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Spotlight

Presbyopia: A part of Aging and Challenges

Clinical

1rem

If approved, OCS-01 has the potential to become the first once-daily, topical, preservative-free corticosteroid for treating inflammation and pain following ocular surgery.

Oculis completes enrollment in Phase 3 OCS-01 OPTIMIZE trial

The regulatory milestone fulfills the company’s goal to file the IND for OCU200 within the first quarter of 2023.

Ocugen submits NDA with FDA to initiate phase 1 clinical trial evaluating OCU200 for treatment of DME

According to Regeneron, the BLA is supported by two pivotal trials demonstrating non-inferior vision gains to aflibercept injection, with a majority of patients maintaining extended dosing regimens through 48 weeks.

FDA accepts aflibercept 8 mg BLA for treatment of wet AMD and DME for priority review

Sharing data between ophthalmologists, optometrists can lead to earlier diagnosis

Early detection and treatment of DR and DME is essential

The Phase 2 SPECTRA clinical trial will assess 4D-150 in patients with DME.

4D Molecular Therapeutics announces FDA clearance of IND application for 4D-150 genetic medicine for the treatment of DME

David S. Boyer, MD, discusses the PHOTON study examining the safety and efficacy of high-dose aflibercept for the treatment of diabetic macular edema (DME) from his presentation at the Angiogenesis, Exudation, and Degeneration 2023 conference with David Hutton, Executive Editor, 

Editor’s note: This transcript has been edited for clarity.

. Dr. David Boyer made a presentation on the safety and efficacy of high dose aflibercept for the treatment of DME at the Angiogenesis 2023 conference. Thanks for joining us today. Tell us a little bit about your presentation.

Thank you very much. It was my pleasure to present the results of the PHOTON study, treating DME. As we all know, the current state of care of clinically significant macular edema is anti-VEGF therapy. And the thought behind this study was that if we increase the Mueller dose of intravitreal, anti-VEGF therapy, that perhaps we can reduce the treatment burden to our patients, and on a hypothetical basis that was found, and indeed it even in animals, it was found that it was helpful in reducing the time interval between the need for retreatment in rabbits that were treated ongoing.

So there has been clinical evaluation now, that shows that an 8 milligram dose, 4 times the normal dose, injected in 70 microliters of fluid into the eye will give you a longer time period before you need additional treatment.

So the study design was very easy. They compare the 8 milligram dose at 12 weeks and 8 milligram dose at 16 weeks, to the 2 milligram currently available dose at 8 weeks. The primary endpoint was at week 48. And what they did is they treated according to label in the 2 milligram dose, which required 5 initial injections, and then every 8 weeks after that, the 12 week, dose of 8 milligrams in the 16 week, dose of eight milligrams had 3 initial monthly injections, reducing the treatment burden. And then the patients were randomized either to 12 weeks or 16 weeks. And this was a worldwide study.

The inclusion criteria were fairly stable for all as compared to other studies that have been done, and included type 1 or type 2 diabetes with macular involvement of center retinal thickness and greater than 300 with the exclusion of active PDR, or status post-PRP or any anti-VEGF therapy within 12 weeks of screening.

So basically, patients received either 5 initial doses if they were in the 2 milligram dose, and then every 8 weeks. The 12-week dose of 8 milligrams was 3 times in the beginning and then went out to week 20, then 1 week out to 32 weeks, 16, again, 3 initial doses, that 8 milligrams at 16 weeks, then initial of dose of 24.

Now the patients could go backwards, if they didn't meet certain criteria as compared to week 12, when they were seen. It was a 10 letter loss and best corrected vision due to persistent fluid and a 50 micron increase in the central retinal thickness.

At week 16, the patients on the Q 12 and the Q 16 weeks can be decreased at month 24. They could also be decreased at week 32 and week 44, again, a decrease to a lower level. So in other words, if you were at 16 weeks, and you met the criteria, you would go to 12. Nobody went lower than 8. So if you were at 12, and you met the criteria, you would go to 8.

So the patient disposition was interesting. Almost 92% of patients completed the trial, which is really amazing. That was a very high percentage. And the baseline demographics were fairly equal in all groups, patients, hemoglobin, A1C was approximately 8 across. Almost 80% of the patients had hypertension, and the remainder of the age race all appeared to be fairly well balanced. Baseline characteristics of the study eye, almost over 40% of patients had previous treatment, at some point for their DME.

The number of injections was definitely reduced. In the Q 8, almost 8 injections were given over the 48 week period, 6 injections in the 12 and 5 injections in a 16 week.

The end result, the primary endpoint, was met with both 8 milligram doses, there was almost a 1.3 letter difference between the Q 8 and the Q 16. With almost 9 over 9 letters, 9.2 letters in the queue 8 and 7.9 letter gain the Q 16. With 8.8 and the Q 12. All were statistically significant.

If you look at the mean change of vision, by baseline best-corrected vision, you'll see that the patients that had poor vision gain more. The patients who had better vision gained a little bit less, which is what we would have expected as they have a ceiling effect if you have very good vision to begin with.

Again, changes in the CRT again showed if you were less than 400 microns, you had improvement of vision in all subgroups. That Q 8, 2 milligram dose the 8 milligram dose Q 12 and Q 16. And if it was greater than 400 microns, you had a bigger improvement of vision, again, equal across all groups. The 2-step improvement was about 25% at week 12, and that continued to be 48.

But if you look at the patients who had the 47 or worse, the 2 step improvement, rivaled what we saw in PANORAMA. Over 70% of patients did get an improvement, the highest being 77%. In the Q 8 with 63% and the Q 16.

The mean change in subretinal thickness was fairly stable. There were fluctuations, there was some saw toothing that was noted. The saw toothing appeared to reduce as we got further out in the study, it was more apparent earlier in the study, and then began to lose its effect.

In the Q 12, 91% of patients met remained in the Q 12, only 9% of patients went to Q 8. In the Q 16 about 7% of patients had to go down to Q 12. And we maintain there with only 4% going to Q 8. And if you look at the overall 93% of all patients went Q 12 or greater at the end of the trial. So this was maintained Fluorescein leakages also decreased fairly equally in all groups. 

The most frequent ocular issues were things that were related to basically the injection technique, there was no real difference between any of the groups, interactive inflammation was minimal. And again, there was no difference in any of the different groups, including the intraocular pressure, which we would have expected possibly to go up is there have been reports of chronic anti-VEGF treatment, giving rise in pressure and also giving a little bit of a larger dose than we would normally give a 0.05ml.

There was really no difference. The ocular safety, obviously, extremely important, you're giving much higher dose of aflibercept. We were worried about APTC changes, and there was really no change compared to the 8 milligram dose. And overall, it was what is seen in other clinical trials, no problems.

So safety was definitely comparable to the 2 milligram dose. There were no cases of endophthalmitis and certainly no cases of inclusive retinal vasculitis, which you’ve seen with other products recently. And the APTC rates and death were similar between all groups.

So, in conclusion, it appears that the 8 milligrams Q 12 and 8 milligrams Q 16 were non-inferior to our present 2 milligrams Q 8, reducing the treatment burden considerably.

At Q 12 weeks, the 8 milligram had a non-inferiority margin of 50% and the proportion of patients with 2-step improvement in DRSS are very comparable. At the end at 8 milligrams randomized at different treatment intervals. 91% of patients maintained the Q 12 89% maintain Q 16. And overall 93% of patients went 12 weeks or greater.

Videos

David S. Boyer, MD, presented data from the PHOTON study examining the safety and efficacy of high-dose aflibercept for treatment of diabetic macular edema at the 2023 Angiogenesis, Exudation, and Degeneration conference. 

Angiogenesis 2023: Efficacy and safety of high-dose aflibercept for treatment of DME

Victor Villegas, MD, discusses how to comanage patients that have macular degeneration, diabetic maculopathy and cystoid macular edema in the setting of cataract surgery from his presentation at the EnVision Summit Ophthalmology 2023 conference with David Hutton, Managing Editor, 

. Joining me today is Dr. Victor Villegas, who presented From a Retina Perspective: Comanagement of AMD, DME and CME in the Setting of Cataract Surgery at this year's EnVision Summit. Thank you for joining us. Tell us about your presentation.

Thank you. So, you know, today we have the opportunity to talk about how to comanage patients that have macular degeneration, diabetic maculopathy and cystoid macular edema. And I think the key important point here is that there is no evidence that cataract surgery is going to worsen in any way, age-related macular degeneration. However, if patients have neovascular age-related macular degeneration, they should be properly treated, and cataract surgery can be delayed until treatment is instituted.

Regarding diabetic retinopathy, in contrast to macular degeneration, there is a high probability that diabetic maculopathy is going to get worse after cataract surgery, and recognizing that will allow cataract surgeons to comanage patients with a retina specialist in order to minimize having any worsening of vision immediately after cataract surgery.

And I think the key point here is there are different ways to do that. But the evidence points that corticosteroids, given as periocular or intraocular injections are probably going to be the best bet in terms of reducing any increase in macular edema, or any development of diabetic macular edema in patients with diabetic retinopathy.

And lastly, regarding cystoid macular edema, and cataract surgery, most of these patients will have complete resolution between three to six months after development of cystoid macular edema, with or without treatment. However, if you treat patients with topical and NSAIDs, you will make recovery faster, you will get to your visual acuity goals faster and most people will use topical NSAIDs as their first line in and I think the caveat here is that you need to be perseverant and not get frustrated. If you see the patient one month after starting treatment, and there's still some macular edema, you just need to hang on tight, keep treating patients and you know, keep seeing them on a monthly basis until there is complete resolution of the edema.

If it doesn't go away, or it seems to be staying the same and you don't see any real improvement, then, you know, you can potentially refer a patient or additional medications. I think overall most of the time, it will go away and you just need to hang on tight. treat patients with NSAIDs that will help give the cataract surgeons a little bit of a pearl on how to see things from a different perspective. And, you know, help develop relationships with retina specialists in the community in order to kind of have a protocol in place and you know, approach this in a team joint collaborative effort so that you know patients end up having the best outcome long-term.

During the EnVision Summit Ophthalmology in Puerto Rico, Victor Villegas, MD, made a presentation titled "From a Retina Perspective: Comanagement of AMD, DME and CME in the Setting of Cataract Surgery," focusing on how to comanage patients that have macular degeneration, diabetic maculopathy and cystoid macular edema.

Cataract Surgery

EnVision Summit 2023: Comanagement of AMD, DME and CME in the setting of cataract surgery

 This is an interesting case because we see a number of good points. This patient who had very severe DME [diabetic macular edema] with poor vision from the onset, but still had to undergo step therapy, perhaps unnecessarily because there’s little effect of the bevacizumab before switching to ranibizumab. Because of compliance and various other factors, it’s hard to tell what the actual effect of the ranibizumab was. Be that as it may, the patient improved greatly with the combination therapy of a single dexamethasone corticosteroid implant, hopefully aimed at reducing the inflammatory cytokines that we see in so many diabetics, more of a chronic inflammatory nature rather than the VEGF given acute nature of some DME. This patient did well after combination therapy. They were switched to aflibercept for one reason or another, and what was nice was they were able to be maintained on the aflibercept every other month without the need for an additional corticosteroid implant. The corticosteroids are great for reducing the cytokine overload, the cytokine storm we see in diabetic macular edema. They do have untoward side effects, such as cataract progression and increased intraocular pressure. In this patient, a younger phakic patient, we like to avoid the formation of cataract with the resultant vision loss. That is my treatment strategy for a lot of diabetic patients, trying to get them stabilized with anti-VEGF biologics. But if that wasn’t going to happen, then oftentimes I’ll turn towards another option, like a corticosteroid dexamethasone implant, to see if they have an effect with that. And then, if they can be maintained on the original anti-VEGFs, then that is an ideal scenario. When do I use laser focal, PRP [panretinal photocoagulation] for eyes with DME? In this case, and in other cases, if the patient has high-risk proliferative diabetic retinopathy, I will apply PRP to try and stabilize that and stave off any vitreous hemorrhage or other problems that may develop. Focal laser I use sparingly, for non-center involved diabetic macular edema. If we see lots of exudates with retinal thickening or big, juicy microaneurysms, those are great targets for focal laser. But, center-involved focal laser has no place now in treating these patients, as we saw from the DRCR [Diabetic Retinopathy Clinical Research Network] Protocol I. Delayed or concurrent focal laser is still not as beneficial as anti-VEGF, whether it be ranibizumab in Protocol I, or even bevacizumab or aflibercept as seen in Protocol T. Center-involved focal laser should have a sparing place in treating diabetic macular edema patients. Thank you for watching this 

 presentation. We hope you found this presentation informative and applicable in your practice.

Daniel F Kiernan, MD, FACS, discusses the use of anti-inflammatory treatment when experiencing sub-optimal response with anti-VEGF therapy in DME.

Impressions and Takeaways From Patient Case #2

The second case of a 49-year-old gentleman referred by an outside optometrist for diabetic macular edema, complaining of blurred vision in both eyes for the last 6 months, much worse in the last 3 months, leading to a disability claim as a matter of fact. Past medical history of type 2 diabetes for 10 years. And this gentleman’s hemoglobin A1C is not under control at 10.5. Visual acuity without correction in both eyes was 20/200 with pinhole improvement to 20/60, though he claims that glasses don’t help. Normal pressures. There’s a history of hypertension that’s not quite under control and is on commercial insurance. This image on the slide is representative of both eyes. You can see a ton of intraretinal and subretinal edema on the OCT [optical coherence tomography] and multiple microaneurysms with light paramacular leakage in the left eye. This person was diagnosed with extensive macular edema OU, and active high risk proliferative diabetic retinopathy in both eyes. Treatment commenced July through September 2021. You can see on July 12, he was given bevacizumab in both eyes. Then he underwent PRP [panretinal photocoagulation] in both eyes in subsequent weeks. On Aug. 9, he was also given a second shot of bevacizumab. There, shown on these images, Aug. 23, his vision was 20/80 in the right, 20/150 in the left. Still had a lot of fluid, unresponsive to the initial 2 shots of bevacizumab. Nevertheless, because of the mandates of step therapy, was given a third shot, with very little effect, as seen on the below image. On Sept. 27, vision was still 20/80 in the right, 20/200 in the left, so he was switched to a different product, ranibizumab, 0.3 mg given in both eyes. The following slide shows, November 2021, that he still had persistent edema in spite of the injection of ranibizumab. There may have been a slight delay in that treatment for one reason or another. And at this point in time, I opted to treat him with a dexamethasone intravitreal implant in both eyes. And 2 months later, as you can see, he returned with near-resolution of the macular edema and a vast improvement of vision in both eyes. In order to continue with the combination therapy, since he obviously did well with the initial dexamethasone implant, I proceeded with ranibizumab in both eyes, asked him to follow up in about a month’s time. Unfortunately, he did not. He was a bit noncompliant and did not follow up until April 4, where he had a major recurrence of the macular edema in both eyes, and a drop in the vision to 20/60 in the right eye and 20/200 in the left eye. We switched to aflibercept in both eyes and saw him back about 2 months later, on June 13, 2022. We could see the edema improved greatly, and the vision also stabilized to 20/50 in the right eye and 20/80 in the left eye. We continued him on maintenance doses of aflibercept in both eyes, and the patient continues that every 8 weeks to maintain a fluid-free macula.

Daniel F Kiernan, MD, FACS, reviews a case of a 49-year-old man with DME with extensive edema and high-risk proliferative diabetic retinopathy (PDR).

Patient Case #2: 49-Year-Old Male With DME

First of all, the patient’s insurance type can oftentimes present the first barrier to their treatment. In this case, the patient had a commercial insurance, which typically dictates step edits or step therapy. And even though the patient should have qualified earlier for aflibercept because their visual acuity was worse than 20/40, and we know from DRCR, the Diabetic Retinopathy Clinical Research Network, that patients with worse vision do better with products such as aflibercept or ranibizumab compared to bevacizumab. Those patients should be able to receive those products regardless of prior authorization or any other factors. But as we know in real life, we often have to jump over the hurdles of the insurance and get their authorization. Otherwise, it can be a financial burden on our practice. We were able to switch the first patient to aflibercept in both eyes after 2 initial treatments of bevacizumab, but that’s still an ongoing problem. Now, how can we implement step therapy without causing vision loss? That’s a great question. Unfortunately, we do have risk of vision loss when we’re giving an inferior product to a patient who needs something that we know works better, and the onus is on the insurance companies to let us give what we think is right for the patient. How does baseline visual acuity impact the choice of anti-VEGF therapy? As mentioned, if it’s worse than 20/40 for diabetic macular edema patients, aflibercept or ranibizumab should be approved rather than bevacizumab, which is an inferior product in those cases. And these are all the factors that we consider before switching patients to other anti-VEGFs. Some total of their fluid and their vision, the most important things. Other treatments we might consider for this patient certainly might be a corticosteroid. There are approved corticosteroids, such a dexamethasone implant or a fluocinolone acetonide 0.19 implant for recalcitrant edema, especially for more chronic appearing edema that might be more inflammatory in nature. In this case, the patient did well, although had limited response to bevacizumab and was able to be switched early on to aflibercept and had a great response to that. Their decision to not undergo cataract surgery is a personal one. I think they would improve with cataract surgery, but once they get stabilized from a retina standpoint, it’s good to then approach them about that rather than the other way around. Diabetic macular edema can certainly worsen if it’s not under control prior to cataract surgery.

Daniel F Kiernan, MD, FACS, shares impressions of a patient case, focusing on challenges in access to care, and implementing treat and extend strategy in DME.

Impressions and Takeaways From Patient Case #1

Hello, I’m Dr Daniel Kiernan, a retina specialist at The Eye Associates in Sarasota, Bradenton and Venice, Florida. I’m excited to share 2 DME [diabetic macular edema] cases we discussed at a recent 

Roundtable. Patient case 1 is a 62-year-old gentleman referred by an outside optometrist for diabetic eye exam as the patient complains of decreased vision, wavy lines, and occasional floaters in both eyes. He does have a past medical history of type 1 diabetes for many years, although his A1C level is currently 6.4, so it is controlled. Medications are typical for a diabetic. On the first day of presentation, 9/27/21, visual acuity in the right eye is 20/80, 20/40 in the left. Normal intraocular pressures and the patient is phakic with a 2-plus nuclear sclerotic cataract, both eyes with dilated fundus exam showing hemorrhage, microaneurysms, and diabetic macular edema. Both eyes consistent with moderate NPDR [nonproliferative diabetic retinopathy] with DME-OU [oculus uterque]. On that same day of presentation, the OCT [optical coherence tomography] of the patient showed a fair amount of diabetic macular edema, left eye greater than the right eye. Because of the patient’s insurance plan, which was a commercial plan requiring step therapy, he was started on bevacizumab injections in both eyes with the plan to follow up for shot number 2 in 1 month. Here on Nov. 1, 2021, visual acuity is 20/70 in the right eye and 20/40 in the left. You can see a reduction, although persistent, diabetic macular edema in both eyes. This was Nov. 1, 2021, and then a month later, Nov. 29, 2021, visual acuity was 20/70 in the right eye and 20/30 in the left. Because of persistent edema and the visual acuity being what it was, aflibercept was requested initially, and approval was finally given because of the vision being worse than 20/40, and because the right eye qualified, the left eye also was approved for aflibercept, which was given on this date because of persistent disease activity and macular edema. A month later, on Dec. 27, 2021, visual acuity was 20/80 in the right and 20/50 in the left. You can see that there’s decreased but persistent fluid still, so aflibercept was given again in both eyes. Then a month later, on Jan. 31, 2022, visual acuity was 20/100 in the right, 20/50 in the left. There was decreased but still a little bit of persistent edema, especially in the right eye, so aflibercept once again given in both eyes. A month later, visual acuity was stable, 20/80 in the right, 20/30 in the left. The relatively dry appearing OCTs, just a little bit of intraretinal edema in the left eye. Aflibercept once again applied in both eyes. Then in April, the following month, April 18, 2022, visual acuity was 20/70 in the right, 20/40 in the left, and vision was improving in both eyes. The right vision is likely limited by cataract, and the cataract surgery discussion was had, but the patient defers any cataract evaluation. OCT was stable, so we decided to extend to every 12 week treatment intervals in both eyes. 12 weeks later, visual acuity is stable, 20/60 in the right, 20/30 in the left. And there was increased fluid but stable vision in the left eye, so we continued q12 week, or 3 month intervals. Ergo, 3 months later, vision was 20/60 in the right, 20/50 in the left. Intraretinal fluid was present, and the visual acuity had dropped in the left eye, so I decided to reduce the treatment interval and see the patient back about 4 to 5 weeks later. Vision stabilized and the edema improved, so we proceeded with the aflibercept shot just in the left. And we at this point felt that the patient had had maximum improvement and was stable, so we could continue the right eye being treated q12 weeks and the left eye q6 weeks.

Daniel F Kiernan, MD, FACS, describes a case of a 62-year-old-man with diabetic macular edema (DME) and nonproliferative diabetic retinopathy (NPDR).

Patient Case #1: 62-Year-Old Male With Diabetic Macular Edema (DME)

 This transcript has been lightly edited for clarity.

Hi, my name is Scott Walter. I'm a retina specialist in Hartford, Connecticut. And I wanted to talk today a little bit about the year 2 data from the TENAYA and LUCERNE trials.

So TENAYA and LUCERNE were the phase 2 pivotal clinical trials leading to the FDA approval of faricimab for the treatment of patients with neovascular AMD. And in year 1 of the trial, we know that patients got 4 monthly loading doses of faricimab and then patients went into extended treatment arms of 8-, 12-, or 16-week fixed dosing intervals. And that was based on disease activity assessments that took place at week 20 and 24.

In year 2 things changed a little bit in terms of the protocol. So beginning at week 60, patients were eligible to extend or shorten their treatment intervals based on disease activity assessments occurring at each study visit. So this became more of a treat-and-extend type protocol, patients could go ahead by 4 weeks or back by 4 to 8 weeks depending on those disease activity assessments. So I think what happens in year 2 is very interesting to us as retina specialist because it kind of—it reflects maybe how we practice in the real world with a treat-and-extend practice pattern.

So in year 2, 60% of patients were able to extend their dosing interval by 4 more weeks, and the vast majority of patients maintain those dosing intervals through the end of year 2 at 112 weeks.

Ultimately, the number of patients who are maintained at Q-60 week dosing intervals increased from 45% at the end of year 1 to 63% at the end of year 2. So it's really impressive how, you know, the the numbers just keep going up in terms of the proportion of our patients who can be maintained at these extended dosing intervals, about 4 out of 5 patients can be treated in a Q-12 to 16 week dosing intervals, throughout 2 years of treatment with faricimab.

So I think this new therapy really has tremendous promise, the best corrected visual acuity gains and central subfield thickness reductions that were observed in year 1 were maintained in year 2, there were no significant safety signals, low rate of intraocular inflammation and really, absolutely no cases of inclusive or non-inclusive retinal vasculitis identified in the second year of the trial.

So I think this gives us a lot of confidence as retina specialists, as we begin transitioning some of our patients from other anti-VEGF therapies to this new molecule, which is both an anti-VEGF agent and a dual pathway inhibitor that also blocks Ang-2 that we can really achieve extended durability in the vast majority of our patients.

Scott Walter, MD, an investigator in the TENAYA and LUCERNE trials discusses the year 2 data for the treat-and-extend regimen of faricimab for the treatment of nAMD and DME.

Promising results for faricimab revealed in TENAYA, LUCERNE year 2 data

 This transcript has been lightly edited for clarity.

. At the American Academy of Ophthalmology 2022 annual meeting in Chicago, Dr. Lloyd Paul Aiello moderated a panel on diabetic retinopathy. Dr. Aiello, thanks for joining us today to discuss this panel. Tell us some of the key points and takeaways from this session.

 Well, thank you very much for this opportunity. It was actually a very exciting session because, as many folks know, the evolution of the care in diabetic retinopathy has been changing dramatically over the last several years. And with recent advances now, we are continuing to have very important questions answered that help us refine that care.

In this session, one of the aspects that was covered was with our recent ability to document the far periphery of the retina now quite easily, we have to understand whether or not findings out there are important in our understanding of the future progression, retinopathy. And the risk factors included with that. And so that was covered by Dr. (Jennifer) Sun, where many of the aspects of the findings in the peripheral retina now are having implications with regard to the progression rates.

Certain findings, particularly with regard to the sourcing angiogram and ultra-widefield imaging, allow us to determine folks that are at higher risk of progression than others in a way that can't be detected with standard photography. We also have some evaluation of different anti-VEGF treatments and other inhibitor treatments that are being done by Dr. Michael Ip. In addition to anti and two outcomes, now showing the prolonged effect of these treatments for diabetic macular edema that was presented by Jennifer Lim.

Dr. (Neil) Bressler addressed a very important and timely question now with regard to using anti-VEGF for the prevention of severe nonproliferative diabetic retinopathy. More specifically preventing severe proliferative retinopathy from moving on to sight-threating complications, such as proliferative diabetic retinopathy. It has been shown that anti-VEGFs can be at least as effective as panretinal photocoagulation in terms of preventing the complications down the road, and in fact, they have some benefits early on, although the outcomes are similar after treatment. But we have the issue with regard to whether or not patients get lost to treatment since with the anti-VEGF they may rebound as opposed to with a diabetic retinopathy where oftentimes they can be quiescent for years too decades.

With regard to whether diabetic patients are being lost to follow up, which is an important follow-on question, this was addressed that with real world data from the group.

And finally, as we started to look into where we are going in the future with additional aspects, the role of inflammation and diabetic macular edema was covered by Dr. Barry Kupperman, because now many targets are addressing suppressing this inflammation to try to have further beneficial effects. And the drugs in the pipeline that are coming down the way a variety of them were covered by Dr. David Boyer to give us some idea of what exciting advances we may be seeing in coming years.

 Ultimately, what can this mean for ophthalmologists and the patients they treat who are diagnosed with diabetic retinopathy?

 Well, this has many implications. And it's very important because our total number of diabetic patients continue to grow a great deal. But what we're finding now is we can further refine who is at risk of progression compared to those that aren't, and furthermore, we are now having additional therapeutic options for those people who may not be responding as well as we would like to some of the early anti-VEGF inhibitor therapies.

Lloyd Paul Aiello, MD, moderated a panel at the American Academy of Ophthalmology’s 2022 annual meeting in Chicago that focused on diabetic retinopathy. He shares some of the highlights of this session. 

Panel discusses treatment options for diabetic eye diseases

This transcript has been lightly edited for clarity.

 We're joined today with Dr. Roger Goldberg, who will be presenting this year from the podium at Academy. Welcome to you, Dr. Goldberg. Could you tell us a little bit more about your talk this year?

 Sure. I'm happy to be presenting some of the details from the YOSEMITE and RHINE clinical trials, and particularly that the arm of the trial where patients were treated with what's called a personalized treatment interval or variable interval, testing kind of the the efficacy and durability of faricimab, now known as Vabysmo, with a generic faricimab, for the treatment of diabetic macular edema.

Fariciamb, of course, is a bispecific antibody designed to inhibit both VEGF-A and Angiopoietin-2. And the YOSEMITE and RHINE trials were twin phase 3 studies, both very large over 900 patient trials, compaing faricimab given every eight weeks, faricimab, with this personalized treatment interval or PTI arm, which is basically kind of a treat-and-extend-based dosing regimen, where patients can be tested anywhere from every 4 all the way out every 16 weeks, based on both changes in the central subfield thickness on OCTs, so the amount of fluid on the OCT, as well as the visual acuity. And the comparator arm was aflibercept, dosed on label at a Q 8-week interval. All of these of course after a couple of loading doses.

Of course, the top line results from both YOSEMITE and RHINE is that faricimab showed excellent results the Q 8 or the PTI arm in terms of visual acuity gains and non inferior to on-label aflibercept. And the central subfield thickness, the OCT changes, again excellent results in both YOSEMITE and RHINE.

And the PTI arm in particular performed excellently both visual acuity wise and anatomic wise looking at the central subfield thickness.

And a lot of us, when we do treat-and-extend algorithms, although the visual acuity of courses is important, that is less consistent in our clinic, unlike in a clinical trial, where they use what's called best-corrected visual acuity, but we rely a lot of course on our exam and on what we see in the OCT. And here, I think it's really important that when we're looking at the efficacy and durability of faricimab, particularly in this PTI arm. How does it compare versus aflibercept? And couple different ways to look at that on OCT.

One is with what they call the absence of DME, which is the central subfield thickness less than 325 microns, or just throughout the macula, absence of intraretinal fluid. And across both of those measures, you know, kind of two different ways to try to quantify what we see on OCT, faricimab, both given every 8 weeks or the PTI arm, again, where patients can be extended up to 16 weeks, excellent results, and statistically better drying agents than aflibercept given every 8 weeks across both of those measures, absence of DME or absence of intraretinal fluid.

And that's really consistent importantly, basically across all time points after the loading period. And what that shows is that even with PTI being able to extend patients out all the way out potentially to 4 months, it's still kind of anatomically a better drying agent. So I think that was an exciting result for the PTI arm.

Now, the question of course, is, well, how many of the patients were able to be dosed at this extended interval, and if you look at the patients in this PTI arm, across both YOSEMITE and RHINE, we saw over three quarters of patients 78%, were able to go Q 12, or Q 16 weeks, so every three or four months. And of that, over 60% of both trials were able to go out to that 16-week interval, so well over half to 16 weeks, and over three quarters to 12 or 16 week interval.

So basically comparable in terms of visual acuity, frankly, better drying agent, and a huge proportion of patients able to go 3 months or longer between treatment. In fact, there was an option for patients to be dropped down into even monthly treatment. And at the end of year 2, there were about 10% of patients on a Q 4 week interval, 7% in YOSEMITE, 10% in RHINE, and that's kind of how the study ended in 2 years. We'll continue to follow these patients in the Rhone-X study.

The safety of faricimab, a very well tolerated, very comparable adverse event profile in the Q 8-week arm, in the PTI arm, and in the aflibercept Q 8-week arm, a safety profile, comparable of aflibercept and frankly, what we expect to see with intravitreal injections.

One of the other ways we tried to look at the kind of this treat-and-extend algorithm, the PTI, is with these heat maps, where it kind of follows every single patient and what their interval of dosing is. And what we see here is that kind of, there's already a huge swath of patients who are able to kind of quickly advance on a monthly interval, most of us do treat-and-extend in 2 weeks steps, but in the PTI arm, they actually were extended 4 weeks at a time. And so there's a big swath of patients are able to increase kind of straight away out to 16 weeks, expanding at 4 week intervals.

And then over time, we see kind of a, an increasing proportion of patients who are able to get out to 16 weeks over time. And then there is a cohort of patients on the order of about 20%, that do seem to have a more variable phenotype, they're able to go up a little bit, they're able to move back a little bit, and it's less consistent. And then of course, there's that very small kind of mid-single digit percentage that does require a Q 4-week treatment even with faricimab.

So I did share a couple of examples in the in the talk here, but obviously in this scenario, I won't be able to show them, but to summarize, the PTI arm really kind of simulates what we do in real clinical practice with treat-and-extend. The majority of patients, again, over three quarters, were able to get to Q 12 or Q 16 week intervals, they're able to kind of get there by week 52 and then maintain it out a year or 2, will actually continue to see further extension during the what's called Rhone-X extension studies, which continues to follow the YOSEMITE and RHINE patients.

And the safety was excellent, no cases of retinal vasculitis and so really shows the promise and potential of enhanced drying and extended durability. So all in all, really important clinical trial program. And I think many of us now have experience using it in the real world.

Roger A. Goldberg, MD, MBA, discusses his 2022 AAO poster: "T&E-Based Personalized Treatment Interval Dynamics in the YOSEMITE/RHINE Trials of Faricimab in DME."

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Faricimab: YOSEMITE, RHINE treat-and-extend data illustrate favorable personalized treatment dynamics for the treatment of DME

Let’s bring it back to the real world to close our conversation. Caroline, it’s been a real pleasure. It’s a fantastic opportunity to talk to you. I could talk to you all evening. We don’t have all evening, so let’s generate some take-home points for doctors who are looking at patients with wet AMD [age-related macular degeneration] and diabetic macular edema in the real world. What would a take-home point be for you about recommending a specific agent for common retinal disease?

My take-home point is that when considering an agent to use, efficacy, durability, and safety are the 3 key drivers that we use in retina. We have this exciting new agent, faricimab, that’s met the standard on efficacy and safety and has this potential for increased durability to benefit our patients.

Thank you, Caroline. That was eloquently stated. My take-home point is to talk to your patients. Educate your patients on their disease. If you talk to your patients and spend some time with your patients, you’ll get the buy-in, you’ll get the improved adherence. The biggest gap we have on a day-to-day basis is the absence of time to educate our patients and to build that rapport, especially our patients with diabetes who have more problems with follow-up. If we talk to our patients about their disease, show them pictures and make a shared decision based their preferences in combination with our scientific knowledge, we can do our very best for them.

Thank you, Caroline, for joining me for this wonderful conversation. I’m David Eichenbaum, and I appreciate you watching this 

. We hope you found this presentation to be rich and informative.

David A. Eichenbaum, MD, FASRS and Caroline Baumal, MD provide take-home messages to providers treating AMD and DME.