open-angle glaucoma, high intraocular pressure, vitiligo, and other treatments. And prostaglandin analogs have been found to have an important role in the hair growth cycle. However, prostaglandin analogs have not been sufficiently studied for hair (including hair, eyelashes, and eyebrows) regeneration. In this study, a systematic review and meta-analysis of topical prostaglandin analogs on hair loss was performed. Objective: The purpose of this meta-analysis is to determine the efficacy and safety of topical prostaglandin analogs for treating hair loss. Methods: We searched PubMed, Embase, and Cochrane Library databases comprehensively. Data were pooled using Review Manager 5.4.1, and subgroup analyses were performed if necessary. Results: There were six randomized controlled trials included in this meta-analysis. All studies compared prostaglandin analogs with placebo, and one trial consisted of two sets of data. The results showed that prostaglandin analogs could significantly improve the hair length and density (p < 0.001). As far as adverse events are concerned, there was no significant difference between the experimental group and the control group. Conclusion: In patients with hair loss, the topical prostaglandin analogs have better therapeutic efficacy and safety than placebo. However, the best dose and frequency of experimental treatment require further studies.

Bimatoprost Implant Biodegradation in the Phase 3, Randomized, 20-Month ARTEMIS Studies.

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.

A Review of Corneal Biomechanics and Scleral Stiffness in Topical Prostaglandin Analog Therapy for Glaucoma.

PURPOSE: The mechanism of action underlying prostaglandin analog (PGA) therapy involves changes in the expression of different metalloproteases to increase permeability of the sclera and allow increased aqueous humor outflow through this alternative drainage pathway. This alteration of structure impacts cornea/scleral biomechanics and may introduce artifact into the measurement of intraocular pressure (IOP) in the clinical setting. METHODS: A literature search reviewing the impact of PGA therapy on corneal and scleral biomechanics was conducted including basic studies, clinical studies with treatment naïve patients, and a clinical study examining the cessation of PGA therapy. Additional literature including engineering texts was added for greater clarity of the concepts underlying ocular biomechanics. RESULTS: One study with an animal model reported significant corneal stiffening with PGA treatment. Most longitudinal clinical studies examining the effects of initiation of PGA therapy in PGA naïve subjects failed to report biomechanical parameters associated with stiffness using the Corvis ST and only included those parameters strongly influenced by IOP. One study reported a significant reduction in scleral stiffness with IOP as a co-variate, highlighting the need to account for the effects of IOP lowering when assessing clinical biomechanics. The report of cessation of PGA therapy on corneal biomechanics showed no change in corneal compensated IOP after 6 weeks, raising the question of reversibility of the PGA-induced structural alteration. CONCLUSIONS: Given that the findings in several clinical studies may merely reflect a reduction in IOP, further studies are warranted using Corvis ST parameters associated with corneal and scleral stiffness. The gold standard for IOP measurement in the clinical setting is Goldmann applanation tonometry, a technique previously shown to be affected by corneal stiffness. Since PGA therapy has been reported to alter not only scleral biomechanics, but also corneal biomechanics, it is essential to consider alternative tonometry technologies in the clinic.

Use of Latanoprostene Bunod as Adjunctive Glaucoma Therapy in Refractory Glaucoma.

Aim: To investigate the long-term efficacy of adjunctive use of latanoprostene bunod (LBN), a new nitric oxide donating prostaglandin medication, in refractory cases of glaucoma at a tertiary care center. Materials and methods: A review for patients who received add-on LBN was conducted from 1st January 2018 to 31st August 2020. A total of 33 patients (53 eyes) met the inclusion criteria of being on ≥3 topical medications, having an intraocular pressure measurement prior to starting LBN, and having adequate follow-up. Baseline demographics, prior treatments, adverse effects, and intraocular pressures measured at baseline, 3, 6, and 12 months were recorded. Results: Mean baseline intraocular pressure (IOP) [mm Hg ± standard deviation (SD)] was 19.9 ± 6.0. At 3 months, 49 eyes had a mean IOP of 17.3 ± 5.5 (p < 0.01) with an absolute reduction of 2.6 ± 6.6 and a percent reduction of 9 ± 28%. At 6 months, 35 eyes had a mean IOP of 17.2 ± 4.7 (p < 0.01) with an absolute reduction of 3.6 ± 7.4 and a percent reduction of 11 ± 30%. At 12 months, 28 eyes had a mean IOP of 16 ± 4.5 (p < 0.01) with an absolute reduction of 5.8 ± 7.4 and a percent reduction of 19 ± 38%. Over the course of the study, 18 eyes were lost to follow-up. Three eyes had a laser trabeculoplasty, and four eyes required incisional surgery. No eyes discontinued the medication due to adverse effects. Conclusion: Adjunctive use of LBN in refractory glaucoma showed clinically and statistically significant IOP reductions at 3, 6, and 12-month time points. IOP reduction in patients was stable throughout the course of the study, with the largest decreases seen at the 12-month interval. Clinical significance: LBN was well tolerated by patients and may be useful as an additive agent in providing long-term intraocular pressure reduction for patients with severe glaucoma on maximal therapy. How to cite this article: Zhou B, Bekerman VP, Khouri AS. Use of Latanoprostene Bunod as Adjunctive Glaucoma Therapy in Refractory Glaucoma. J Curr Glaucoma Pract 2022;16(3):166-169.

Single Administration of Intracameral Bimatoprost Implant 10 µg in Patients with Open-Angle Glaucoma or Ocular Hypertension.

INTRODUCTION: This study evaluated the intraocular pressure (IOP)-lowering efficacy and safety of a single intracameral administration of bimatoprost implant 10 µg in adults with open-angle glaucoma or ocular hypertension. METHODS: Two identically designed, randomized, 20-month, parallel-group, phase 3 clinical trials (one study eye/patient) compared three administrations of 10- or 15-µg bimatoprost implant (day 1, weeks 16 and 32) with twice-daily topical timolol maleate 0.5%. An open-label, 24-month, phase 1/2 clinical trial compared one or two implants administered in the study eye with once-daily topical bimatoprost 0.03% in the fellow eye. Separate analyses of the pooled phase 3 and phase 1/2 study datasets evaluated outcomes in the 10-µg bimatoprost implant and comparator treatment arms after a single implant administration, up to the time of implant re-administration or rescue with IOP-lowering medication. RESULTS: In the phase 3 studies, 10-µg bimatoprost implant single administration demonstrated IOP reductions (hour 0) of 4.9-7.0 mmHg through week 15 from a mean (standard deviation, SD) baseline IOP of 24.5 (2.6) mmHg (n = 374); IOP in the topical timolol BID group was reduced by 6.0-6.3 mmHg from a mean (SD) baseline IOP of 24.5 (2.6) mmHg (n = 373). In the phase 1/2 study (n = 21), median time to use of additional IOP-lowering treatment (Kaplan-Meier analysis) was 273 days (approximately 9 months), and 5 of 21 enrolled patients (23.8%) required no additional IOP-lowering treatment up to 24 months after single administration. In each study, after a single implant administration there were no reports of corneal edema, corneal endothelial cell loss, or corneal touch, and no patients had 20% or greater loss in corneal endothelial cell density. CONCLUSIONS: Bimatoprost implant single administration lowers IOP and has a favorable safety profile. Additional studies are needed to further evaluate the duration of effect and factors predicting long-term IOP lowering after a single implant administration. TRIAL REGISTRATION NUMBERS: ClinicalTrials.gov NCT02247804, NCT02250651, and NCT01157364.

Triple Fixed-Combination Bimatoprost/Brimonidine/Timolol in Glaucoma and Ocular Hypertension in India: A Multicenter, Open-Label, Phase 3 Study.

Introduction: To evaluate the intraocular pressure (IOP)-lowering efficacy and safety of a triple fixed-combination of bimatoprost, brimonidine, and timolol (TFC) in patients with glaucoma or ocular hypertension (OHT) treated with fixed-combination or unfixed brimonidine and timolol therapy (dual-combination therapy). Methods: In this multicenter, open-label, phase 3 study, patients who received 4-8 weeks of dual-combination therapy twice daily and had an IOP >18 and <34 mmHg in at least one eye were switched (at baseline) to treatment with TFC twice daily for 12 weeks. At Weeks 4, 8, and 12 on TFC, IOP was assessed at Hours 0, 2, and 8. Primary efficacy variable: mean diurnal IOP change from baseline in the study eye at Week 12 (modified intent-to-treat [mITT] population). Sensitivity (per-protocol [PP] population) and subgroup (≤65 vs >65 years) analyses were performed. Safety, including adverse events (AEs), was assessed at each visit. Results: Of 126 patients enrolled, 121 and 103 formed the mITT/safety and PP populations, including 109 (90.1%) and 94 (91.3%) who completed the study, respectively. In the mITT/safety population, mean age was 58.6 years. Patients had open-angle glaucoma (51.2%), angle-closure glaucoma with patent iridotomy (36.4%), and/or OHT (13.2%). At Week 12, the mean diurnal change in IOP from dual combination-treated baseline was statistically significant (P<0.001) with TFC in the mITT (-3.98 mmHg) and PP (-4.22 mmHg) populations. Results were similar at all visits, regardless of the age subgroup. The most frequent treatment-related AEs were conjunctival hyperemia (14.0%) and dry eye (4.1%); 5.8% of the patients discontinued treatment due to ocular AEs. Conclusion: TFC offers a beneficial therapeutic alternative for patients with glaucoma or OHT whose IOP is not sufficiently controlled with dual-combination therapy. Safety and efficacy findings support those of published studies of TFC in primary open-angle glaucoma and OHT, despite differences in study designs.

The Dual Effect of Rho-Kinase Inhibition on Trabecular Meshwork Cells Cytoskeleton and Extracellular Matrix in an In Vitro Model of Glaucoma.

The trabecular meshwork (TM) is the main site of drainage of the aqueous humor, and its dysfunction leads to intraocular pressure elevation, which is one of the main risk factors of glaucoma. We aimed to compare the effects on cytoskeleton organization and extracellular matrix (ECM) of latanoprost (LT) and a Rho-kinase inhibitor (ROCKi) on a transforming growth factor beta2 (TGF-ß2)-induced glaucoma-like model developed from primary culture of human TM cells (pHTMC). The TGF-ß2 stimulated pHTMC were grown and incubated with LT or a ROCKi (Y-27632) for 24 h. The expression of alpha-smooth muscle actin (αSMA) and fibronectin (FN), and phosphorylation of the myosin light chain (MLC-P) and Cofilin (Cofilin-P) were evaluated using immunofluorescence and Western blot. The architectural modifications were studied in a MatrigelTM 3D culture. TGF-ß2 increased the expression of αSMA and FN in pHTMC and modified the cytoskeleton with cross-linked actin network formation. LT did not alter the expression of αSMA but decreased FN deposition. The ROCKi decreased TGF-ß2-induced αSMA and FN expression, as well as MLC-P and Cofilin-P, and stimulated the cells to recover a basal cytoskeletal arrangement. In the preliminary 3D study, pHTMC organized in a mesh conformation showed the widening of the TM under the effect of Y-27632. By simultaneously modifying the organization of the cytoskeleton and the ECM, with fibronectin deposition and overexpression, TGF-ß2 reproduced the trabecular degeneration described in glaucoma. The ROCKi was able to reverse the TGF-ß2-induced cytoskeletal and ECM rearrangements. LT loosened the extracellular matrix but had no action on the stress fibers.

Reviewing the evidence surrounding preservative-free tafluprost/timolol fixed-dose combination therapy in open-angle glaucoma and ocular hypertension management: a focus on efficacy, safety, and tolerability.

INTRODUCTION: Elevated intraocular pressure (IOP) is the most important modifiable risk factor for irreversible sight loss in open-angle glaucoma (OAG). The topical fixed-dose combination (FC) of preservative-free (PF) tafluprost (0.0015%) and timolol (0.5%) (tafluprost/timolol) is among the second-line IOP-lowering options for OAG and ocular hypertension (OHT). AREAS COVERED: PubMed searches identified publications reporting key evidence from randomized controlled trials (RCTs) and real-world studies examining the safety, tolerability, and IOP-lowering efficacy of PF tafluprost/timolol FC therapy in OAG/OHT management. EXPERT OPINION: Glaucoma patients are more likely to have ocular surface disease, and treatment should be individualized so that target response may be achieved while considering tolerability and quality of life, according to European Glaucoma Society guidelines. PF FC therapies, such as PF tafluprost/timolol FC, avoid ocular surface exposure to toxic preservative agents and reduce the required number of treatment administrations. These properties may enhance treatment tolerability and adherence, resulting in improved IOP-lowering efficacy and disease control. Treatment outcomes from RCTs and real-world studies examining PF tafluprost/timolol FC therapy support this hypothesis, with significant IOP reductions and/or improvements in tolerability parameters demonstrated, regardless of the prior topical therapy used and even when switched directly to PF tafluprost/timolol FC treatment (without washout).

Updates on the Diagnosis and Management of Glaucoma.

Glaucoma is the leading cause of blindness throughout the world (after cataracts); therefore, general physicians should be familiar with the diagnosis and management of affected patients. Glaucomas are usually categorized by the anatomy of the anterior chamber angle (open vs narrow/closed), rapidity of onset (acute vs chronic), and major etiology (primary vs secondary). Most glaucomas are primary (ie, without a contributing comorbidity); however, several coexisting ophthalmic conditions may serve as the underlying etiologies of secondary glaucomas. Chronic glaucoma occurs most commonly; thus, regular eye examinations should be performed in at-risk patients to prevent the insidious loss of vision that can develop before diagnosis. Glaucoma damages the optic nerve and retinal nerve fiber layer, leading to peripheral and central visual field defects. Elevated intraocular pressure (IOP), a crucial determinant of disease progression, remains the only modifiable risk factor; thus, all current treatments (medications, lasers, and operations) aim to reduce the IOP. Pharmacotherapy is the usual first-line therapy, but noncompliance, undesirable adverse effects, and cost limit effectiveness. Laser and surgical treatments may lower IOP significantly over long periods and may be more cost effective than pharmacotherapy, but they are plagued by greater procedural risks and frequent treatment failures. Traditional incisional procedures have recently been replaced by several novel, minimally invasive glaucoma surgeries with improved safety profiles and only minimal decreases in efficacy. Minimally invasive glaucoma surgeries have dramatically transformed the surgical management of glaucoma; nevertheless, large, randomized trials are required to assess their long-term efficacy.