Cheryl Guttman Krader, BS, Pharm

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Results of a phase 2 trial suggest that dexamethasone cyclodextrin nanoparticle ophthalmic suspension 1.5% mg/mL (OCS-01, Oculis), a novel topical formulation of dexamethasone, has the potential to become the first once-daily and preservative-free topical corticosteroid for treating pain and inflammation after ocular surgery, said Eric D. Donnenfeld, MD, at the 2020 ASCRS virtual meeting.

Donnenfeld reported results from the SKYGGN study that randomly selected 153 patients 1:1:1 to treatment with OCS-01 once daily, OCS-01 twice daily, or vehicle for 14 days. The study met its primary endpoints analyzing absence of anterior chamber cells at postop day 15 and absence of ocular pain at postop day 4. There were no efficacy differences between the two OCS-01 dosing regimens and both were safe and well-tolerated.

“Inflammation and pain remain expected consequences of ocular surgery. Although available topical steroids are effective for treating these sequelae, potency and compliance with products that need to be used several times a day are major issues,” said Donnenfeld, a SKYGGN investigator who is clinical professor of ophthalmology, New York University Langone Medical Center, New York, and Founding Partner, Ophthalmic Consultants of Long Island and Connecticut, Garden City, NY. “Using a novel and proprietary nanoparticle formulation, OCS-01 was developed to deliver a potent anti-inflammatory effect and excellent safety profile with once-a-day dosing.”

Donnenfeld noted that the concentration of dexamethasone in OCS-01 is 15-fold greater than that found in commercially available topical dexamethasone suspension. In addition, the novel vehicle used for OCS-01 increases ocular surface residency time to hours compared with minutes using conventional dexamethasone 0.1% suspension. Furthermore, the proprietary nanoparticle technology enhances penetration of the active ingredient. As another benefit, the formulation is preservative-free.

A total of 20 US centers participated in the SKYGGN study. Patients were eligible for enrollment if they had an anterior chamber cell score ≥ 2 at their first postoperative visit 18 to 30 hours post-uncomplicated cataract surgery and a pin-hole ETDRS visual acuity without any other correction that was >20 letters (approximately 20/400) in the operative eye and >35 letters (approximately 20/200) in the fellow eye. Follow-up visits were scheduled at postoperative days 4, 8, 15, and 22.

The three study groups were similar at baseline in their demographic characteristics, and 148 patients completed the study. Mean age of patients across the three groups ranged from 66 to 68 years, approximately two-thirds of subjects were female, and the vast majority were Caucasian.

The percentage of patients with absence of anterior chamber cells on day 15 in the OCS-01 once daily, OCS-01 twice daily, and vehicle groups was 51.0%, 66.7%, and 19.6%, respectively (

<.0001 for both OCS-01 groups versus vehicle). Absence of pain on day 4 was achieved by 72.5% of patients treated with OCS-01 once daily and 45.1% of controls (

<.005). In the OCS-01 twice-daily group, 62.7% of patients were pain-free on day 4 (

“Data on percentage of patients with absence of anterior chamber cells from earlier postoperative visits show a statistically significant difference favoring the once-daily OCS-01 group versus vehicle was achieved on day 8. The results for the pain assessment showed the proportion of patients who were pain-free increased in all groups as follow-up continued, but the difference was statistically significant between both OCS-01 groups and vehicle at days 8 and 15,” Donnenfeld said.

One patient in the vehicle group and one patient treated with OCS-01 twice daily withdrew from the study because of an adverse event. However, there were no significant ocular or systemic adverse events. Importantly, IOP ≥30 mm Hg was not observed in any patients at any follow-up visits nor did any patient have a ≥10 mm Hg increase from baseline IOP.

“The overall adverse event rate was higher in the vehicle group than in the OCS-01 groups, probably because the adverse events were procedure-related rather than treatment-related,” Donnenfeld said.

Donnenfeld noted that the potent activity, safety, and tolerability of OCS-01 observed in SKYGGN are consistent with results of another phase 2 trial investigating the novel steroid formulation as a treatment for diabetic macular edema. The latter study enrolled 144 patients and found a statistically significantly greater decrease in central macular thickness in patients treated with OCS-01 compared with vehicle-treated controls. There were no significant ocular adverse events in the OCS-01 group.

Articles

A vehicle-controlled phase 2 study investigating once- and twice-daily administration of a novel, preservative-free topical formulation of dexamethasone as treatment for pain and inflammation after cataract surgery met its primary endpoints.



Novel dexamethasone formulation shows efficacy and safety with once-daily use

This article was reviewed by Subhransu K. Ray, MD, PhD

nterim data from a cross-sectional study raise concerns that repeated intravitreal injections of an anti-VEGF agent may be associated with a decline in cognitive health.

The findings from the first 143 patients with 

 enrolled in the Brain Health Assessment in Macular Degeneration (BHAM) study were presented by Subhransu K. Ray, MD, PhD, at the virtual meeting of the American Society of Retina Specialists. 

He reported that patients who received higher cumulative anti-VEGF injections performed significantly worse on a test of cognition.



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“It is essential to remember that our study does not establish a causal link between cumulative doses of anti-VEGF injections and cognitive function, but the data demonstrate an association between higher treatment number and increased risk of mild cognitive impairment,” said Ray, who is with Bay Area Retina Associates, Clinical Trial Center, in Walnut Creek, California.

Ray added that investigators are continuing to enroll patients in this study, and these initial findings need to be validated using other cognitive tools and assays.

“Furthermore, we need to evaluate confounding factors such as the impact of even moderate vision loss in one eye,” Ray pointed out. “In addition, we have begun a prospective trial that is following 200 patients who are just initiating anti-VEGF injections.”


The BHAM study was undertaken considering that anti-VEGF agents injected into the vitreous are detectable in the systemic circulation at biologically active levels, that there is direct communication from the vitreous cavity to the central nervous system (CNS) in rare pathological states, and that VEGF has an essential role in CNS health.

“However, very little is known about how the normal vitreous-CNS barrier is affected by repeated intravitreal injections of anti-VEGF compounds,” Ray said. “Furthermore, despite the fact that millions of intravitreal injections are performed yearly in the United States, there have been no formal studies assessing the impact of these repeated injections on cognitive performance in this vulnerable age group.”

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Ray wrote the BHAM study protocol that is enrolling patients aged 65 to 85 years with BCVA of 20/50 or better in at least 1 eye and a diagnosis of AMD. 

Patients were ineligible if they had any history of CNS disease or previous systemic anti-VEGF exposure. The study is targeting enrollment of 100 patients with dry AMD and 300 patients with 

Cognitive performance was evaluated using the Brain Health Assessment (BHA) test, which was developed at the University of California, San Francisco, School of Medicine and validated for use in research dementia care centers. 

The BHA test is a 10-minute, tablet-based tool that has been shown to have high specificity and high sensitivity for detecting dementia and early cognitive impairment, exceeding the sensitivity of the Montreal Cognitive Assessment. 

It includes subsets of memory, executive function and speed, visuospatial skills, and language. Results are generated as an age-adjusted Z-score.


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“The experience in our study using the BHA test also shows that cognitive testing can be effectively performed within the flow of a retina clinic,” Ray said.

Based on their BHA Z-score, patients in the study were categorized into groups of low, moderate, and high likelihood of having mild cognitive impairment. 

They were also stratified into 4 groups based on the number of intravitreal anti-VEGF injections they received: 0 (n = 38), 1 to 10 (n = 41), greater than 10 (n = 64), and greater than 20 (n = 51).

Mean age was similar for the 4 injection subgroups (range 77.1 to 78.2 years), but the percentage of patients with a BHA score placing them at high likelihood of having mild cognitive impairment was higher in the group that had received greater than 10 intravitreal injections compared with both the group who had no injections and the group who had received 1 to 10 injections (45.3% versus 34.2% and 36.5%).

 In the group that had received greater than 20 injections, 49% of patients had a high likelihood of mild cognitive impairment, Ray said.



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Another analysis compared the mean Z-scores among the 4 intravitreal injection groups. It found that the Z-score was significantly lower (indicating higher likelihood of having mild cognitive impairment) for both the patients who had received greater than 10 injections and those who had received greater than 20 injections versus those who had none.

Ray noted that because of the limited sample size, analyses were not done to investigate potential differences in Z-scores with patients divided according to anti-VEGF agent received. 

Furthermore, many patients switched anti-VEGF agents during the course of their treatment.

“Once the full enrollment is completed, we hope to be able to address several factors at a more granular level, including whether choice of anti-VEGF agent had any impact,” Ray said. “More importantly, we hope that the final data set will help us to address potential confounding factors, including the impact of vision loss itself on the BHA score.”



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Ray added that investigators also hope to further refine the analysis of injection number versus injection duration and even age-dependent risks.

“In the end, whether there is or is not a statistically significant risk associated with anti-VEGF injections, we feel this is a question that needs to be formally addressed,” he said.

In addition, Ray suggested topics for future studies to explore a potential biologic basis of an effect of intravitreal anti-VEGF injections on cognitive function. These would include targeted neuroimaging of the hippocampus in patients with high cumulative anti-VEGF exposure, careful examination of optic nerve integrity prior to and after repeated intravitreal injections, further preclinical studies, and direct evaluation for anti-VEGF agents in post-mortem CNS tissues and CSF from patients who have received numerous intravitreal anti-VEGF injections.

“Developing such assays is complicated and time consuming, but might be valuable as we pursue longer acting and constitutively expressed anti-VEGF agents,” he said.



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Ray cautioned that clinicians should not allow this very preliminary interim analysis to alter treatment protocols, but rather to use it to be aware of a patient’s mental health during the course of therapy. 

“Frankly, limiting appropriate anti-VEGF therapy resulting in unnecessary vision loss may be more of a risk factor on cognition,” he said.

In extending thanks to his colleagues for supporting the research, Ray said that any retina clinics interested in additional information or participating in the BHAM clinical trial may reach out to him at sray@bayarearetina.com.



Ray has no relevant financial interests to disclose.

Interim data from a cross-sectional study raise concerns that repeated intravitreal injections of an anti-VEGF agent may be associated with a decline in cognitive health.

Study results link frequent anti-VEGF injections, risk of cognitive impairment

A number of compounds have shown promising potential for preventing and reversing cataracts in preclinical studies and warrant further investigation as possible pharmacotherapy alternatives to surgical management, according to authors of an article that reviewed the effects of natural and synthetic agents on experimentally induced cataracts.

Interest in pharmacotherapy for cataract stems from the recognition that the number of people affected with cataracts is expected to increase in association with population aging while access to cataract surgery is limited in areas throughout the world.

The authors of the article wrote, “With the projected increase in life expectancies, the number of people affected with cataract is predicted to increase worldwide. The prognosis of the disease is at best oblique in low-income nations that lack easy and affordable access to cataract surgery. Therefore, the potential therapeutic and economic benefits of pharmacological cataract treatments are immeasurable, ranging from a reduction in economic burden to better quality of life.”

The authors go on to suggest that plant-derived compounds or extracts are particularly attractive, especially in developing nations. They explain that compared with traditional medications, the costs of both development and patient use may be lower with the plant-derived agents given their accessibility.

The extensive 41-page review article includes 288 references. As background to the discussion of treatment strategies for cataracts, the authors describe lens anatomy, physiology, transparency, and antioxidant systems. They also provide an overview of the molecular mechanisms of cataract formation that include models based on protein aggregation and/or loss of protein solubility.

The summary of compounds identified by the researchers as having been investigated for anti-cataract activity includes plant-derived agents, herbal remedies, ketoacids/amino acids, and other agents with antioxidant and free radical scavenging activity. The compounds investigated also include pharmacological chaperons that bind α-crystallins in the lens to reverse protein aggregation and enhance protein solubility as well as agents that target glycation-specific mechanisms, phase separation, the transforming growth factor-β pathway, and matrix metalloproteinase.

The paper features two tables that summarize key features of studies relevant to pharmacotherapy for cataracts. One table focuses on the 

 cataractogenesis studies and the other lists the 

 studies of cataractogenesis. The latter studies were done almost entirely in murine models with just two experiments performed in rabbits and a single experiment in guinea pigs. The modes of application include subcutaneous injection, dietary modification, topical treatment, oral (including gavage/gastric intubation), and intraperitoneal or subcutaneous injection.

Noting that lutein/zeaxanthin supplementation did not have a significant benefit for decreasing progression of senile cataract in the Age-Related Eye Disease Study 2 and that an extensive Cochrane review failed to find any anti-cataract benefit of antioxidant vitamin supplementation, the authors suggested that better drug delivery methods might allow for better efficacy.

Looking ahead, the researchers also suggested that a better understanding of the mechanisms of cataract development should be pursued as it could lead to the identification of new therapeutic targets for pharmacological strategies to prevent or reverse lens opacity.

Heruye SH, Maffofou Nkenyi LN, et al. Current trends in the pharmacotherapy of cataracts. 

Interest stems from the recognition that the number of people affected with cataracts is expected to increase in association with population aging while access to cataract surgery is limited in areas throughout the world.



Abundance of studies explore pharmacotherapy for cataract

This article was reviewed by Yusen Huang, MD, PhD

Adding cefuroxime to the irrigating solution used during cataract surgery appears to be a safe and effective method for reducing the risk of postoperative endophthalmitis, according to researchers who reported their experience with this technique in a recently published retrospective study [Ma X, Zie L, Huang Y. 

The investigation included 61,299 eyes. Of the total cohort, 15,948 eyes were operated on between January 1, 2012 and December 31, 2014 using plain balanced salt solution (BSS) as the irrigating solution (control group), and 45,351 eyes underwent cataract surgery between January 1, 2015 and December 31, 2019 using irrigating solution that contained cefuroxime 1500 µg/mL. The mixture was prepared by withdrawing 10 mL BSS from the irrigating solution and injecting it into a vial of cefuroxime 750 mg. The reconstituted solution was injected back into the BSS container.

The rate of endophthalmitis was significantly decreased after the transition to intraoperative irrigation with cefuroxime. Endophthalmitis occurred in 11 eyes (0.07%) in the group that did not receive intraoperative cefuroxime and in 5 eyes (0.01%) when cefuroxime was used in the irrigating solution (

 < .01). Cultures were positive for bacteria in 4 of the 11 cases in the control group and in 1 of the 5 eyes in the intraoperative cefuroxime group (P >.05). There were no safety issues associated with intraoperative cefuroxime irrigation.

Discussing the research, Yusen Huang, MD, PhD, Shandong Eye Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Qingdao, People’s Republic of China, said, “Although intracameral antibiotics are already widely accepted as a method for endophthalmitis prophylaxis in patients undergoing cataract surgery, the optimal choice of prophylactic routes and antibiotics are controversial. In European countries, commercial cefuroxime formulation (Aprokam) has been widely used and the dose administered is the same as in the European Society of Cataract and Refractive Surgeons (ESCRS) randomized prospective study demonstrating its efficacy. Elsewhere, however, surgeons have been reluctant to adopt intracameral cefuroxime because it is off-label and carries potential risks related to its two-step dilution process.”

“In our study, the manner of cefuroxime preparation was modified so that it involved only a one-step process, which makes it simpler, saves resources, and could reduce the potential risks of both preparation errors and contamination. Although the intracameral concentration achieved with our approach is estimated to be 1500 µg/mL, or only about 45% of the ESCRS recommendation, we found that it reduced the rate of postcataract surgery endophthalmitis by about seven-fold. Furthermore, during the last 2 years in our hospital where more than 25,000 cases of cataract surgery have been performed using intraoperative cefuroxime irrigation, not a single patient developed endophthalmitis. It should be noted, however, that this method is not recommended for use in patients with a history of vitrectomy considered the potential for rapid posterior segment diffusion of the antibiotic and potential macular toxicity.”

Although adding cefuroxime to the irrigating solution is still an off-label use of the medication, the authors suggested that it represents a good option for countries where there is no product that is licensed for intracameral use for endophthalmitis prophylaxis, and particularly in developing regions where the risks for both endophthalmitis and a poor outcome may be higher given a variety of contributory factors.

Throughout the entire study period, all patients received the same preoperative antisepsis with application of topical povidone-iodine. In addition, all patients started using topical levofloxacin 0.5% solution preoperatively and continued it postoperatively along with a topical steroid and topical nonsteroidal anti-inflammatory drug.

Postoperative follow-up visits were scheduled at 1 and 4 days, 4 weeks, and 12 weeks, but patients were instructed to seek care if they developed pain, redness, or loss of vision. The analyzed outcome was onset of acute-onset endophthalmitis, which was diagnosed if a patient presented within 6 weeks of surgery with eye pain, anterior chamber reaction or flare, hypopyon, and/or vitritis with causes for intraocular inflammation other than endophthalmitis excluded.

The 16 cases of endophthalmitis that were recorded during the 9-year study period developed at a median of 7.56 days after cataract surgery (range 1 to 21 days). None of the cases occurred in a patient who had an intraoperative complication or was noted to have incision leakage at the time endophthalmitis was identified.

Isolates from the culture-positive cases of endophthalmitis in the control group included 

 was identified as the causative pathogen in the culture-positive case of endophthalmitis among patients who received intraoperative cefuroxime, and the organism was found susceptible to cefuroxime.

Huang did not indicate any proprietary interest in the subject matter.

Findings from large retrospective study support intraoperative cefuroxime irrigation 

Cheryl Guttman Krader, BS, Pharm

Articles

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