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Victor H Gonzalez,1 David L Wirta,2 Martin Uram,3 Audrey Schupp,4 Michelle Widmann,5 Gary D Novack6,7 1Valley Research Institute, McAllen, TX, USA; 2Eye Research Foundation, Newport Beach, CA, USA; 3American Genomics, LLC, Hobe Sound, FL, USA; 4CMC Turnkey Solutions, Bailey, CO, USA; 5Cal Clinical Solutions, Apex, NC, USA; 6PharmaLogic Development, Inc., San Rafael, CA, USA; 7Department of Ophthalmology & Vision Science, University of California, Davis, School of Medicine, Sacramento, CA, USACorrespondence: Gary D Novack, PharmaLogic Development, Inc., 17 Bridgegate Drive, San Rafael, CA, 94903, USA, Tel +1 415 472-2181, Email gary_novack@pharmalogic.comBackground: We wanted to develop a new topical ocular anesthetic with good bioavailability in anterior segment tissues. Given concerns about contamination and sterility in multi-dose products, we selected a unit-dose, nonpreserved presentation of AG-920 (articaine ophthalmic solution) in blow-fill-seal containers (similar to currently marketed pharmacological therapies for dry eye disease).Methods: Consistent with US Food and Drug Administration guidance, two pivotal, Phase 3, randomized, placebo-controlled, double-masked, parallel design studies conducted at two US private practices in 240 healthy subjects. A single dose of AG-920 or identical looking placebo into one (study) eye (2 drops 30 s apart). Subjects underwent a conjunctival pinch procedure and assessment of the pain associated with the pinch. The main outcome measure was the proportion of subjects with rating of “No pain at 5 minutes”.Results: AG-920 provided a rapid onset of local anesthesia (less than one minute) with clinically and statistically significantly greater effect in AG-920 (68% and 83%) than placebo (3% and 18% for Study 1 and Study 2, respectively, P< 0.0001). The most frequent adverse event was instillation site pain (27% vs 3%) followed by conjunctival hyperemia (probably related to the pinch, 9% vs 10%) in the AG-920 and placebo groups, respectively.Conclusion: AG-920 was found to be have a rapid onset and useful duration of local anesthesia with no major safety issues, and may be useful for the eye-care professional. Registered with clinicaltrials.gov as NCT04513652 and NCT04829344.Keywords: local anesthesia, articaine, controlled trial

PurposeTo perform a phase Ⅰ/Ⅱ evaluation of an H-1337 ophthalmic solution in subjects with primary open-angle glaucoma (POAG) or ocular hypertension (OHT).DesignThis was a phase I/II, randomized, double-masked, vehicle-controlled, dose-response study conducted at 6 private practice sites in the United States. The study was registered with clinicaltrials.gov as NCT03452033.ParticipantsEighty-seven subjects with bilateral POAG or OHT were enrolled.MethodsAfter washout of ocular hypotensive medications as required, the subjects were randomized to receive either the H-1337 ophthalmic solution at 0.06%, 0.2%, and 0.6% or its vehicle twice daily unilaterally in the study eye for the first 3 days and then twice daily in both eyes from day 4 to28.Main outcome measuresThe primary efficacy end point was the mean change in intraocular pressure from baseline (day 0) for each group on day 28 at hour 4 compared with the vehicle.ResultsIn the primary efficacy end point, i.e., mean change from the baseline on day 28 at hour 4, the mean change from the baseline was- 4.45 ± 3.801,- 5.16 ± 3.114,- 4.93 ± 3.110, and- 0.39 ± 2.355 in the 0.06%, 0.2%, and 0.6% H-1337 and vehicle groups, respectively. The difference between each active group and the vehicle group was statistically significant (P < 0.0001). Treatment-emergent adverse events (TEAEs) occurred in 49% of subjects who received H-1337 (range, 41% [0.2% arm]-64% [0.6% arm] across the H-1337 arms) and 18% of subjects who received the vehicle. The majority of TEAEs were mild in severity; 3 subjects who received H-1337 had a TEAE of moderate intensity (instillation site erythema, blurred vision, and muscle strain).ConclusionsThe H-1337 ophthalmic solution showed clinically and statistically significant ocular hypotensive activity and was well tolerated, with a relatively low incidence of hyperemia.Financial disclosure(s)Proprietary or commercial disclosure may be found after the references.

N-of-1 trials are randomized, prospective, controlled, multiple crossover trials in a single patient. Effects of one or more treatments are studied by following individual patients who receive alternative treatments (eg, therapeutic intervention). Such trials may provide a path to assess treatments for rare diseases with rigor equal to or greater than that afforded by parallel group randomized clinical trials provided that the condition is reasonably stable during the trial and has a sign/symptom that responds reversibly to the therapy and that can be measured repeatedly. In this article, the authors propose that N-of-1 trials may improve the feasibility and affordability of clinical trials for patients with rare inherited retinal diseases.

Evaluate the initial ocular safety and tolerability and efficacy of VVN001 Ophthalmic Solution (VVN001), a small-molecule antagonist of lymphocyte function-associated antigen-1 (LFA-1), in subjects with dry eye disease (DED).This was a multi-center, double-masked, randomized, dose-response, vehicle-controlled, parallel-group study conducted in 170 subjects with DED. Subjects were randomized to receive VVN001 (1% or 5%) or its vehicle, twice-daily in both eyes for 84 days. The primary outcome measure was inferior region corneal fluorescein staining (iCFS, 0-4 scale) at Day 84. Visual Analogue Scale eye dryness (VAS, 0-100 scale) was a secondary outcome.The primary and first secondary outcomes were not met. At Day 84 treatment effects in favor of VVN001 5% relative to its vehicle for iCFS were 0.29 units (p = 0.054), and for VAS were 3.18 units (p = 0.533). In other secondary outcomes, treatment effects in favor of VVN001 5% relative to its vehicle were seen in total CFS (1.61 units, 0-20 scale, p = 0.004) and Schirmer score (1.77 and 2.32 mm, p = 0.049 and p = 0.17 at Days 14 and 28 respectively). Adverse events of incidence 5% or greater in either active treatment group were instillation site pain (3/57, 5.3%), dysgeusia (3/56, 5.4%) and urinary tract infection (3/57, 5.3%).There were no major safety issues of note. Appropriately powered studies will be required with a priori selection of the efficacy endpoints to evaluate VVN001's therapeutic potential.

Low-concentration atropine is commonly prescribed to slow myopia progression in children but is not Food and Drug Administration-approved for that indication and is only available in the United States from compounding pharmacies. The purpose of this study was to ascertain its reported compounding and labeling in the United States.US compounding pharmacies were identified through a survey of eye doctors, social media, conferences, and web search. Twenty-eight pharmacies were identified and contacted through telephone and asked a standard set of questions about their methods to compound and label low-concentration atropine.Twenty-six pharmacies across 19 states provided responses, with 21 answering all nine items (81%) and a mean of 8.7 of nine responses. The most frequently reported bottle size was 5 mL (interquartile range [IQR]: 3.5-10). For storage, 10 pharmacies (38%) recommended refrigeration and 16 (62%) stated room temperature was sufficient. The median beyond-use date provided was 65 days (IQR: 45-158). For preparation, 12 pharmacies (50%) used commercially available 1% solution, 9 (38%) used powdered atropine, 2 (8%) used both, and 1 (4%) stated their approach was proprietary. For the added excipients, 11 (42%) used artificial tears only, 6 (23%) added 0.9% saline only, 7 (27%) used more than one ingredient, and 2 (8%) were proprietary. Only two pharmacies mentioned adding boric acid and two mentioned "pH-adjusted" saline.There were a wide variety of formulation methods in the United States, which may affect atropine stability and potency. Similarly, there are a wide variety of storage and beyond-use recommendations. Further research is needed to assess how these variations may affect the efficacy and safety of low-concentration atropine and of myopia control.

In our University journal club we discussed a large, retrospective study of cataract surgery endophthalmitis rates before and after instituting the use of an intracameral fluoroquinolone antibiotic. We identified several factors involved in the use of off-label, compounded moxifloxacin in intraocular surgery. The introduction of phacoemulsification for cataract surgery led to the potential for smaller incisions. Intraocular lens technology improved to allow for foldable lenses, obviating the requirement to enlarge the incision. This allowed for clear corneal incisions, which unfortunately allow bidirectional passage of liquid. Preservatives were introduced into multi-dose ophthalmic products in the mid 20th century to retard microbial growth. However, more recently, chronic use of benzalkonium chloride has led to concerns about concerns about conjunctival toxicity, especially in patients with ocular surface disease. In the formulation of ocular moxifloxacin, developers were able to develop a "self-preserved", multi-dose product. Other concerns with eyedrops include varying levels of adherence and performance, and the expansion of compounding pharmacies from a named-patient basis to widespread national delivery, with concerns for lower quality. Integrating these factors, use of intracameral moxifloxacin as a prophylactic during cataract and other anterior segment surgery has become a standard of care in much of the U.S. We are concerned that the current position is on a narrow ledge-the standard of care for millions of surgeries each year based upon off-label, compounting use of a single product. We discuss possible ramifications and solutions to this public health issue.

Introduction: Currently, the only modifiable risk factor to slow or halt the progression of glaucoma is the lowering of intraocular pressure (IOP). Netarsudil 0.02% is a new medication that was app...

Purpose To evaluate netarsudil 0.02% ophthalmic solution in patients with open-angle glaucoma (OAG) and ocular hypertension (OHT). Design Double-masked, randomized, multicenter, parallel-group, noninferiority clinical study. Methods After a washout of all prestudy ocular hypotensive medications, 756 eligible patients with elevated IOP were randomized to receive netarsudil 0.02% once a day (q.d.) (251); netarsudil 0.02% twice a day (b.i.d.) (254); or timolol 0.5% b.i.d. (251) for 12 months, as well as a noninterventional Corneal Observation Study (COS) for patients manifesting cornea verticillata. Results On treatment, mean IOP at 8:00 AM decreased from a baseline IOP of 22.5-22.6 mm Hg to 17.9-18.8 mm Hg, 17.2-18.0 mm Hg, and 17.5-17.9 mm Hg for netarsudil q.d., netarsudil b.i.d., and timolol, respectively, over 12 months. The most frequently reported adverse events (AEs) were ocular, with the most frequent ocular AE being conjunctival hyperemia, with an incidence of 61%, 66%, and 14%, respectively. The next most frequent AEs were corneal deposits (corneal verticillata), with an incidence of 26%, 25%, and 1%, respectively, and conjunctival hemorrhage (typically petechial), with an incidence of 20%, 19%, and 1%, respectively. All 3 AEs were generally scored as mild, with conjunctival hyperemia and/or hemorrhage appearing sporadically during the study. In the observational follow-up component of this study, there was no clinically meaningful impact of corneal verticillata on visual function in affected patients. Conclusions In this randomized, double-masked trial, once-daily dosing of netarsudil 0.02% was effective, consistently lowering IOP through 12 months, and was tolerated by the majority of patients.

The use of contact lenses as ocular drug delivery systems has been considered intuitive for decades. However, at this time, there are no approved products using such systems. In this article, we review the challenges with current therapies, pharmacokinetics, and pharmacodynamics of different drug classes and the patient population. In addition, we note the relative lack of clinical studies, and list potential products in active development at this time. In particular, we address the alignment of time course of the therapeutic need, the pharmacokinetics of the molecule, and the delivery characteristics of the systems (e.g., pulsatile vs. zero-order). We also discuss the needs of various populations including the elderly (who may have motor and cognitive issues as well as presbyopia) and the young. While a contact lens delivery system may also provide refractive correction, to date, most of the studies have used noncorrective (plano) lenses. We also considered nanotechnology-based carrier systems. We generalize the development of contact lens delivery systems to all ocular delivery systems in which there are relatively few product approvals and long development times.

Because of the epidemic of myopia with both its short-term and long-term effects, we desperately need ways to slow myopic progression. In this study which was part of a myopia prevention symposium, the author answers the following question: Assuming that researchers did come up with a pharmacological treatment to slow myopic progression-what would it take to obtain regulatory approval from the United States Food and Drug Administration (FDA)? Previous publicly available information (a 2003 FDA advisory committee on this topic, International Conference on Harmonisation guidances on drug development, and published articles) as well as the author's experience is used. Development pathways including preclinical safety, chemistry, manufacturing and controls, and early- and late-stage clinical studies are presented. In particular, challenges for the conduct of multi-year controlled double-masked studies are presented. As any treatment would have to be chronic, prophylactic, and pediatric, there are a host of concerns as to efficacy, safety, and benefit/risk (therapeutic index). Although more challenging than some short-term indications in ophthalmology, nonetheless the pharmaceutical community is investing in seemingly equally challenging conditions such as retinal degeneration. The author looks forward to working with colleagues in academia and industry to evaluate and develop novel therapies to slow the development of myopia.

Purpose: Netarsudil, an inhibitor of Rho kinase and a norepinephrine transporter, has been shown to lower elevated intraocular pressure (IOP) in controlled studies of patients with open-angle glaucoma and ocular hypertension, and in healthy volunteers. The mechanism of this ocular hypotensive effect in humans is unknown. Methods: The objective of this study was to evaluate the effect of netarsudil 0.02% on aqueous humor dynamics (AHD) parameters. In this double-masked, vehicle-controlled, paired-eye comparison study, 11 healthy volunteers received topical netarsudil ophthalmic solution 0.02% or its vehicle once daily for 7 days (morning dosing). The primary endpoints were the change in AHD parameters, compared between active and vehicle-treated eyes. Results: In netarsudil-treated eyes, diurnal outflow facility increased from 0.27 ± 0.10 μL/min/mmHg to 0.33 ± 0.11 μL/min/mmHg (+22%; P = 0.02) after 7 days of treatment. In placebo-treated eyes, diurnal outflow facility did not significantly change (P = 0.94). The difference between netarsudil and placebo eyes in diurnal change of outflow facility was 0.08 μL/min/mmHg (P

To evaluate the efficacy and ocular and systemic safety of netarsudil 0.02% ophthalmic solution, a rho-kinase inhibitor and norepinephrine transporter inhibitor, in patients with open-angle glaucoma and ocular hypertension.Double-masked, randomized noninferiority clinical trials: Rho Kinase Elevated IOP Treatment Trial 1 and 2 (ROCKET-1 and ROCKET-2).After a washout of all pre-study ocular hypotensive medications, eligible patients were randomized to receive netarsudil 0.02% once daily (q.d.), timolol 0.5% twice a day (b.i.d.), and (ROCKET-2 only) netarsudil 0.02% b.i.d. Data through 3 months from both studies are provided in this report.Enrolled into the 2 studies were 1167 patients. Treatment with netarsudil q.d. produced clinically and statistically significant reductions from baseline intraocular pressure (P.001), and was noninferior to timolol in the per-protocol population with maximum baseline IOP25 mm Hg in both studies (ROCKET-2, primary outcome measure and population, ROCKET-1, post hoc outcome measure). Netarsudil b.i.d. was also noninferior to timolol (ROCKET-2). The most frequent adverse event was conjunctival hyperemia, the incidence of which ranged from 50% (126/251, ROCKET-2) to 53% (108/203, ROCKET-1) for netarsudil q.d., 59% (149/253, ROCKET-2) for netarsudil b.i.d., and 8% (17/208, ROCKET-1) to 11% (27/251, ROCKET-2) for timolol (P.0001 for netarsudil vs timolol).In 2 large, randomized, double-masked trials reported here, once-daily dosing of netarsudil 0.02% was found to be effective and well tolerated for the treatment of patients with ocular hypertension and open-angle glaucoma. The novel pharmacology and aqueous humor dynamic effects of this molecule suggest it may be a useful addition to the armamentarium of ocular hypotensive medications.

This article presents an Executive Summary of the conclusions and recommendations of the 10-chapter TFOS DEWS II report. The entire TFOS DEWS II report was published in the July 2017 issue of The Ocular Surface. A downloadable version of the document and additional material, including videos of diagnostic and management techniques, are available on the TFOS website: www.TearFilm.org.

To discuss recent advances in the medical management of glaucoma and to highlight future medical therapies currently in development.In 1996, latanoprost (Xalatan) was approved in the United States as a new chemical entity and new class (prostaglandin analogs) for the topical treatment of ocular hypertension and glaucoma. In the period from the late 1990s-2010s, while there were additional new chemical entities, fixed dose combinations, and formulation improvements, there were no new classes of ocular hypotensive medications approved worldwide. We summarize new pharmacological treatments that are currently in clinical trials - new classes, new molecules and new delivery systems.Although challenges in medical treatment of glaucoma exist, particularly in patient adherence, medical therapy remains the first line treatment for almost all glaucoma patients. Few new medications for glaucoma therapy are currently available for our patients, but multiple drugs with novel mechanisms of action, new formulations, and new delivery mechanisms are currently in development.

The ideal biomarker would be a simple laboratory or clinical evaluation before treatment, which would predict subsequent therapeutic response. This might include selection of which patients might respond to that treatment. While other disciplines such as neurology and oncology have biomarkers, ophthalmology is limited to one-elevated intraocular pressure as a surrogate for progressive glaucomatous field loss. US law in 2016 required the Food and Drug Administration (FDA) to set up a system to qualify biomarkers. The system now exists-with most validated or pending biomarkers limited to safety and infection. The American Academy of Ophthalmology selected dry eye disease as one of three diseases in which to standardize outcomes in ophthalmology research. There have been a number of biomarkers proposed for evaluating ocular surface disease and its treatment. None currently meets the scientific or regulatory basis for being a valid biomarker-however, additional research may result in validity. Given the FDA's scientific basis, it is unlikely that an unproven biomarker could be used for regulatory approval, even for a "SubPart H" conditional new drug application. Elsewhere in ophthalmology, we know that even patients who share the same disease gene or mutation may differ substantially in penetrance and clinical expression. Thus, it is not unexpected that ocular surface disease, a heterogeneous disease with a variable presentation of signs and symptoms, has yet to have validated biomarkers that reach the level of evidence that allows their use for diagnosis, prognosis, therapy, and for making decisions in drug development.

Purpose To provide a first-hand account of a retinal detachment suffered by one of the authors and how it relates to electronic health record (EHR) interoperability. Design Single-patient, observational. Methods 1) Personal patient perspective - symptom, surgery, recovery and the worry about potential long lasting sequelae, and the need to reiterate detailed medical information several times during a stressful period. 2) U.S. National perspective regarding EHRs. S etting : Out-patient and community hospital. P atient or S tudy P opulation : Single patient. I ntervention or O bservation P rocedure(s) : Retinal surgery. M ain O utcome M easure(s) : Visual acuity. Results Patient had a favorable outcome, but was required to provide medical history data multiple times to multiple providers. Only 41% of hospitals in the United States have EHR from outside providers or sources when treating a patient. Physicians in outpatient settings fare worse with only 14% of office-based physicians sharing data with providers outside of their organization. Conclusions While adoption and use of EHRs are incentivized by the federal government in the United States, the lack of interoperability between different physician and hospital systems means that we are far from achieving meaningful digitization of records. This case report provides a close look at how it may be difficult to receive care in a fragmented health care model in which physician and hospital do not share the same EHR. Information blocking, now prohibited by federal law, still remains an obstacle to interoperability. It will take continued effort and commitment from key stakeholders such as health care providers, patients, the federal government, and industry to bring this dream to fruition.

Cell therapies present many unique challenges to regulators. The science is continuing to advance. Cell replacement therapy is part of the Audacious Goals Initiative of the U.S. National Eye Institute, and viewed as having great promise in restoring vision through regeneration (Levin et al., Ophthalmology 124:926–934, 2017). However, the risks to patients, including unethical promotion by unscrupulous organizations, are real. The U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) each have published guidance on many aspects of the investigational use of cell therapy—part of the larger group of human cells, tissues, or cellular or tissue-based products (HCT/Ps). HCT/Ps are regulated primarily as biologics.

The purpose of this article is to review the current status of cannabis in the treatment of glaucoma, including the greater availability of marijuana in the USA.The potency of marijuana, as measured by the concentration of Δ-tetrahydrocannabinol, has increased from ∼2 to 3% in the 1970s to ∼20% today. Many US states have passed laws allowing either medicinal or recreational use of marijuana.The pharmacology of marijuana and its effect on intraocular pressure has not changed since the research in the 1970s and 1980s. Marijuana is an effective ocular hypotensive agent. However, cardiovascular and neurological effects are observed at the same dose, and may theoretically reduce the beneficial effect of lowering intraocular pressure by reducing ocular blood flow. The clinician must be cognizant of this potential in diagnosis, prognosis, and therapy.

To evaluate the ocular hypotensive efficacy of fixed-dose combinations of the Rho kinase inhibitor and norepinephrine transport inhibitor AR-13324 (0.01% and 0.02%) and latanoprost (PG324 Ophthalmic Solution) relative to the active components AR-13324 0.02% and latanoprost 0.005%, used bilaterally at night.This was a double-masked, randomised, parallel comparison study in patients with open-angle glaucoma or ocular hypertension. After washout, patients were randomised to one of four treatment arms and treated for 28 days. The primary efficacy variable was mean diurnal intraocular pressure (IOP) at day 29.We randomised 298 patients, of whom 292 (98%) completed the study. Mean unmedicated diurnal IOPs (study eye) was 25.1, 25.1, 26.0 and 25.4 in the PG324 0.01%, PG324 0.02%, latanoprost and AR-13324 0.02% groups, respectively. On day 29, mean diurnal IOP decreased to 17.3, 16.5, 18.4 and 19.1 mm Hg, respectively. For the primary efficacy variable of mean diurnal IOP at day 29, PG324 0.02% met the criterion for statistical superiority relative to both latanoprost and AR-13324 0.02% (p0.0001), providing additional IOP lowering of 1.9 and 2.6 mm Hg, respectively. PG324 0.01% also met the criterion for superiority. The most frequently reported adverse event was conjunctival hyperaemia with an incidence of 41% (30/73), 40% (29/73), 14% (10/73) and 40% (31/78) in the PG324 0.01%, PG324 0.02%, latanoprost and AR-13324 0.02% groups, respectively.In this short-term study, the fixed-dose combination of AR-13324 0.02% and latanoprost 0.005% in PG324 Ophthalmic Solution provides clinically and statistically superior ocular hypotensive efficacy relative to its individual active components at the same concentrations. The only safety finding of note was transient asymptomatic conjunctival hyperaemia which was typically of mild severity.NCT02057575.

he Wall Street Journal T recently reviewed venture capital funding of health care companies by organ system over the past 15 years. The largest recipient of funding has been “.the eyes and ears, as investors have poured money into treatments for diseases causing blindness, hearing loss and other diseases affecting an aging population. At the same time, venture capital is pulling back from two historical leaders, heart and orthopedic conditions, in part because of difficulties in bringing medical devices for those ailments to market.” In 2013 and 2014, $1.3 billion was invested in ophthalmic opportunities in over 50 companies, which is comparable to that invested in cardiovascular and neurology firms (http://graphics.wsj. com/venture-capital-and-the-humanbody). Some years ago in this journal, I stated “.In capitalistic societies, the cost of drug development is largely borne by the private rather than governmental sector. Thus, investors must believe that there is a chance of reward for investment to balance the risks, extensive capital, and long drug development process.” Thus, as ophthalmic scientists, researchers and clinicians, we should find this continued interest in ophthalmology promising.