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SUBSPECIALTY NEWS: Endophthalmitis data at ARVO, an AMD patient survey, AMD nonresponders, and more.

Endophthalmitis a Key Focus at ARVO

Five studies shed new light on the disease.

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■ Numerous research studies covering various aspects of endophthalmitis were a highlight of the 2019 meeting of the Association for Research in Vision and Ophthalmology (ARVO). Among the many presentations was a retrospective review by French researchers of more than 1.8 million intravitreal injections from 2012 to 2015. They found that antibiotic prophylaxis offered no additional benefit in protecting against endophthalmitis and that it increased costs and the potential of antibiotic resistance.

A large-scale study conducted at Wake Forest Baptist Health covering an 18-year period concluded that 10% betadine was more effective than the usual 5% betadine in protecting against endophthalmitis, although there were more patient complaints of postinjection irritation with the higher amount. A UK study of 10,825 intravitreal injections found that patients who had no or reduced preoperative povidone-iodine prophylaxis were at greater risk for endophthalmitis (1 in 200 injections) than patients who received full-strength povidone-iodine prophylaxis (1 in 2,500 injections). The researchers recommended that practitioners find prophylactic alternatives to patients with povidone-iodine sensitivity.

A retrospective study of 43,896 anti-VEGF injections from 2014 to 2018 with either a 30- or 32-gauge needle at a retina private practice was conducted by Austin Retina Associates in Texas. The primary goal was to identify development of endophthalmitis within 1 week of injection based on needle gauge. The rate of endophthalmitis detected was 0.04% in the 30-gauge group and 0.05% in the 32-gauge group. Although there was a slightly lower rate of endophthalmitis in the 32-gauge group, this was not deemed statistically significant.

In another study of more than 10,000 intravitreal injections from 2012 to 2018 undertaken at the University of Rochester School of Medicine, researchers identified 9 cases of postintravitreal injection endophthalmitis. The most common condition being treated was wet AMD (4 of 9; 44%). Three patients had negative culture. Six had positive culture, and coagulase-negative Staphylococci (3 of 6; 50%) was the most common organism isolated. Initial treatment consisted of vitreous tap and intravitreal antibiotics in 4 of 9 (44%) patients and vitrectomy and intravitreal antibiotics in 5 of 9 (56%) patients. Postinfection visual acuity outcomes ranged from 20/60 to no light perception, with 1 patient requiring enucleation. The researchers concluded that the rate of endophthalmitis after intravitreal injection (0.085%) in the study was very low and consistent with previous studies.

Survey Shows Wet AMD Impact on Patients

Most patients say vision is their highest health priority.

■ In an initiative facilitated by the Angiogenesis Foundation and reported at the recent ARVO meeting, researchers and practitioners set out to determine the overall impact of wet AMD on patients. A total of 962 patient surveys were completed, with a wide geographic representation throughout the United States. All respondents were patients being treated for wet AMD. A large majority (68%) reported vision as their highest health priority, even when compared to other health-related concerns of an older population.

The vast majority (95%) agreed with the importance of having a prompt eye exam after noting vision problems. However, there was a delay in diagnosis in 32% who waited more than 3 months to seek care. With anti-VEGF injections, 80% of patients reported stable or improved vision — 47% reported receiving monthly injections, 27% every other month, 9% less than every other month, and 19% pro re nata treatments. Although 97% of patients make a priority of compliance with scheduled injections, 26% said they missed injections or took “time off” from injections. Of those who missed injections, 23% reported losing vision.

Challenges that hindered appointment compliance included transportation (32%), anxiety (15%), fatigue (13%), and scheduling difficultly (4%). This first study of AMD patients supports the self-perceived importance of maintaining good vision, treatment compliance, and the need for continued patient and caregiver education as part of the retina specialist-patient partnership.

Anti-VEGF “Nonresponders” May Be Brief Responders

Study finds evidence of some early benefit.

■ Researchers from Massachusetts Eye and Ear Infirmary have determined that some patients who have been deemed nonresponders to anti-VEGF do show a response 2 weeks after injection. However, the response is brief and is not evident at a later follow-up.

The prospective, multicenter trial conducted in Greece investigated the duration of anti-VEGF treatment effect in patients with wet AMD, DME, and RVO to determine if nonresponders or poor responders at the standard 4-week interval actually demonstrate a treatment response at an earlier time point.

Patients received intravitreal anti-VEGF (0.5 mg ranibizumab) injections and subsequently were assessed weekly for a total period of 4 to 6 weeks by spectral-domain OCT (SDOCT) for reduction in central retinal thickness (CRT) and the presence of intraretinal and subretinal fluid. Data collected included age, sex, visual acuity, past ocular history, total retinal volume, axial length, and lens status.

Fifty-two eyes of 52 patients (54% treatment naive) were assessed. More than half (51.5%) presented with maximal CRT reduction on SDOCT 2 weeks post injection and almost all had significantly increased CRT at week 4 compared to week 3 or week 2. Eyes that showed no to minimal CRT reduction at week 4 and therefore would have been classified as nonresponders in the usual clinical evaluation were found to have CRT reduction at weeks 2 or 3 post injection. There was a higher proportion of nonresponders and poor responders at week 4 in DME eyes (7 of 12, 58%) compared to wet AMD eyes (6 of 25, 24%). The time to maximal CRT reduction was not related to axial length, age, lens status, or prior history of injections.

The study, presented at the recent ARVO meeting, suggests that almost all nonresponders or poor responders to anti-VEGF therapy are responders if assessed at an earlier time point. The study is the first to describe the treatment response in patients previously considered to be nonresponders. Larger prospective studies are needed to optimize dosing intervals and to assess the benefit of more frequent anti-VEGF treatment in this cohort.

Retina OCTA Scan May Help Identify Alzheimer Disease

Duke study offers clues for early diagnosis.

■ A study of more than 200 people conducted by Sharon Fekrat, MD, and Dilraj Grewal, MD, at the Duke Eye Center suggests the loss of blood vessels in the retina could signal Alzheimer disease (AD). The study was reported in Ophthalmology Retina.

In the eyes of 39 people with AD, the web of microscopic blood vessels in the retina was less dense and even sparse in places as seen with OCT angiography (OCTA) imaging. The differences in density were statistically significant after researchers controlled for factors including age, sex, and level of education, said Dr. Fekrat, the study’s senior author.

“It’s possible that changes in blood vessel density in the retina could mirror what’s going on in the tiny blood vessels in the brain, perhaps before we are able to detect any changes in cognition,” said Dr. Fekrat. She added that previously published studies have suggested that cognitively healthy individuals with preclinical AD have retinal microvascular abnormalities as well as architectural alterations, and that these changes occur at earlier stages of AD. “We are analyzing images right now of asymptomatic persons at genetically high risk for sporadic AD and comparing them to persons who are genetically low risk,” she said.

The Duke study is the largest prospectively imaged group of patients with AD (70 eyes of 39 patients) and with mild cognitive impairment (72 eyes of 37 patients) with a large control group of 254 eyes in 133 patients that resulted in a 4:1 control-to-case ratio. The researchers also assessed structural OCT changes. The data excluded conditions that could confound study findings, such as glaucoma, diabetes, uncontrolled hypertension, and other retinal diseases.

“In collaboration with our neurology colleagues, the ophthalmology profession is poised to have significant impact in the diagnosis of AD and possibly other neurodegenerations,” concluded Dr. Fekrat. “Ultimately, the goal would be to obtain multimodal images of the retina and optic nerve that would result in a suite of biomarkers predicting one’s risk of AD, similar to getting a lipid panel.”

IN BRIEF

Research and industry news in retina.

BY JERRY HELZNER, CONTRIBUTING EDITOR

Novartis Files for Approval of Brolucizumab for Wet AMD

■ Novartis said the FDA has accepted the company’s Biologics License Application (BLA) for brolucizumab (RTH258) for the treatment of wet AMD. Brolucizumab is a humanized single-chain antibody fragment that is the most clinically advanced of its kind to reach this stage of development. Single-chain antibody fragments are highly sought after in drug development due to their small size, enhanced tissue penetration, rapid clearance from systemic circulation, and drug-delivery characteristics. The proprietary innovative structure results in a small molecule (26 kDa) with potent inhibition of, and high affinity to, all VEGF-A isoforms.

Seeking to make brolucizumab available as quickly as possible, Novartis used a priority review voucher to expedite FDA review in 6 months rather than the standard 10 months. If approved by the FDA, Novartis anticipates launching brolucizumab by the end of 2019. The regulatory application is primarily based on phase 3 data from the HAWK and HARRIER trials. The primary endpoint of these studies was noninferiority to aflibercept (Eylea; Regeneron) in mean change in BCVA from baseline to week 48. Novartis noted that HAWK and HARRIER are the first and only global head-to-head trials in patients with wet AMD that prospectively demonstrated efficacy at week 48 starting with a 12-week dosing regimen.

Aerpio DR Therapy Misses Endpoint in Phase 2b

■ Aerpio Pharmaceuticals, a developer of compounds that activate Tie2 to treat ocular diseases and diabetic complications, announced topline 1-year results from the company’s 167-patient TIME-2b study, a phase 2b clinical trial designed to assess the efficacy and safety of its lead candidate, AKB-9778, for patients with moderate to severe nonproliferative diabetic retinopathy.

Subcutaneous self-administration of AKB-9778 twice daily did not meet the study’s primary endpoint of the percentage of patients with an improvement of 2 or more steps in the study eye diabetic retinopathy severity score compared to placebo. The percentage of patients achieving this endpoint for AKB-9779 were 9.6% for twice-daily administration and 9.6% for placebo. In all qualified eyes, the percentage of eyes achieving this endpoint was 8.6% for twice-daily administration and 2.7% for placebo. The rates of progression to sight-threatening complications, including DME and proliferative diabetic retinopathy during the 48-week treatment period were similar between treatment groups.

AKB-9778 did show encouraging data in a number of prespecified key secondary endpoints, consistent with the observations in the prior phase 2a (TIME-2) trial, including changes in urine albumin-creatinine ratio, a measure of kidney function, and in IOP. The company plans to advance a topical drop formulation of AKB-9778 into clinical development and expects to initiate a phase 1b study, with results anticipated by the end of 2019. AKB-9778 also was found to be safe and well tolerated in this patient population through 48 weeks of twice-daily dosing.

Manufacturing Changes Lower DARPin Inflammation Rate

■ Allergan and Molecular Partners announced improvement of inflammation rates for abicipar from the MAPLE study, a 28-week open-label study that enrolled 123 wet AMD patients and evaluated the safety of the DARPin (abicipar pegol) produced via a modified manufacturing process. In this single-arm study, treatment-naïve or prior anti-VEGF-treated patients received 3 monthly 2 mg abicipar injections followed by 2 mg injections every 8 weeks for up to a total of 5 injections through week 28.

As a result of the improvements in the manufacturing process, the companies reported that incidence of intraocular inflammation (IOI) was 8.9% in the MAPLE study, which was lower than the 15% rate observed in prior phase 3 studies. Most IOI events were assessed as mild to moderate in severity. The incidence of severe IOI was 1.6%, with 1 reported case of iritis and 1 reported case of uveitis. There were no reported cases of endophthalmitis or retinal vasculitis in this study. The company says it plans to submit a biologics license application for abicipar in the first half of 2019.

Geographic Atrophy Drug Promising in Phase 1 Study

■ In the phase 1 ReCLAIM study conducted by Stealth Biotherapeutics, 40 mg of mitochondrial-targeted elamipretide, administered by subcutaneous injection daily for 24 weeks, showed encouraging results in both improved visual acuity and greatly increased low-luminance reading ability (mean of +5 lines) in a subgroup of 19 individuals with noncentral geographic atrophy (NCGA). Patient-reported outcomes on the low luminance and VFQ-39 questionnaires demonstrated statistically significant improvement in daily quality-of-life measures, especially those related to low-luminance visual function.

A second 21-patient subgroup of the ReCLAIM study with dry AMD and high-risk drusen but no GA diagnosis also received elamipretide under a similar protocol and also showed mean improvement in visual acuity and low-luminance reading ability at 24 weeks. Elamipretide received fast-track status from the FDA in December. Stealth has recently advanced elamipretide into a 48-week, 180-patient phase 2 study for NCGA.

Researchers led by Scott Cousins, MD, of the Duke Eye Center, reported the data at the recent ARVO meeting. Dr. Cousins noted that individuals with NCGA have significantly better baseline BCVA than people with central GA, with a better potential for vision improvement.

Alkahest Studies Oral Therapy for Wet AMD

■ Alkahest said its oral therapy for wet AMD produced encouraging results in a 29-patient phase 2a study. The data demonstrated that AKST4290, a highly selective and potent small-molecule antagonist of CCR3, was safe, well-tolerated, and provided a mean 7+ letter BCVA increase in treatment-naïve subjects. Approximately 83% of subjects’ eyes had maintenance or improvement of BCVA, while 21% of subjects gained >15 letters. Investigators also observed trends in morphologic changes in retinal pigment epithelium detachment height in correlation with increases in BCVA, which will be further investigated in future trials. No serious adverse events or discontinuations due to adverse events were seen in the trial, and the drug was well tolerated. The ALK4290-201 study was a 6-week oral treatment regimen of AKST4290 400 mg twice per day (800 mg total) in newly diagnosed wet AMD patients.

More AI Information Helps Physicians’ Decision-Making

■ A new study from Google AI Research shows that retina specialists who have access to AI diabetic retinopathy screenings can more accurately diagnose the disease if AI provides them with more detailed information, such as the level of confidence in the AI diagnosis and a more detailed picture of how AI arrived at its diagnosis. Without this assistance, general ophthalmologists were significantly less accurate than the algorithm, while retina specialists were not significantly more accurate than the algorithm. With assistance, general ophthalmologists matched but did not exceed the model’s accuracy, while retina specialists started to exceed the model’s performance.

“What we found is that AI can do more than simply automate eye screening, it can assist physicians in more accurately diagnosing diabetic retinopathy,” said lead researcher, Rory Sayres, PhD. “AI and physicians working together can be more accurate than either alone.”

Ozurdex for Chronic Edema in DR and RVO

■ Researchers from Retinal Consultants of Arizona set out to determine if the Ozurdex dexamethasone implant (Allergan) could be effective in resolving the macular edema (ME) that is one of the most common causes of central vision loss in patients with diabetic retinopathy (DR) and retinal vein occlusion (RVO), because at least 40% of eyes demonstrate an incomplete response to anti-VEGF drugs. This study aimed to evaluate the effectiveness and safety of Ozurdex in treating ME that is persistent despite anti-VEGF treatment.

The study is a retrospective chart review of 36 patients with persistent ME despite anti-VEGF treatment who were treated with Ozurdex. Only patients with at least 3 years of follow-up were included. Baseline demographic information including age, gender, duration of ME, and number and type of anti-VEGF treatments were documented. Primary endpoints included changes in BCVA and central subfield thickness (CST) measured on OCT scans. Secondary endpoints included changes in IOP and cataract formation.

Overall, 49 eyes of 36 patients with ME secondary to nonproliferative diabetic retinopathy (22), proliferative diabetic retinopathy (18), branch RVO (5), and central RVO (4), were included in the study. Mean follow-up was 32.5 months. There was no statistically significant change in BCVA after Ozurdex treatments (mean: 5.9). CST improved by a mean of 104.7 µm. Mean change in IOP was +1.6 mmHg; however, only 4 patients required treatment for ocular hypertension. Cataract progression was documented in 10% of patients, with 5% requiring cataract surgery during the follow-up period.

The researchers, who presented their results at the recent ARVO meeting, concluded that Ozurdex demonstrated anatomical improvement in cases of persistent ME despite anti-VEGF treatment. However, similar gains in vision were not seen in this study. This may be attributable to the chronicity of the edema prior to steroid treatment.

Calcium Does Not Increase AMD Risk

■ Eating a calcium-rich diet or taking calcium supplements does not appear to increase the risk of AMD, according to the findings of a study by scientists at the National Eye Institute (NEI). The study findings were published in JAMA Ophthalmology. The findings contradict an earlier study indicating that high levels of calcium were associated with increased prevalence of AMD, but they are consistent with another suggesting that calcium has a protective role in AMD.

“Although the findings suggest that high calcium intake may be protective, the jury is still out on whether people should alter their calcium intake to prevent the onset or progression of AMD,” said the study’s lead investigator, Emily Chew, MD, deputy clinical director at NEI, which is part of the National Institutes of Health. “These latest findings provide no need to change the management of calcium intake for individuals who are already taking calcium for other medical indications,” Chew said.

DecisionDx Predicts Metastatic Risk in Eye Cancer

■ Castle Biosciences presented 5-year outcomes from a prospective, multicenter study showing that DecisionDx-UM accurately predicts metastatic risk for patients with uveal melanoma. The CLEAR study was designed to track clinical management and metastatic outcomes of patients with uveal melanoma who were tested with the DecisionDx-UM gene expression profile (GEP) test as part of their diagnostic work-up.

“An accurate understanding of metastatic risk is critical to guiding surveillance planning for patients with uveal melanoma since clinicopathologic staging alone is insufficient,” said investigator Thomas M. Aaberg Jr., MD, ocular oncologist with Retina Specialists of Michigan, who presented the study at the International Society of Ocular Oncology 2019 Conference.

In the study, 89 patients from 4 centers were enrolled between March 2011 and January 2017. Median follow-up time for patients without metastasis was 4.7 years.

Overall, 49 patients (55%) had a low-risk class 1 test result; 40 patients (45%) had a high-risk class 2 test result. All patients with class 2 test results were managed with high-intensity surveillance (imaging and/or liver function tests every 3 to 6 months), while 80% of class 1 patients were managed with low-intensity surveillance (imaging and/or liver function tests at a maximum of once each year).

Three (6%) class 1 patients and 22 (55%) class 2 patients developed metastasis. Median time to metastasis was 3.2 years for class 1 and 2.5 years for class 2. Five-year metastasis-free survival rates were 92% for class 1 and 42% for class 2. These findings are consistent with results from previously published prospective studies documenting the accuracy of DecisionDx-UM and impact on patient management.

Regeneron Makes Major Investment in RNA Interference Therapy

■ Regeneron said it would invest up to $800 million as part of a collaboration with Alnylam Pharmaceuticals to discover, develop, and commercialize new RNA interference (RNAi) therapeutics for a broad range of diseases by addressing disease targets expressed in the eye and central nervous system, in addition to a select number of targets expressed in the liver. The collaboration will leverage both companies’ scientific and technological expertise and will build on Alnylam’s recent preclinical data showing potent and highly durable delivery of RNAi therapeutics to achieve target gene silencing in the eye and central nervous system. The collaboration will also encompass Regeneron’s VelociSuite technologies and capabilities from the Regeneron Genetics Center.

Online Diagnoses a Recipe for Misinformation

■ People who went online to get a diagnosis of their eye problems from WebMD Symptom Checker in 2017 had a 74% chance of being misdiagnosed, according to a study led by Carl Shen, MD, an ophthalmology resident at McMaster University in Canada. The study was recently reported in JAMA Ophthalmology.

The WebMD diagnosis at times recommended self-care at home when the patient should have been headed for an emergency room. In conducting the study, 42 clinical scenarios with a known and accurate diagnosis were put into the WebMD Symptom Checker. The correct diagnosis appeared within the top 3 online results 40% of the time but was not mentioned in 43% of the cases.

The online checker also failed at correctly evaluating the severity of emergency cases. In about 60% of the cases, the WebMD symptom checker gave incorrect advice as to what the patient should do next, sometimes recommending home care when immediate treatment was the better choice. WebMD has since updated its algorithms.

Apellis Resumes Dosing in Phase 3 GA Trials

■ Apellis Pharmaceuticals, which focuses on treating retinal disease through the inhibition of the complement system, announced that with the agreement of the independent safety monitoring committee for the company’s phase 3 clinical program for APL-2 in patients with geographic atrophy (GA), the company has resumed enrollment in its 2 phase 3 GA trials, DERBY and OAKS, with intravitreal APL-2.

“Patient safety is our first priority and we feel that we can now reinitiate our phase 3 program for patients with geographic atrophy with confidence following an in-depth investigation and modifications to the manufacturing process,” said Cedric Francois, CEO and cofounder of Apellis. “We remain on track for full enrollment by the end of the first quarter of 2020, as originally guided.”

The APL-2 intravitreal drug product produced from the modified manufacturing process was introduced into the company’s ongoing phase 1b trial in low-vision patients with GA. Ten patients in the trial have received at least 1 intravitreal injection of APL-2 manufactured through the modified process and there has been no inflammation observed in any patient injected with APL-2 from this new manufacturing lot.

“Geographic atrophy is a major cause of visual impairment across our society, profoundly and negatively impacting routine activities like driving and reading, leading to loss of independence and inability to perform every-day life activities,” said Charles Wykoff, MD, PhD, director of research at Retina Consultants of Houston and investigator for the Apellis phase 1b, 2, and 3 trials. “It is incredibly frustrating to patients and physicians that there are no approved treatments for this common, blinding disease. It is an important and exciting step forward to be reinitiating these phase 3 trials as it brings much needed hope to the GA community.”

In October, Apellis said the company had voluntarily implemented a pause in dosing in the DERBY and OAKS phase 3 trials due to observed cases of noninfectious inflammation in patients treated from a single manufacturing lot of APL-2 intravitreal investigational material. Inflammation in all affected patients was resolved. RP