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Clinical Focus

Ehsan Rahimy, MD, speaks on the highlights of a study he presented at this year's virtual AAO 2020 meeting that aimed to integrate an artificial intelligence screening system for managing diabetic retinopathy referrals in a primary care setting — with limited specialty support.



Read and watch more AAO 2020 coverage here

Ehsan Rahimy, MD, speaks on the highlights of a study he presented at this year's virtual AAO 2020 meeting that aimed to integrate an artificial intelligence screening system for managing diabetic retinopathy referrals in a primary care setting — with limited specialty support.

Integrating AI to manage DR in a primary care setting

Kriya is developing gene therapies targeting chronic diseases such as geographic atrophy, trigeminal neuralgia, and type 1 diabetes.

Kriya Therapeutics raises $313.3 million in funding

Research reveals that GLP-1 medications, including semaglutide, do not increase diabetic retinopathy risks, offering reassurance for patients and prescribers.

Q&A: Andrew J. Barkmeier, MD, on the risk of sight-threatening diabetic retinopathy with GLP-1 RA use

Annexin Pharmaceuticals initiates a Phase 2a study for ANXV in diabetic retinopathy to explore new treatment options and improve patient outcomes.

UK MHRA approves phase 2a study for ANXV for diabetic retinopathy

A new study highlights the effectiveness of ERG/pupillometry in predicting diabetic retinopathy progression, surpassing traditional imaging methods.

Study identifies electroretinography/pupillometry as top predictor of DR progression, vision-threatening complications

The agreement is for a planned clinical trial of AXPAXLI (also known as OTX-TKI) for the treatment of non-proliferative diabetic retinopathy (NPDR).

Ocular Therapeutix secures FDA SPA agreement for AXPAXLI registrational trial

Ultra-wide field imaging shows non-perfusion and leakage independently predict diabetic retinopathy progression, suggesting earlier treatment with anti-VEGF or photocoagulation may prevent complications.

Retinal Non-Perfusion Reveals Advanced Diabetic Eye Risk

Yasha S. Modi, MD, associate professor of ophthalmology at NYU Langone Health, discusses highlights from his presentation, "Retinal Nonperfusion in 

," that he presented during the 2025 Retina World Congress annual meeting.

"What we were looking at was really to go and say, relative to the DRSS, kind of like the gold standard for diabetic retinopathy staging, is there value in looking at leakage and nonperfusion? And whether you look at the posterior pole or the far periphery–sort of has that which has been described in the DRC, our protocol, Protocol AA," Modi said.

"What we see is that by ultra-wide field FA, both nonperfusion and leakage, independent of the diabetic retinopathy scoring system, carries an increased risk of progressing to more advanced forms of diabetic retinopathy. So this becomes clinically relevant when you think you have somebody with what would otherwise be moderately severe or very severe NPDR, and in order to really, truly understand their risk, I believe that we probably need imaging in the form of ultra wide field imaging and perhaps earlier treatment, whether that's in the form of anti-VEGF medications or panretinal photocoagulation before a complication occurs."

The research builds on decades of ophthalmological understanding, tracing back to the ETDRS findings in 1991 that identified leakage and nonperfusion as risk factors. Modern imaging technologies now allow for more precise identification and potential targeted treatments.

"So when we think about anti-VEGF and its effect on nonperfusion, I think there's a really interesting literature that we learned by looking back at clinical trials. And from the earliest RISE and RIDE studies, which FDA-approved ranibizumab for the treatment of diabetic macula edema, what we have learned is that when you give anti-VEGF on a monthly basis, nonperfusion remains relatively stable, as opposed to the sham arm, where nonperfusion continues to grow," Modi said.

"Now, if you look at Charlie Wyckoff's study from recovery, he asked the question, is it dose dependent? In other words, if you're injecting the medication on a quarterly basis versus a monthly basis, is there some value in doing it less frequently? And the answer is that nonperfusion continued to progress when you gave aflibercept every quarter, but when you give it every month, it appeared to have some stabilizing effects on nonperfusion.

The caveat is that at no point in time in any study have we been able to definitively demonstrate a improvement to nonperfusion. So whatever level of nonperfusion we start with, that's effectively what we're going to end with in the best case scenario. But it does sort of provide some sort of evidence to say that anti-VEGF may modulate progression of nonperfusion when given very frequently, but doesn't reverse it."

Key findings include the potential for earlier intervention through ultra-wide field imaging. When patients exhibit classic signs like four dot plot hemorrhages, two quadrants of venous speeding, and one quadrant of Intraretinal Microvascular Abnormalities (IRMA), clinicians should immediately pursue advanced imaging.

Videos

Ultra-wide field imaging shows nonperfusion and leakage independently predict diabetic retinopathy progression, suggesting earlier treatment with anti-VEGF or photocoagulation may prevent complications.

Retinal nonperfusion reveals advanced diabetic eye risk

Priya Vakharia, MD, spoke with our team about her presentation at the Women in Ophthalmology Summer Symposium being held in Marco Island, Florida.

- This transcript has been edited for clarity.

We're joined today by Dr. Priya Vakharia who is presenting at this year's WIO or Women in Ophthalmology conference in Marco Island, Florida. Welcome to you. We're so delighted to have you. And so curious to hear about an update on the novel ref-1 inhibitor for the treatment of diabetic retinopathy. Can you tell us about your presentation?

Thank you. Thank you so much for having me. So my presentation focuses on an oral pill that can be used, that was used in a phase 2 trial to see if it could prevent progression of diabetic retinopathy. So first, let's talk about a little bit of background when it comes to the treatment of diabetic retinopathy. We've had a lot of studies in the retina space showing that anti-VEGF injections can be given to patients at regular intervals, and that, you know, helps with progression of DRSS scores, or diabetic retinopathy severity scores. And so we know that anti-VEGF injections work, but this is a novel mechanism looking at an oral pill that inhibits a transcription factor called rev-1. And this transcription factor is actually upstream in the cascade of inflammation in angiogenesis. You know, further downstream we have our more common VEGF molecule, but this is much more upstream in that cascade to see if by taking this pill, can you get similar results in terms of improvement at DRSS. So this was a phase 2, randomized, placebo-controlled trial, in which patients got randomized 1:1 to either get APX3330, which is the ref-1 inhibitor versus a placebo control. And so there were 103 patients in the study. And in this study, you know, the primary endpoint was looking at two step improvement in diabetic retinopathy severity score at week 24. That's the typical endpoint that we've historically been looking at with anti-VEGF studies. And at week 24 patients on the APX3330 arm had the same percentage of improvement of that two step DRSS compared to placebo. So this study did not meet its primary endpoint. However, when you look at the patients who actually had worsening, so three step worsening of DRSS, none of the patients in the APX3330 arm had worsening. Whereas there were patients in the placebo arm that had worsening specifically there were 16%. And so that brings up the question that perhaps this inhibitor is, while it may not be improving disease, perhaps it's preventing worsening, and the theory makes sense, because this ref-1 inhibition could just promote physiologic VEGF states rather than decreasing it like our traditional anti-VEGF. And so that's the summary of the study.

It's fascinating, really that research. Is there anything else that you'd like to add that we haven't even touched upon?

I think the next steps for this study would be to go back to the FDA for the phase three and see if this is an approvable endpoint, you know, this is three step worsening. This is binocular three step worsening, which I didn't mention before. So there is a meeting slated with the FDA to see that if to see if the binocular three step worsening could be an approvable endpoint for a phase three trial. So those are kind of the next steps from here. And we look forward to updating everyone as as that information becomes more clear.

WIO 2023: ZETA-1 phase 2 trial safety and tolerability results for APX3330

Kerrie Brady, BPharm, MBA, MS, Chief Executive Officer and President of OcuTerra Therapeutics spoke with our team about some updates from the company including the development of OTT166 at the 2023 ASRS annual meeting.

[I'm] Kerrie Brady, Chief Executive Officer and President of OcuTerra Therapeutics. We're an ophthalmology-focused biotech company based in Boston. [The] focus of our pipeline is developing OTT166, which is a selective integrant inhibitor, [in] which the molecule has been engineered so that it can be delivered via an eyedrop. We have very compelling Phase 1b data in patients, showing that the molecule gets to the retina and has a significant biological effect after eyedrop administration. Just last week, we announced the big news that we are fully enrolled our Phase 2 trial, the Diabetic Retinopathy: Early Active Management trial, [or] the DR:EAM study. In this study, we're testing 2 dose levels of our eyedrops OTT166 in patient population that have nonproliferative diabetic retinopathy, moderately severe to severe. Also, a portion of patients who have proliferative diabetic retinopathy but mild. All the patients do not yet have vision threatening complications, such as diabetic macular edema. The aim of the study is to determine if we can not only improve the health of the retina, but also delay or prevent progression to a vision threatening complication, which would then require some invasive treatment. The study population that we have are 225 patients. This study has been conducted entirely in the US, and we look forward to bringing you news of our topline results in the first quarter of next year. For ophthalmologists and for their patients, this means for the first time, there's a locally-acting, non-invasive treatment for those patients who are currently managed where the standard of care is active surveillance, or watch and wait. So, with a non-invasive patient administered eye drop, we can move from active surveillance to active treatment earlier in the disease process.

Kerrie Brady, Chief Executive Officer and President of OcuTerra Therapeutics shared updates from the company including the development of OTT166 at the 2023 ASRS annual meeting.

ASRS 2023: OcuTerra Therapeutics update on OTT166 eye drops

David Lally, MD, spoke with our team about the ZETA-1 phase 2 trial efficacy results for APX3330, a novel, oral ref-1 inhibitor for the treatment of diabetic retinopathy at the 2023 ASRS annual meeting.

My name is David Lally and I am a practicing physician at New England Retina Consultants in Springfield, Massachusetts. Diabetic retinopathy is the most common cause of blindness among working-age adults. Currently, the majority of these patients are not being treated, as patients are typically asymptomatic, and they are reluctant for frequent eye injections. 

The current treatment paradigm for the majority of physicians is to wait and monitor nonproliferative diabetic retinopathy disease with anti-VEGF, or steroid injections, or laser treatment reserved for those patients who develop proliferative diabetic disease or develop diabetic macular edema. Developing an alternative route of administration orally could reduce the treatment burden for our patients and allow us to intervene earlier in the stages of diabetic retinopathy and APX3330 is a first-in-class, novel medication that inhibits Ref-1, which is a transcription factor regulator. By inhibiting Ref-1, you block activation of both HIF-1alpha and NF-kappaB, leading to down regulation of inflammation and VEGF. 

This drug was well studied previously, initially in patients with hepatitis and solid tumors, and the safety profile was good in those trials. The ZETA-1 trial is a Phase 2 randomized, multi centered, placebo-controlled trial that investigated APX3330 for the treatment of diabetic retinopathy. Subjects with moderately severe to severe NPDR or PDR were randomized in a 1 to 1 fashion to receive either APX3330 at the 600 milligram dose daily or placebo daily for 24 weeks. The primary outcome measure was the percent of subjects that had a 2-step or greater improvement on their DRSS scores at week 24. In this trial, there was 103 subjects that were randomized across 25 US sites. Now, APX3330 did not meet its primary endpoint, and the percent of subjects that had 2 or greater steps improvement on DRSS scores. However, in Phase 2 trials, we are often learning about a drugs potential efficacy in a disease for the first time, and those other signals beyond the primary endpoint can sometimes redirect development plans into Phase 3. 

The ZETA-1 trial may be one of these instances because what we saw when we looked at the change in binocular DRSS scores over 24 weeks, was that none of the APX treated patients developed a binocular 3-step or worse DRSS progression scores. That's in comparison to the placebo arm, where 16% of those subjects did develop 3-step or greater DRSS worsening on binocular scores. So APEX3330 may be showing us an ability to stabilize diabetic retinopathy disease, as opposed to improving it. Now, the FDA has previously remarked that they may consider the prevention of diabetic retinopathy worsening as a potential valid primary endpoint. There is an end of Phase 2 meeting planned with the FDA to discuss this primary outcome measure later this year. Thank you.

ASRS 2023: ZETA-1 phase 2 trial efficacy results for APX3330 with David Lally, MD

Cindy Cai, MD, shared insights from her presentation from ASRS 2023 on "Health disparities in lapses in diabetic retinopathy care" with Sheryl stevenson, our Group Editorial Director. 

We're joined today by Dr Cindy Cai, who will be presenting at this year's ASRS meeting in Seattle. Welcome to you, Dr Cai.

We're really curious to hear more about your talk regarding health disparities in lapses in diabetic retinopathy care. That sounds like such a timely topic right now. Can you tell us more about your talk?

Yeah, thanks so much for that question. As you know, Sheryl, diabetic retinopathy is the ophthalmic manifestation of diabetes. Even though we have great preventive strategies and treatments for diabetic retinopathy, it's still the leading cause of blindness among the working age adults in the US. That's because a lot of times our patients with diabetes aren't returning to eye care as recommended by their provider, [and] they have what we call a lapse in their diabetic retinopathy care. 

So in our study, we looked to see whether there were differences in rates and lapses in diabetic retinopathy care by different racial and ethnic groups. We included about 40,000 patients with diabetes who had come through the Wilmer Eye Institute for diabetic retinopathy screening or treatment, and found that overall, about three-quarters of patients have a lapse in diabetic retinopathy care at some point during the first 2 years of follow up. These rates were different by race and ethnic groups, whereby our non-Hispanic black patients and Hispanic patients had a much higher chance for having a lapse in diabetic retinopathy care as compared to otherwise similar non-Hispanic white patients. This was a statistically significant finding, and obviously very important. 

Of course, identifying these health disparities by race and ethnicity is just the first step. Ultimately, we want to develop interventions and strategies to eliminate the health disparities that we're seeing. So, we're in the process of taking this methodology that we've developed to identify lapses in diabetic retinopathy care, and deploying it in real time in our electronic health record, so that we can identify lapses in care as they're happening and provide additional resources for patients who might need the most support. So, this is ongoing work and I encourage everyone to stay tuned.

ASRS 2023: Health disparities in lapses in diabetic retinopathy care

Eyenuk has received U.S. Food and Drug Administration (FDA) clearance for the use of the Topcon NW400 retinal camera in association with the company’s EyeArt AI system for the automatic detection of diabetic retinopathy. This joins the Canon CR-2 AF and Canon CR-2 Plus AF cameras, which have already been approved for use with the company’s Ai system. This makes the EyeArt v2.2.0 system the first AI system to be FDA-cleared for use with multiple cameras by different manufacturers.

This clearance comes after a multi-center clinical trial (NCT04984200) showed 94.4% sensitivity and 91.1% specificity for more-than-mild DR detection, and 96.8% sensitivity and 91.6% specificity for vision-threatening DR detection.

The FDA’s decision also includes Real-Time Image Quality Feedback and an upgraded image quality assessment module, achieving best-in-class gradability (conclusive reports) without eye dilation.

The system has also been approved by the European Union under the MDR class IIb to perform a single test that can detect DR, age-related macular degeneration (AMD), and glaucomatous optic nerve damage.

To further discuss this clearance for the EyeArt system, the Ophthalmology Times team say down with Kaushal Solanki, PhD, Founder and CEO of Eyenuk.



Editor's note - This transcript has been edited for clarity.

I'm David Hutton of Ophthalmology times. This week, Eyenuk received FDA clearance to use the Topcon NW400 retinal camera with its EyeArt AI system to automatically detect diabetic retinopathy. Joining us to discuss this clearance is Dr. Kaushal Solanki, founder and CEO of Eyenuk. Thank you so much for joining us today. Tell us what this means for ophthalmologists and the patients they treat.

Thank you, David for having me. So with this expansion of EyeArt, our flagship AI product for autonomous detection of diabetic retinopathy, which was formally cleared for use with Canon cameras, we now have clearance with Topcon camera as well. Making it the first and only system that is cleared by the FDA for use with multiple camera systems or multiple camera models from different manufacturers. What it means for the community is that now they have choices. Now, they can use the fully automated Topcon camera, or they can use the Canon camera with excellent imaging and resolution. So this also means that we have the community, the clinicians have additional choices, they may have these cameras already installed, and they can just get just a software upgrade with EyeArt and start using AI in the practice. So it means greater access to patients. That is one of the primary thing we are achieving through this clearance.

Tell us a little bit about the technology that's received the clearance.

 So the technology is, it's a series of artificial intelligence algorithms that detect lesions related to diabetic retinopathy to provide output that is either more than mild diabetic retinopathy or vision threatening diabetic retinopathy. We are the only FDA cleared system that is approved for detecting vision threatening disease. Which has been true since our first initial clearance in 2020. What we also bring to market through this clearance is an upgrade to the image quality assessment module. And we are also providing to our customers a real time image quality feedback. Youu know, this does get a bit technical. But what it does for our customers is that it brings patient and clinic friendly features to the market.Achieving the best in class gradeability without dilation. So in a clinical trial that was used to support this clearance, we achieved over 90% gradeability without dilation, which is a significant upgrade or, you know, some competition where you know, they needed like a quarter of patients needing dilation. So this is also a significant upgrade that we are bringing to the market today.

One of the things that I've heard from a few people I've talked to is the cost in reimbursements. Could this pose a hurdle? Or how is this a challenge that you could overcome?

This technology is reimbursed by Medicare through a new Category 1, CPT code called 92229. That doesn't change. Meaning to say this reimbursement has been, a national reimbursement has been in place since 2022. And now, what what this upgrade brings is that those customers with different camera models are now compatible, and they can start using AI for instant reads, and they can also be reimbursed by Medicare and commercial payers.

With this clearance. Does this mean that the new option is available now? Or if not, when will it be available to ophthalmologists?

And what impact can this have on say the workflow of a practice? How can it make an ophthalmologist more efficient?

This will make the clinicians more efficient, for one, by all the usability features that I just talked about. The real time quality feedback, so when the patient is there, they get feedback on image quality through use of artificial intelligence, and the new image can be taken right away if the [original image] is no good. And so that significantly improves the patient workflow. For vast majority of patients over 90%. They get an actionable conclusive EyeArt report without needing dilation, but if dilation is to be recommended for the other, you know, less than 10% the software itself makes that recommendation. It really makes the workflow very seamless.

Lastly, is there anything that maybe I haven't asked you today?

So this upgrade goes to our existing customers, you know, with the likes of, you know, Temple University and several others. It also allows those with the Topcon camera to just upgrade and start using AI. We are also the first and only system that is cleared by EU under a Class IIb MDR, for detection of multiple diseases; diabetic retinopathy, AMD and glaucoma. So, and that all goes towards our mission to screen every eye in the world to ensure timely diagnosis of vision threatening conditions.

New FDA Clearance Makes Eyenuk the First Company with Multiple Cameras for Autonomous AI Detection of Diabetic Retinopathy. Eyenuk. June 22, 2023. Accessed June 28, 2023. https://www.eyenuk.com/us-en/articles/news/eyenuk-fda-multiple-cameras/

Get caught up on the approvals and hear directly from Kaushal Solanki, PhD, Founder and CEO of Eyenuk.

NOINDEX

NOFOLLOW

Eyenuk receives clearance for detecting diabetic retinopathy with the EyeArt AI system

Kaushal Solanki, PhD, CEO and founder of Eyenuk, updated our onsite team about the company's EyeArt system, which uses AI and is cleared by the FDA to detect diabetic retinopathy.

I'm Kaushal Solanki, founder and CEO at Eyenuk, and Eyenuk is the developer of EyeArt, fully autonomous artificial intelligence system that is a first and only system to be cleared by the FDA for autonomous detection of both more than mild and vision threatening diabetic retinopathy. 

I'm here to give you another exciting update of our European class to be MDR approval of diabetic retinopathy, macular degeneration, and glaucoma. And this is really exciting because we now, our users in the European Union, can detect AMD and glaucoma in addition to previously cleared diabetic retinopathy, but also, they can help [a] lot more patients who would be at risk of AMD and glaucoma as well. 

Back here in the US, we continue to grow our footprint with adoption and usage of our autonomous AI technology growing month over month and adding more and more institutions and hospitals using our technology. Thank you.

Kaushal Solanki, PhD, CEO and founder of Eyenuk, shared news about the company's EyeArt AI, which is cleared by the FDA to detect diabetic retinopathy.

ARVO 2023: Eyenuk CEO and founder, Kaushal Solanki shares EU update on EyeArt

Edmund Arthur, OD, PhD, FAAO, shared how retinal imaging can be an important tool for early detection of diabetic retinopathy in underserved communities.

I'm Edmund Arthur. I'm an assistant professor of the University of Alabama at Birmingham School of Optometry. I'm this year's Genentech Career Development Award recipient for Underrepresented Emerging Vision Scientists. My research is on the early detection of diabetic retinopathy in underserved communities.

Diabetic retinopathy is the most common cause of vision loss in working-age adults in most developed countries, including the United States. Early detection of this condition will lead to early refer out to a primary care physician for control of systemic glucose or systemic A1C. But the pathological changes that occur in diabetic patients precedes clinical retinopathy. In other words, the changes are occurring in diabetic patients, you know, okay, long before they are clinically detected. So if we can detect these early changes with advanced retinal imaging, then we can refer to a primary care physician and then start early management of their systemic A1C and yet systemic glucose.

So the focus of my research that is sponsored generously by Genentech is to use advanced retinal imaging called optical coherence tomography angiography to develop a novel retinal vascular biomarker for early detection of diabetic retinopathy and diabetic macular edema, so that we can refer to the primary care physician early enough, and then we can manage this condition early enough. Thank you.

ARVO 2023: Using retinal imaging for early detection of diabetic retinopathy in underserved communities

What are the various treatment options available for diabetic retinopathy and macular edema? Could you tell us a little about the benefits, limitations, long-term efficacy, and safety of each of those treatment options?

We’ve had anti-VEGF therapy now for almost 12 years for diabetic macular edema [DME]. What we’ve learned is that anti-VEGF therapy is probably the gold standard: the best outcome with the lowest safety profile of any of the 3 drugs or other options we have. Because it has good efficacy and good safety, it really has been a game changer for us in this field. Think about that. In a 12-year span, we’ve been able to treat patients with this condition, which has been a huge benefit to our patients and our population in general.

We use steroids as a second-line option and sometimes a third-line option, with laser photocoagulation of the macula being important for patients with nonproliferative disease and diabetic macular edema. With proliferative disease, you have to go to the larger laser. You go to the panretinal laser with which you manage the entire retina and ablate the retina, but that’s not always necessary.

The way I measure patients’ vision in practice is first and foremost go by their baseline acuity to decide what I’m going to do. Then, given the anatomical parameters, I go along with that to follow the patient over time. For example, if the patient is 20/40 or better, I might consider them in a Protocol V category or Protocol T category depending on how bad their vision is. That’s the biggest driver for the final outcome of these patients, which has been important to see.

You touched on some of this already, but when should patients with diabetic retinopathy start anti-VEGF therapy or other treatments to improve vision or prevent vision loss?

This has been a controversial topic in our field. For DME, the end result is clear. Everyone should get anti-VEGF therapy for that condition. We monitor with OCT [optical coherence tomography], see what the responses are, and start to tailor therapy based on that. For nonproliferative disease, there are few retina specialists I’m aware of who give in to the concept that preventing vision-threatening retinopathy complications is a good thing. I always think about it like it’s my eye or your eye, Dr Majcher. If you had this condition, is it easier to not suffer a vision-threatening retinopathy complication rather than [receive] a single injection in your eye maybe once every 2 to 3 months depending on which study results you’ve seen, what you evaluate, and what drug you’re using?

Overall, what I’ve been able to surmise is that we could be doing much better at using these treatment option approaches for patients. Yet we know that anti-VEGF therapy has the best long-term options for patients, the best efficacy and safety in that population, and has little benefits to risks. With steroids, there’s a concern about glaucoma, and we have to monitor for cataract progression as well. Finally, with photocoagulation, although it sounds easy enough to do, it can cause permanent scotomas to develop, problems with mydriasis or having the pupil dilate, and other issues that are related to the treatments themselves.

Rishi Singh, MD, provides an overview of the various treatment options available for diabetic retinopathy and diabetic macular edema (DR/DME).

Available Treatments for DR/DME

Dr Singh, could you please describe and define the various stages of diabetic retinopathy and the retinal findings associated with each stage?

We have an established classification stream going back to the diabetic retinopathy severity trials that were done in the early 1980s. This was when they established that laser was treatment necessary for patients with proliferative disease. The way I describe it to patients is the way I know it in my own practice, which is that mild and moderate diseases essentially are where the pericytes or the supportive cells in the retinal vascular are lost. You start having tight junctions, and you start developing dot and blot hemorrhages in the retina. It’s not until you get to severe nonproliferative disease where you get some of the more important findings. That’s defined as 4 quadrants of hemorrhage, 2 quadrants of venous beading, and 1 quadrant of IRMA [intraretinal microvascular abnormalities]. [Any] of those categories makes you a patient with severe nonproliferative disease.

All that is prior to the next phase, which is proliferative disease in the non–high-risk or high-risk category. I think that whole classification has gone out the window. At this point, we consider patients as having proliferative disease or not. That’s when you have neovascularization of the disc, neovascularization elsewhere, neovascularization of the iris, or even vitreous hemorrhage present in the eye. That would be a sign of proliferative disease. Each of these stages is important. The more important stages are the mild to moderate together vs the severe vs the proliferative stages, which determine progression of disease more severely. Interestingly, we find that patients with the highest risk of progression are those in the severe nonproliferative category. If they have severe nonproliferative disease, they’re highly likely to develop proliferative disease within a 1- to 2-year period of time.

What factors do you consider when selecting therapy for patients with diabetic retinopathy or diabetic macular edema?

When we talked about this in the beginning, about the drivers for outcome, it is around baseline vision. That’s how studies have been shown to be beneficial in this category. For good vision categories, we can follow Protocol V or Protocol T where they both say in those trials done by the DRCR [Diabetic Retinopathy Clinical Research] Retina Network, that as long as the vision is very good, you can just manually observe the patient. With vision of 20/25 to 20/40, you have lots of different options for treatment, albeit bevacizumab is the cheapest option for those patients. When you get to baseline vision of 20/50 or worse, that’s when the other drugs matter. In particular, aflibercept was shown to be beneficial in the management of these patients over time, and therefore it was used for treatment for many of these patients. There is an opportunity to choose any of these drugs or at least go to one drug and then switch to another, but this is what the evidence has shown thus far from many of the randomized clinical trials we’ve been able to see.

Rishi Singh, MD, provides an overview of the stages of diabetic retinopathy and diabetic macular edema (DR/DME) and the retinal findings associated with each stage as well as factors to consider when selecting therapy.

Stages of DR/DME and Therapy Selection

We have a variety of different treatment options available to us, and there are some that are coming out. We can discuss limitations with the current treatment options and then talk about the newer agents that are here. Obviously, our limitations are that the frequency is high and that the burden is high. It is socioeconomically almost impossible for patients to get a full bevy of treatments, and we do the best we can, but there are other drugs that are becoming available. Dr Loewenstein, can you comment on faricimab as a start?

First of all, I want to say a word about the burden. The burden is not only for the patient. Of course, for patients with diabetes, the burden is terrible because they have many other things that they need to do. They need to go to the podiatrist, they need to go to the cardiologist, and they need to go to other specialists. The burden on them, on the system, and of course on their caregivers is terrible, so we need to lower the burden somehow.

Faricimab is one of the most promising drugs. It is a drug that is bispecific. It is anti-ANG2 [angiopoietin 2]. ANG2 is a trigger in the Tie2 pathway to cause destabilization of the blood vessels. The drug also enhances the activity of VEGF. If you have a molecule that has elements of being both anti-ANG2 as well as anti-VEGF, it theoretically and pharmacologically has the potential to be a good option for our patients. We have preliminary studies, both on AMD [age-related macular degeneration] and on DME [diabetic macular edema] showing that the drug is effective. For DME, the efficacy was better than with the comparator. In AMD, the efficacy was similar. Regarding the duration in both phase 2 trials, when we looked at the second phase of the trial and looked the durability and the survival curve, when did the patient need another treatment, it had great potential when compared to the comparator.

Another important thing about faricimab is that, because it is anti-ANG2, it’s also anti-inflammatory. We know that it’s not the end, but at least in the studies, there wasn’t any issue with inflammatory response. With other drugs that are coming, such as brolucizumab, we have results from phase 3 trials on AMD in the form of the HAWK and HARRIER trials that showed a great benefit. Unfortunately, both in the trials and in the post-marketing surveillance, it has been established that about 4% of the patients developed an inflammatory reaction. In 1% of the patients, it can cause a significant abrupt decrease in visual acuity, and that’s for AMD.

For DME, we have the results for the KITE trial. I didn’t see the readout of the KESTREL trial yet, but I looked at the results for DME, and it again seems to be a promising drug. I’m worried about the inflammatory response. I know that the company is looking into it and trying to find the reason, the root cause, the risk factors, and the management options. Until then, it’s a bit problematic to use this drug.

Regarding KSI-301 and gene therapy, the data are promising, but it is not yet close to clinical use on a large scale. I’m not saying that it will not be. I hope that it will, but I’m not seeing it coming up that soon. Another option that I see coming up is the slow-release device, like the PDS [port delivery system]. We know that it’s now only being studied for diabetes, but for AMD we have pretty good results. There is a small issue of safety. We have to look into the cases of endophthalmitis there, but the rates will probably come down as we go through the learning curve, obviously. We have a lot of things coming up. We have to weigh the risks and the longer durability that we see coming up. I see faricimab as the most promising drug for the future.

Dr Ferrucci and Dr Chous, you could speak about on the optometry side. If you had to look forward, thinking about some devices or technologies, what would make it much easier for you to do your work and help patients achieve the best possible outcomes for diabetic eye disease?

That’s a tough question. I don’t know. I’m not sure I can think of anything right now. Paul?

Something that I’ve been interested in is the retinal flavoproteins. It’s not specific to diabetes, but it’s the earliest marker of photoreceptor oxidative stress in diabetes, AMD, and in glaucoma they’ve even shown. I’m interested in that as an early marker in improving glucose control and improving those markers to keep the patients from needing to see the retina specialist. In optometry, my goal is to keep the patient from needing an injection in the eye or needing photocoagulation, if I possibly can. If there is anything with which I can detect disease earlier that’s easy to do and cost-effective, it appeals to me.

Steve, do you have anything to add to that?

I would mention that there be more OCT [optical coherence tomography] imaging out there. With more accessibility to OCT imaging, that would be a great way to help monitor for diabetic macular edema. More affordability in OCT moving forward will help more optometrists have access to them, which should help take better care of patients and look for diabetic macular edema.

I want to thank my panelists for today’s discussion, and thank you to the viewing audience for listening to the program. We hope you found this 

 program to be rich and informative. We hope to see you soon.


A panel of experts in ophthalmology and optometry review the diagnosis and treatment of diabetic eye disease including emerging agents in the field.

Emerging agents for the treatment of DR/DME

Let’s talk about COVID-19 [coronavirus disease 2019] and its impact on caring for some of these patients. Steven, lead off and tell us how COVID-19 has affected your patient clinics [with the Sepulveda VA Hospital].

It’s been difficult because, for a while, we were shut down and tried to perform only urgent and emergent examinations. It unfortunately pushed back some exams for patients with diabetes, especially routine exams, yearly exams, and 6- or 9-month follow-ups. It’s been a challenge with those patients because some of them got delayed treatment or at least delayed exams. We now seem to getting around the corner, and we seem to be doing a bit better, at least with getting our patients back in.

Dr Chous, would you like to comment on how COVID-19 affected your practice [at Chous Eye Care Associates]?

Yes, it slowed things down dramatically for a while, and I’m now back to seeing a lot of patients who are 80 or 90 years old who have had type 2 diabetes for 30 or 40 years. The most important message we can give is that these patients are at dramatically increased risk for bad outcomes if they end up in the hospital for COVID-19, and it’s directly related to their glycemic control. If you have poor blood sugar control, you’re 5 to 10 times more likely to suffer a fatality. That’s the first thing I stress to my patients when I see them. We need to assure patients that they can safely come to our offices and that we’re taking proper protocols to disinfect the office. My advice to my colleagues is to minimize face-to-face exam time because the patient’s risk is higher the longer they’re in an enclosed room. That’s sound advice for anybody in this time.

Dr Loewenstein, I have the same question. How has COVID-19 affected your practice [at Tel Aviv University] with regard to volume of patients, and what’s now happening when the patients return?

Yes. First, at the peak of the pandemic, we had to slow down. We also worked in capsules, so we had only one-third of the staff come to the hospital every day, and two-thirds of the staff were free. What we did was this: we reached out to the patients. We opened with 3 optional solutions. First, we tried to provide the safe environment in our hospital, but for the patients who did not want to come, we also opened a remote clinic outside of the hospital. We got a donation from WeWork in Israel, and we did an injection clinic there. We did OCT [optical coherence tomography] imaging with a clinical examination and treated the patients. That was wonderful.

We did another thing. Since I had a lot of physicians who were not in the capsule working, I sent people to patients’ homes to inject. Physicians were going to patients’ homes. For example, for patients who were in loading phases, or for whom you knew treatments were needed on a fixed regimen, we injected in patients’ homes. Nowadays, everyone is in to work. We don’t work in capsules anymore, so I don’t have the resources to do that. I need the physicians in the hospital. We’re trying to provide exactly what was said here. We’re trying to give a safe environment. We’re keeping social distance. We’re trying to not admit patients into the clinic until they’re going to be seen by physicians. We’re sending them a text message that we are ready to see them. If patients are worried and don’t want to have the time spent in the clinic, I agree that the shorter the visit that we do, the better the patients are. If the patient doesn’t want to have an OCT, I sometimes move to a fixed regimen.

There have been a lot of rumors that we may not need to do visual acuity examinations so often. I’m talking about the physicians. Some people say we should only do OCT imaging and treat the patient, that’s it; the visual acuity examination does not make such a big difference, at least not by the physician at every visit. Rather, the patient can go to the optometrist and have this done. Also for the OCT, if they don’t need an injection, it may be a safer environment than the hospital.

Challenges to diabetes management

Dr Loewenstein, we’ve had a plethora of data in the past years about how to treat these patients with DME [diabetic macular edema]. Can you talk a bit about the data that now help guide your treatment algorithm for patients with DME?

I can talk about this for hours, but I’ll try to summarize it. First of all, we have the data from the Protocol V trial that says exactly what Steven said: If a patient has good visual acuity, according to Protocol V, you don’t need to treat them up front if you follow up on them. If it’s a patient who will not come to follow-up visits, then I would even treat a patient with good visual acuity. Once the visual acuity is not perfect, if the edema is not in the center, then I might also follow up with the patient.

If I have central macular edema, I will usually treat the patient. If the patient has good visual acuity, then according to Protocol V, all 3 treatments that we have available for us nowadays, which are bevacizumab, ranibizumab, and aflibercept, are all good treatments. They are the same, but if the patient has less than optimal visual acuity, 20/50 or worse, then there is an advantage to one drug over the other. I’m not saying that the difference is huge. The difference is mainly toward bevacizumab, but I try to switch as fast as I can to one of the registered drugs. This is one aspect of the clinical trials.

Another aspect of the clinical trials is the issue that we can treat peripheral disease with anti-VEGF therapy, and we have that from the Protocol S trial from the DRCR.net [Diabetic Retinopathy Clinical Research Network] as well as from the CLARITY trial. That is another trial outside of the DRCR.net. For me, these are the most important trials that show how to treat patients with diabetic macular edema and diabetic retinopathy. There are many other trials, as well as trials that show that it’s not usually helpful enough to use anti-VEGF treatment in patients with NPDR [nonproliferative diabetic retinopathy] to lower the chances of developing [proliferative diabetic retinopathy]. That is probably not needed at this point, according to the knowledge we have from the newer trials.

When you look at the treatment options, what about the safety data that you see? Are all these drugs considered safe at this point for diabetic macular edema? Is there any concern about the systemic or local adverse effect profiles of these drugs?

From the drugs that we have in our armamentarium nowadays, the 3 main drugs don’t have significant local safety issues. We have new drugs that came out that showed an inflammatory response, some of which includes occlusive vasculitis with closure of blood vessels. Blood vessel closure, even with larger blood vessels, raises an ocular safety concern. With the 3 main drugs that we are using recently, there is still a question about whether there is a systemic adverse effect issue. There have been multiple meta-analyses, one of which said that yes, there is an issue there. The researchers said that the studies are not powered to show an issue, so I’m not sure if there is an issue, but I do have it in the back of my mind.

If I have a patient who just had a stroke or an MI [myocardial infarction], I will probably refrain from giving an anti-VEGF agent in the first month or two even though it’s not 100% proven that I’m right by doing so. In many of these cases, I will use a steroid as the primary therapy, with all the caveats that they have. We can also use intravitreal steroids by way of long-lasting implant of dexamethasone, and I use it as primary treatment mostly for patients who cannot come for monthly treatment, but they can measure the pressure, or I use it for patients who just had a stroke or an MI.

Treatment options for DR/DME

In this section, we’ll be discussing treatment options for diabetic retinopathy [DR] and diabetic macular edema [DME]. We’ll start off with Dr Ferrucci, and we’ll ask what the recommended treatment guidelines are. When is observation appropriate for the patient with DME or diabetic retinopathy?

As an optometrist, when we have a patient with mild or moderate nonproliferative diabetic retinopathy, I’d feel that we can safely see those patients. Once the retinopathy starts to get a bit worse rather than moderate, it makes sense to consider a referral. For diabetic macular edema, if the patient’s vision is reduced from the diabetic macular edema, then that’s a clear-cut time to get a referral to a retinal specialist. The patients who have diabetic macular edema with great or perfect vision are a bit more complicated. I will usually get a second opinion for those patients. I realize that they might not always be treated, but it makes sense to at least get a second opinion.

Dr Chous, we have all these guidelines from the ADA [American Diabetes Association] with regard to follow-up in these patients. Tell us about how you use them. Do you go by the book on all of them as far as 6 months for a mild nonproliferative to a patient with moderate nonproliferative disease? How do you practically use those guidelines from the ADA?

The ADA says it should be 1 to 2 years if the patient has no or minimal DR and good metabolic control. They amorphously say good metabolic control. I’m looking at that, and what is more important than A1C [glycated hemoglobin], which is what the new endocrine research is showing, is what percentage of the patient’s life are they within a normal glucose range, which is called the glucose time in range. It’s independently predictive of DR and vision loss outside of hemoglobin A1C.

My general strategy if a patient has mild or no disease is to perform an annual examination. It could be done less often to save money, which I get from an economic standpoint, but there is value in habituation for the patient, which means getting used to having annual dilated exams. As optometrists, we see this all the time. We tell patients, “Throw your contact lenses away every 2 weeks or every month,” and sure enough, when they come back, we learn that they’re throwing them away every 6 months. There’s value in getting patients acclimatized to coming in more often.

ADA guidelines for DR/DME management

Dr Ferrucci, what are the keys to getting successful communication to our providers? What do you send in that referral letter? What information do you think is helpful to them?

There are a couple of things. Number 1, it is often the case that the patients we see as optometrists may have been seen in our practice for many years. It may be a patient with type 2 diabetes who we’ve seen for many years, and we’re now seeing their vision take a turn for the worse. When I send the patient to a retina specialist, I give a brief background and tell them what my concern is and why I’m concerned. I highlight the main concern without a lot of extraneous information. You should get down to the meat and bones of why the patient is being sent over, what you want them to look at, and what you would like their opinion on.

Dr Chous, how does the primary care provider [PCP] fit into this discussion in that case?

It’s important that we’re giving consistent messages to patients. Regardless of whether a patient has diabetic retinopathy [DR], it’s imperative that all of us in primary eye care send a note to the PCP letting them know that, if the patient has developed any DR, they need referral to a retina specialist. The other important thing is what the surveillance interval is. When does the patient need to be seen by us again to monitor their disease if they have any diabetic retinal disease? It’s a great opportunity for collaboration with PCPs. We know that DR in particular is linked to many other comorbidities of diabetes, so it represents an opportunity to collaborate not only with PCPs but a variety of subspecialists, as well.

I want to add to that that the role of the optometrist is crucial. It doesn’t matter in which country you live because the patients often don’t even go to an ophthalmologist. They are often going just to change their glasses. They would then go to optometrists all over the world, and…that’s a chance to catch the patient, examine them, and decide whether to send them to a specialist. It’s a crucial role.

What do you look for, Dr Loewenstein, in your referrals? What are you hoping to hear from your optometrist or any other eye care provider when they’re sending a patient to you? What do you want to hear from them about the diabetes?

It is exactly what Paul and Steve said. I want to know that they have had good visual acuity until now, and they have now seen the visual acuity deteriorate. I want to know that they followed up with them for many years and didn’t see any diabetic retinopathy and that this is something for which the patient now doesn’t get maximal visual acuity.

Diabetic Retinopathy

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