SUBSPECIALTY NEWS: Port drug delivery in DME, integrin inhibitors, treatment for XLRP, eye drops for DME, gene therapy, and more.


Genentech Begins PDS Test in DME

Noninferiority study will enroll nearly 550 patients.

■ Genentech and Roche have initiated a new phase 3 clinical trial investigating the Port Delivery System with ranibizumab (PDS) in individuals with diabetic macular edema (DME). The PDS is an investigational first-of-its-kind refillable eye implant designed to continuously release a customized formulation of ranibizumab over a period of months.

The PAGODA trial is a multicenter, randomized, active-comparator, noninferiority study that will evaluate the efficacy, safety, and pharmacokinetics of the PDS for the treatment of DME. In total, nearly 550 patients with DME will be randomized to receive either the PDS 100 mg/mL refilled at fixed 6-month intervals or monthly intravitreal injections of ranibizumab 0.5 mg. The primary endpoint of PAGODA is the change in BCVA from baseline averaged over weeks 48 and 50. The PDS includes an implant, ancillary devices, and ranibizumab. The PDS allows continuous delivery of ranibizumab and thus is intended to reduce the burden of frequent eye injections by allowing people with DME to potentially go several months before needing a refill of the implant, and to address undertreatment that could lead to vision loss.

“We are excited that patient enrollment in PAGODA has begun. This is the first clinical trial to investigate the PDS in DME,” said Anne Fung, MD, global development lead of the PDS at Genentech and a practicing retina specialist in San Francisco, California. “While we have effective therapies for DME, the treatment burden on patients can be high, with as often as monthly injections. With the PDS, our hope is that these patients may be able to go up to 6 months between treatments.”

The PDS is also being studied in patients with wet AMD in the phase 3 Archway trial, which recently completed patient enrollment. The Archway trial was initiated based on the results of the phase 2 LADDER study, announced last year, which showed that nearly 80% of patients in the PDS 100 mg/mL arm were able to go 6 months or longer between the implant of the device and the first required refill.

AGTC Reports Positive Trial Data in XLRP

Improvements seen in visual function, BCVA.

■ Applied Genetic Technologies Corporation (AGTC) reported positive interim 6-month data from its ongoing phase 1/2 clinical program in X-linked retinitis pigmentosa (XLRP). The results show that patients treated centrally with its product candidate demonstrated durable improvement in visual function 6 months after dosing.

“These promising results further demonstrate that our XLRP candidate has tremendous potential to provide meaningful benefit to XLRP patients who today have no treatment options,” said Sue Washer, president and CEO of AGTC. “The positive results observed to date give us confidence that the data as a whole will support advancement of our XLRP clinical program to a pivotal trial in 2020.”

Of the 17 patients for whom there are current trial data, 8 peripherally treated patients showed stable visually function through 6 months, and 9 centrally treated patients showed improvement in visual function as measured by microperimetry and/or BCVA at both 3 and 6 months. At the 6-month time point for the same 9 centrally dosed patients, measurable improvements were observed in visual sensitivity for 4 of the evaluable 8 patients. All 9 patients treated centrally also had stable or improving visual acuity, with 78% seeing a 5-letter or more improvement.

Patients who had improvement in either visual sensitivity or BCVA also anecdotally reported noticeable improvement in visual function, including greater clarity and reduced night blindness. Preliminary data for additional patients enrolled at a new higher dose group are consistent with previous data.

AGTC also reported promising biologic activity and a positive safety profile in 2 early-stage clinical trials for achromatopsia. These data, encompassing a total of 22 patients, also demonstrate positive changes in light discomfort testing and encouraging patient anecdotes describing real-world improvements in visual function. The company is currently dosing 2 higher-dose groups in adults and 3 groups of pediatric patients at the 3 highest dose groups in both trials.

Oxurion Reports Positive Early Data in DME

Integrin antagonist shows rapid onset of action.

■ Oxurion has reported positive top-line data from a phase 1 study of THR-687, a novel, potent, pan-RGD (arginylglycylaspartic acid) integrin antagonist for the treatment of DME. The open-label, multicenter, single dose-escalation study evaluated the safety of a single intravitreal injection of 3 increasing doses (0.4 mg, 1.0 mg, 2.5 mg) of THR-687. Patients recruited into the study had a history of response to prior anti-VEGF and/or corticosteroid treatment. At baseline, the study population had a mean best-corrected visual acuity (BCVA) of 56 letters, and a mean central subfield thickness (CST) of 542 µm.

Top-line data from the 12-patient trial show that THR-687 is well tolerated and safe with no dose-limiting toxicities. No serious adverse events were reported at any of the doses evaluated in the study. Across all doses, a rapid onset of action in mean BCVA was observed from day 1 with an increase of 3.1 letters, which further improved to 9.2 letters at month 1. This activity was maintained with a mean BCVA improvement of 8.3 letters at month 3 following a single injection of THR-687.

A clear dose response was seen with the greatest positive effect on BCVA and CST, with the highest dose of THR-687. For this highest dose, a mean BCVA Improvement of 11 letters was noted at day 14, with a peak improvement of 12.5 letters at month 3. Similarly, a peak mean CST decrease of 106 µm was observed at Day 14 with the highest dose.

THR-687 is the second VEGF-independent clinical candidate in development for diabetic eye disease by Oxurion. THR-149, the company’s other and most advanced VEGF-independent treatment, also delivered positive phase 1 results in July 2019.

Arshad Khanani, MD, MA, director of clinical research at Sierra Eye Associates in Reno, Nevada, and clinical investigator in this study, said: “The top-line data from this phase 1 study show that THR-687 is safe and well tolerated at all of the dose levels tested. I am very encouraged to see excellent signs of efficacy so quickly post treatment. We also noticed a durability of effect on the patient’s vision as measured by BCVA following just a single injection of THR-687. This promising initial data indicate that THR-687 could have the potential of being an effective monotherapy for patients with DME.”

Oxurion said it plans to begin a phase 2 study of THR-687 in treatment-naive DME patients later this year.

Oculis Has Positive Early Data on DME Eye Drop

Vision gain along with reduced CMT

■ Switzerland-based Oculis has reported positive data from a 133-patient, phase 2 study of OCS-01, a novel eye drop formulation of dexamethasone, in development for the treatment of DME. OCS-01 was developed using the company’s proprietary Soluble NanoParticle technology (SNP), which acts as an ocular drug carrier to enhance bioavailability of drugs in the posterior segment of the eye.

The study was a prospective, multicenter, randomized, double-masked, parallel group, vehicle-controlled study. Type 1 or 2 diabetic patients with DME and central macular thickness (CMT) of ≥310 μm by SD-OCT and ETDRS BCVA letter score ≤73 and ≥24 in the study eye were randomized to treatment with OCS-01 or matching vehicle eye drops, 1 drop 3 times per day for 12 weeks. About two-thirds of the patients in each group were treatment-naive. Efficacy was evaluated based on the change from baseline to week 12 of CMT and ETDRS BCVA letter score. Safety was assessed in terms of adverse events and ophthalmology examination.

Mean CMT showed a greater decrease from baseline in the OCS-01 group than the vehicle arm at week 12 (-53.6 μm vs -16.8 μm, P=.0115). Mean change in ETDRS BCVA letter score from baseline to week 12 was higher in the OCS-01 group than the vehicle group (+2.62 letters vs +1.04 letters, P=.125). P values met the prespecified conditions in the protocol for statistical superiority of OCS-01 vs vehicle. Local ocular tolerability was not significantly different between the OCS-01 and vehicle groups, with the exception of change in intraocular pressure. Increase in intraocular pressure was more common with OCS-01 than vehicle during the treatment period, consistent with known dexamethasone effects.

New Study of KSI-301 Focuses on Durability

A majority of patients extended to 4 months or longer.

■ Kodiak Sciences has announced additional positive safety, efficacy, and durability data from the ongoing phase 1b study of its investigational therapy KSI-301, an intravitreal anti-VEGF antibody biopolymer conjugate, in patients with treatment-naïve wet AMD, DME, and RVO.

“With further maturation of the phase 1b study, the safety and efficacy of KSI-301 continue to be very encouraging, and we continue to see the potential for KSI-301 to have class-leading durability across all of the common retinal vascular diseases,” said Jason Ehrlich, MD, PhD, CMO of Kodiak Sciences. “Our belief is that a next-generation biologic should bring nearly all wet AMD and DME patients to a 3-month or longer dose interval and the majority of RVO patients to a 2-month or longer interval.

Dr. Ehrlich added that the data presented recently at Angiogenesis 2020 showed that 84% of wet AMD eyes and 76% of DME eyes were extended to 4 months or longer after the last loading doses before receiving their first retreatment. Also, 55% of wet AMD eyes and 64% of DME eyes were extended to 6 months. In RVO, more than half of the study patients were extended beyond 3 months after 3 loading doses and without receiving retreatment.

“Compared to the data previously presented, more patients have been followed for longer intervals. The safety, efficacy, and durability data continue to be robust and are suggesting the potential for KSI-301 to demonstrate a novel generation 2.0 durability profile,” said Victor Perlroth, MD, CEO of Kodiak Sciences. “We are very pleased with what we continue to learn about the clinical performance of KSI-301 in this exploratory study, and we are using the data to thoughtfully design high-conviction pivotal studies of KSI-301 in each of the core indications.”

KSI-301 has shown an encouraging safety profile, with zero cases of intraocular inflammation after 420 doses in 130 patients.

Gene-Derived Anti-VEGF Saw No Retreatment at 50 Weeks

Adverum reports that cohort 1 remains rescue free.

■ Adverum Biotechnologies said the first cohort of 6 patients in its OPTIC 1 phase 1 trial for gene-derived anti-VEGF in wet AMD reached the 50-week median with no rescue injections needed. The mean change in BCVA at the 50-week median was -1 letter. The mean change in central retinal thickness at 50 weeks was -25.5 microns.

In addition, Adverum released the first data on cohort 2. Given a threefold lower dose than the patients in cohort 1, 4 of the 6 patients in cohort 2 did not need rescue injections at week 24. The mean change in BCVA at the 24-week mark was -4.8 letters for the full cohort, with the mean loss in BCVA for the rescue-free patients less than 1 letter.

“I am very encouraged that this difficult-to-treat patient population enrolled in OPTIC is maintaining vision and anatomical improvements for an extended period of time,” said David S. Boyer, MD, senior partner, Retina-Vitreous Associates Medical Group. “Additionally, ADVM-022 continues to be safe and well tolerated, with ocular inflammation that is manageable with steroid eye drops. Patients with wet AMD and their caregivers carry a significant treatment burden from the current standard-of-care anti-VEGF injections, and real-world vision outcomes are suboptimal due to undertreatment. ADVM-022 as a one-time intravitreal injection therapy could transform the treatment paradigm for patients and their caregivers.”

Aaron Osborne, MBBS, chief medical officer of Adverum, added, “OPTIC is progressing well, with the key objectives for cohorts 3 and 4 being to further evaluate dose response and to assess a 6-week prophylactic course of steroid eye drops instead of the 13-day oral steroid prophylaxis used in cohorts 1 and 2.”

In related news, Adverum plans to begin a phase 1/2 clinical trial for ADVM-022 in diabetic retinopathy later this year.


Research and industry news in retina.


Coronavirus Kills Chinese Ophthalmologist Who Warned About the Illness

■ Li Wenliang, 34, an ophthalmologist at Wuhan Central Hospital in China who had issued an early warning about the deadly coronavirus and been censured by authorities for spreading rumors, died of the illness in early February. A statement from the hospital confirmed his death from the virus, which he contracted while treating coronavirus patients. Chinese social media erupted with messages of sadness and outrage, with many bloggers calling the doctor a hero.

Aflibercept Reduces Vision-Threatening Events in NPDR

■ Regeneron announced positive 2-year results from the 402-patient phase 3 PANORAMA trial evaluating Eylea (aflibercept) injection 2 mg (0.05 mL) in patients with moderately severe to severe nonproliferative diabetic retinopathy (NPDR). The 2-year prespecified exploratory data demonstrate that untreated moderately severe and severe NPDR can lead to vision-threatening events, which includes vision-threatening complications (VTCs; proliferative diabetic retinopathy or anterior segment neovascularization) and center-involved diabetic macular edema (CI-DME). Based on a Kaplan-Meier analysis, more than half (58%) of patients in the untreated sham arm developed a VTC or CI-DME within 2 years of entering the trial, while EYLEA treatment was shown to reduce the likelihood of these vision-threatening events by at least 75%.

“These data reinforce that regular EYLEA treatment can be highly effective at reducing the risk of new vision-threatening events among patients with moderately severe to severe non-proliferative diabetic retinopathy,” said Charles C. Wykoff, MD, PhD, PANORAMA investigator, retina surgeon and ophthalmologist with Retina Consultants of Houston. “The PANORAMA trial shows that more than half of all untreated patients developed vision-threatening events over 2 years, underscoring the value of treating patients proactively and regularly.”

In other Regeneron news, the company recently reported that fourth-quarter Eylea US net sales increased 13% to $1.22 billion vs fourth quarter 2018 and full year 2019 Eylea US net sales increased 14% vs 2018.

Lineage Gets Go-Ahead to Accelerate Dry AMD Study

■ Based on promising preliminary results from its ongoing phase 1/2 clinical study for dry AMD, including using its new thaw-and-inject formulation of OpRegen with Gyroscope Therapeutics’ Orbit Subretinal Delivery System (SDS), Lineage Cell Therapeutics has been informed by the study’s independent data safety monitoring board that the protocol-mandated treatment stagger can be removed. In addition, Lineage is opening 2 new clinical sites to accelerate patient enrollment and broaden surgical experience among dry AMD experts.

All 5 patients in cohort 4, those with better baseline vision and that represent the company’s intended patient population, have shown increases in BCVA. Notably, the first cohort 4 patient dosed with both the company’s new thaw-and-inject formulation and Orbit SDS, gained 25 readable letters (or 5 lines) at 6 months following administration of OpRegen RPE cells as assessed by the Early Treatment Diabetic Retinopathy Scale (ETDRS).

Notal Vision Gets CPT Codes for AMD Monitoring

■ Notal Vision, Inc., a privately held ophthalmic diagnostic services company extending disease management from the clinic to the home, said the American Medical Association’s (AMA) current procedural terminology (CPT) editorial panel has established 3 new category III codes (0604T, 0605T, 0606T) to report patient-initiated remote retinal OCT scans, performed using Notal Vision’s home-based OCT pipeline technology.

“This milestone marks the first step toward establishing physician and patient reimbursement for our home OCT pipeline technology,” said Kester Nahen, PhD, CEO of Notal Vision. “We applaud the AMA’s CPT editorial panel for establishing codes for billing remote diagnostic services and patient home monitoring services. We believe that a home-based OCT will be the future of monitoring patients with wet AMD, one that allows doctors to individualize their patients’ treatment.”

The new CPT codes allow for billing for the initial device provision, set-up, and patient education on use of the home OCT, as well as a means for the company’s Notal Vision Diagnostic Clinic to provide technical support, data analyses, and reports to physicians and patients who can benefit from this technology. Prescribing physicians or other qualified health care professionals will be able to bill for reviewing, interpreting, and reporting data analyses every 30 days.

Study: Treat-and-Extend Matches Monthly Regimen

■ In the CANTREAT randomized clinical trial of 580 patients with treatment-naive choroidal neovascularization secondary to acute macular degeneration, Canadian researchers found that at month 24, visual acuity outcomes in the treat-and-extend group were not worse than those in the monthly group. All patients were treated with Lucentis. This outcome occurred despite a mean of 17.6 injections and visits in the treat-and-extend group compared with 23.5 in the monthly group.

Iveric bio Sets Pivotal Trial Design for Zimura in GA

■ Iveric bio has announced the design of the second pivotal clinical trial for Zimura (avacincaptad pegol), a novel complement C5 inhibitor, in development for the treatment of geographic atrophy (GA) secondary to dry AMD. This second trial will be an international, multicenter, double-masked, sham-controlled clinical trial.

The company plans to enroll approximately 400 patients to be randomized to receive monthly administration of Zimura 2 mg or sham during the first 12 months of the trial. The prespecified primary endpoint, mean rate of change in GA growth over 12 months, will be measured by fundus autofluorescence based on readings at 3 time points (baseline, month 6, and month 12) consistent with the previous Zimura pivotal clinical trial design. At month 12, the company plans to re-randomize patients in the Zimura 2 mg arm to receive either monthly or every-other-month administration of Zimura 2 mg. The final evaluation will occur at month 24.

Bionic Eye Provides Functional Vision in Study

■ Bionic Vision Technologies (BVT) has announced interim results of a pilot study involving 4 patients with late-stage retinitis pigmentosa (RP) implanted with a visual prosthesis designed to improve awareness of external objects and patient surroundings. Results demonstrated improved combined performance of all 6 functional vision tests at 44 weeks of active use of the device.

“Based on these positive results, BVT intends to initiate a worldwide clinical trial for the commercialization of our Gen3 device, which will offer improved performance and usability as well as a streamlined external design, similar to the appearance of traditional eyeglasses,” said Ash Attia, CEO.

This current 2-year pilot study, being conducted at the Centre for Eye Research Australia (CERA) and the Bionics Institute in Melbourne, Australia, involves 4 adult participants with near total blindness caused by RP. Each study participant was unilaterally implanted with the BVT Gen2 suprachoroidal visual prosthesis in the eye with the least remaining vision. Mobility testing was initiated after a 2-month surgical healing period, followed by a 16-week period of vision rehabilitation training. Participants were asked to complete a series of 6 tests at 17 weeks following training and then at 3 monthly intervals from week 20 with the device turned both “on” and “off” to assess performance. Data will continue to be collected for up to 104 weeks.

The most significant improvement was observed with the “primary obstacle avoidance task,” which relies on participants identifying obstacles in their pathway. At 44 weeks, patients detected 74.3% of obstacles when the device was turned on, compared to only up to 4% of obstacles when the device was turned off. Considerable improvement was also recorded for the “location task,” which relies on study participants identifying and touching an object similar to the shape of a window on a wall. At 44 weeks, subjects were able to locate and touch the window 70.3% of the time when the device was turned on, compared to only up to 24.4% of the time when the device was turned off.

IRIS Receives Microsoft Grant for AI Initiative

■ Intelligent Retinal Imaging Systems (IRIS), an industry leader in telemedicine solutions for diabetic retinal evaluation, has been named as one of 6 initial grantees for the Microsoft AI for Health Initiative. AI for Health, Microsoft’s newest initiative under their AI for Good program, will encompass a $40 million, 5-year program that will leverage AI to empower organizations like IRIS, and other companies in the realm of improving health.

“It has always troubled me when patients would come into my practice with severe late-stage eye damage and I couldn’t do anything to save their eyesight,” said Sunil Gupta, MD, a retinal surgeon and the founder of IRIS. “The opportunity to work with some of the most talented people in the world at Microsoft means that together we will generate new ideas and insights that will ultimately improve access to care, improve our ability to find and treat retinal disease earlier, all the while allowing us to more successfully save eyesight.”

Microsoft’s collaboration in the development of an AI solution will empower IRIS to bring retinal evaluations to underserved populations across the globe in an effort to end preventable blindness.

As a current example, IRIS has been working with West Virginia University Eye Institute’s retina specialists to bring diabetic retinopathy screening to primary care providers in the state. To date, more than 5,400 patients have been screened across 10 participating sites, including WVU Medicine outpatient clinics in Morgantown, Fairmont, Reedsville, and Harpers Ferry, as well as multiple Community Care of West Virginia and Valley Health Systems sites. Of those, approximately 21% had evidence of diabetic retinopathy. Moreover, the IRIS scan detected other ophthalmic pathology, such as glaucoma, cataract, or macular degeneration, in 28% of scanned patients.

Gemini Begins Phase 1 Study in Dry AMD

■ Gemini Therapeutics has initiated enrollment in its phase 1 study of GEM103, a recombinant, native complement factor H (CFH) for the treatment of dry AMD.

“Gemini was founded to deliver precision medicines for eye disorders by combining genetic insights with clinical and biological expertise in complement. We are excited to take GEM103 into the clinic as a novel approach in complement modulation for a devastating disease with no therapeutic options,” Jason Meyenburg, CEO of Gemini, said in a news release. “We look forward to top-line data from this study and the potential to initiate a phase 2 study, supported by data from our ongoing CLARITY natural history study examining the pathogenesis and progression of dry AMD in patients carrying CFH risk variants.”

Complement factor H risk variants are reported to occur in more than 40% of patients with dry AMD and are strongly associated with the risk of developing the disease. The complement system, of which CFH is a modulator, is dysregulated in patients with these risk variants and results in amplification of aberrant inflammatory responses in the eye. Over time, this dysregulation leads to damage to the macula. GEM103 is a fully functional recombinant native CFH protein intended to address dysregulation caused by loss of CFH function variants in the eyes of these AMD patients.

MacuLogix Launches Upgraded Dark Adaptometer

■ MacuLogix announced the next generation of dark adaptation functional testing with the introduction of the AdaptDx Pro guided by Theia. The company’s original AdaptDx automated dark adaptometer was introduced in 2014 and has since been used by more than 1,000 eye care professionals to identify and monitor AMD. The new AdaptDx Pro headset was custom designed and tested for patient comfort and includes all the functionality and accuracy of the company’s tabletop dark adaptometer. As a self-contained wearable headset, the AdaptDx Pro requires no darkroom or external computer and features an artificial intelligence-driven onboard technician called Theia. After the in-office technician selects the testing protocol and places the device on the patient’s head, Theia takes over to facilitate a reliable, consistent testing experience by using automated instructions and adaptive feedback spoken directly to the patient.

“What makes the AdaptDx Pro so special is that it combines high-tech innovation and high-touch patient care without sacrificing functionality or results,” says William McPhee, president and CEO of MacuLogix.

Editas to Begin First Gene Editing Trial

■ Editas Medicine, which uses CRISPR gene editing to treat a range of serious diseases, said it will dose the first patient in the Brilliance clinical trial of EDIT-101 for the treatment of Leber congenital amaurosis 10 (LCA10) in the first quarter of 2020, and it will complete dosing the adult low- and mid-dose cohorts by the end of the year. Editas is partnering with Allergan in this indication and in 2 other indications: Usher syndrome 2A and autosomal dominant retinitis pigmentosa.

Topical Therapy Being Developed for Retinal Diseases

■ Exonate, an early stage biotechnology company, has entered into a strategic collaboration agreement with Janssen Pharmaceuticals, Inc., one of the Janssen Pharmaceutical Companies of Johnson & Johnson. Through the collaboration, Exonate will work with Janssen Research & Development scientists to develop an eye drop treatment for retinal vascular diseases such as wet AMD and DME by using mRNA targeted therapies. Exonate has developed small molecules that inhibit the production of proangiogenic VEGF through the selective inhibition of serine/threonine-protein kinase-mediated VEGF splicing.

EyePoint to Study Tyrosine Kinase Inhibitor

■ EyePoint Pharmaceuticals has signed an exclusive license agreement with Equinox Science, LLC to develop vorolanib, a tyrosine kinase inhibitor, for the treatment of wet AMD, diabetic retinopathy, and retinal vein occlusion. Vorolanib is being developed as EYP-1901 using Eyepoint’s bioerodible Durasert technology, a miniaturized, injectable, sustained-release intravitreal drug delivery system with a 6-month duration. The company recently completed a positive type B pre-investigational new drug meeting with the FDA, clarifying the pathway for a phase 1 clinical trial. The company expects this phase 1 trial to provide data in the second half of 2021.

Ocuphire Licenses Oral Drug for DR and DME

■ Ocuphire Pharma has entered into an agreement with Apexian Pharmaceuticals, granting Ocuphire an exclusive worldwide sublicense to Apexian’s Ref-1 Inhibitor program, including its lead drug candidate, APX3330, for all ophthalmic and diabetic indications. The drug APX3330 is a first-in-class, orally administered, small-molecule drug candidate that selectively targets and inhibits the Ref-1 (reduction-oxidation effector factor-1) protein, a novel upstream regulator of critical transcription factors controlling inflammatory and angiogenesis pathways that are implicated in diabetic retinopathy and diabetic macular edema. APX3330 may improve eye health in patients with diabetes by reducing inflammation, hypoxia signaling, and abnormal angiogenesis.

The drug has been dosed twice a day in more than 400 subjects across 11 phase 1 and phase 2 trials, with few systemic adverse events reported and clinical data that supports chronic administration. Mark R. Kelley, MD, associate director of basic science at Indiana University Simon Cancer Center, discovered and characterized the Ref-1 target and its mechanisms and led the team that identified APX3330 as an effective Ref-1 inhibitor. Dr. Kelley co-founded Apexian, which initially explored APX3330’s utility in advanced solid tumors, with recent presentations at scientific meetings, and then ophthalmic and other clinical indications. Based on APX3330’s clinical and preclinical data, Ocuphire plans to begin a phase 2 proof-of-concept study in nonproliferative diabetic retinopathy and diabetic macular edema in 2020. RP