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Q&A: María Berrocal's Ingrid Kreissig Award Lecture at EURETINA 2025

Optain Health secures $26 million in Series A funding to enhance AI-driven retinal disease detection and expand its technology.

 Optain Health secures $26 million Series A funding

Q&A: Marion Munk on IntRIS symposium at EURETINA 2025

A new study explores the "drusen ooze" hypothesis, revealing how drusen can regress without atrophy in age-related macular degeneration.

Researchers propose new explanation for drusen regression without atrophy

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Ophthalmology Times – Clinical Insights for Eye Specialists

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Celltrion announces phase 3 trial data for EYDENZELT

Ashvattha Therapeutics reveals phase 2 results for migaldendranib, showing significant vision improvements and reduced injection needs in retinal disease patients.

Ashvattha reports positive phase 2 results for migaldendranib in DME and nAMD

A study reveals similar risks of sight-threatening diabetic retinopathy in pregnant women with type 1 diabetes compared to nonpregnant controls.

Diabetic retinopathy in pregnancy

An eye on how patients perceive their retinal diseases

RAMQ is a public organization introduced in 1970, following the adoption of the universal health care system in Canada.

Roche Canada announces Vabysmo (faricimab injection) is now publicly funded for macular edema secondary to RVO on RAMQ

Risk of sight-threatening diabetic retinopathy with GLP-1 RA use: Comparative effectiveness of semaglutide, dulaglutide, liraglutide, and exenatide

Andy J. Barkmeier, MD, an associate professor of ophthalmology and vitreoretinal surgery at Mayo Clinic in Rochester, Minnesota, presented findings on GLP-1 medications and their relationship to diabetic retinopathy complications at the 2025 ASRS meeting in Long Beach, California. 

He began by explaining that GLP-1 medications had become increasingly popular among patients with type 2 diabetes due to substantial evidence demonstrating their cardiovascular and kidney benefits. The uptake of these medications was rapidly rising as more cardiovascular outcome trials confirmed their systemic advantages. However, Barkmeier noted that the SUSTAIN-6 trial, which examined semaglutide, had revealed a concerning finding alongside its cardiovascular benefits: an increased risk of diabetic retinopathy complications. This increased risk occurred in the context of rapid hemoglobin A1c lowering and weight loss, leaving researchers uncertain whether this was a medication-specific effect or simply related to the significant systemic improvements, similar to what had been observed in previous studies like the DCCT. 

The challenge was that existing cardiovascular outcome trials had examined only specific patient subsets over short periods, focusing on those with high cardiovascular risk. This limited the generalizability of the findings to broader patient populations using these medications in routine clinical practice. To address this gap, Barkmeier's team conducted a study examining a more representative population of patients who received different GLP-1 medications in real-world clinical settings. They specifically looked for differences in diabetic retinopathy outcomes, including treatment for diabetic macular edema and proliferative diabetic retinopathy. The study yielded reassuring results: no differences were found between any of the GLP-1 medications regarding the risk of treatment for diabetic macular edema or proliferative diabetic retinopathy. 

Importantly, the findings did not replicate the increased diabetic retinopathy complications risk seen in the SUSTAIN-6 trial, even for semaglutide, one of the most commonly prescribed medications in this class. Barkmeier concluded that these findings provided reassurance to both patients and prescribers, allowing them to select the most appropriate GLP-1 medication without concern about theoretical increased diabetic retinopathy risks.

Videos

ASRS 2025: The risk of sight-threatening diabetic retinopathy with GLP-1 RA use

Dilsher Dhoot ASRS 2025

At ASRS 2025 in Long Beach, Dilsher Dhoot, MD, of California Retina Consultants presented promising preclinical data on avoralstat, a plasma kallikrein inhibitor being explored as a novel treatment for diabetic macular edema (DME). In his talk, Dhoot highlighted that while anti-VEGF therapies have significantly advanced DME treatment, up to 40% of patients—according to studies such as Protocol T—still experience persistent fluid and edema, suggesting the involvement of alternative biological pathways.

Avoralstat targets the plasma kallikrein-bradykinin pathway, which is distinct from the VEGF pathway and has been implicated in vascular leakage. The molecule is a potent and small (513 daltons) inhibitor of plasma kallikrein. In preclinical studies using the DL-AAA rabbit model, avoralstat effectively reduced vascular leakage. Dhoot emphasized the molecule's durability, noting that therapeutic levels (EC90) were sustained for up to six months, an encouraging sign for long-term disease control.

Importantly, avoralstat is being delivered via suprachoroidal injection, which may enhance its bioavailability and retinal penetration—a potential improvement over earlier kallikrein inhibitors that failed to meet primary endpoints in clinical trials. Dhoot speculated that limited efficacy in previous studies may have been due to insufficient drug levels reaching the retina.

The research is now advancing into a Phase 1b clinical trial in Australia, which has already begun enrolling patients. This 3x3 dose-escalation study will involve recently diagnosed DME patients and aims to further assess safety, durability, and early efficacy signals. Preliminary results are expected by late 2025 or early 2026.

Looking ahead, Dhoot suggested that avoralstat could offer a monotherapy option for patients unresponsive to anti-VEGF treatment, potentially reshaping the treatment landscape for DME. He expressed optimism that with better drug delivery and a novel mechanism of action, avoralstat may finally unlock the potential of plasma kallikrein inhibition in retinal disease

ASRS 2025: ASRS 2025: Suprachoroidal avoralstat stops vascular leakage in a well-established rabbit model

ARVO 2025 Mark Barakat, MD and Dilsher Dhoot, MD, FASRS

At ARVO 2025, in Salt Lake City, Utah, Dilsher Dhoot, MD, FASRS, and Mark Barakat, MD, talked about the PHOTON trial, 8 mg versus 2 mg during the matched dosing phase, and outcomes of shortened, maintained, or extended dosing intervals

Editor's note: The below transcript has been lightly edited for clarity.

Hi, I'm here at ARVO 2025, and I'm presenting a poster for EYLEA HD and looking specifically at the PHOTON data. This is a post-hoc analysis. As you recall, the photon trial is a phase 3 trial comparing EYLEA HD to EYLEA 2 milligrams. And so EYLEA 2 mg was dose on label, which is 5 monthly loading doses followed by every 8-week dosing. EYLEA HD had 3 monthly loading doses followed by every 12- or 16-week dosing. In this post-hoc analysis, we're looking specifically at patients who met criteria for shortening at weeks 16 through 48, and we're asking the question, "How do these patients do at the matched dosing interval at week 12?" So week 12 was a unique time where all the patients had received 3 doses, and 4 weeks later, we can compare vision and anatomy. And so, looking at that population that required or more injections, shortening of their interval, how did they do? It turns out that at baseline, very similar visual acuities. We saw thicker retinas in those patients who required shortening at baseline, and we see that patients at week 12 who required shortening in the HD group had drier retinas in their counterparts, who hypothetically would have required shortening in the 2 mg group. The visual acuity was similar. All in all, this post-hoc analysis tells us that in patients who have a higher need for treatment, we can do better with EYLEA HD at this interval: week 12. In fact, there was a faster time to drying also, and we look at the Kaplan Meier median time to central thickness less than 300 microns; this occurred sooner in HD patients in this harder-to-treat population.

We've had HD in our hands for over a year now, and I think we're learning more and more about who the most appropriate patients for this drug are. In general, me-to-all-comers, really could benefit from HD. You can see faster time for drying, dryer retinas. And so I think that, in general, you know, having second-generation anti-VEGFs is really a come-up for retina. In particular, if we look at patients, though, that have the higher demand, those patients seem to do better with HD than their counterparts with 2 milligrams.

My name is Mark Barakat from Retina Macula Institute of Arizona, and I'm here at ARVO 2025 to present findings from the PHOTON trial. It's actually looking at the baseline characteristics of those patients that were on the 8 mg, so the high-dose aflibercept, in terms of whether they're shortened, extended, or maintained at their intervals. As you all know this is for DME patients that were assigned to either 12-week or the 16-week interval. And some were shortened. It turns out it was 17% or less. Most were maintained or extended. All of them actually really benefit in terms of vision and CST. And then the question was, well, if you look at the baseline characteristics, which one were more likely to be shortened, which one were more likely to be extended? And the short answer is the longer duration of diabetes ahead of time at baseline actually favored extension and maintenance in terms of the CST. So if you had worse CST to begin with, you're more likely to be shortened, less likely to be extended. So in short, all of those subjects actually did really well throughout the trial, regardless of whether they're shortened, maintained, or extended. That 17% or less of those patients were, in fact, shortened, and that it turns out to be a duration of diabetes and the CST going into the trial.

Another pearl that we got from this analysis, if you're looking at the vision going into it. If the vision was 63 letters, that was sort of the threshold for those patients that were—if it was less than 63 letters, they were more likely to be shortened. And in terms of the CST, the cutoff was about 427 microns or so, so in that sense, if the CST was worse than that, again, more likely to be shortened. But ultimately, in the clinical setting, we do what's best for the patients; we just have to be a little bit more flexible. It just gives us the peace of mind to know that not many patients, in fact, needed to be shortened, and those patients that were shortened were still only shortened to the 8-week duration, so still pretty, pretty long durability.

I mean, ultimately, it's a conversation with the patient, right? And I think it begins with keeping them informed and also letting them know this is what the OCT looks like. This is a nice biomarker. This kind of tells us what you're doing. In addition to the vision, and then again, just having flexibility. Yes, I think the vast preference amongst all of us is treat and extend. And I think treat and extend still fits well within this paradigm. This, of course, was a clinical trial setting where things were much more rigorous, more rigid in some ways as well. But yeah, I think it's adaptable.

ARVO 2025: Shortened, maintained, or extended dosing intervals through 96 weeks in PHOTON

David Almeida, MD, PhD, MBA, a vitreoretinal surgeon and clinician scientist, presented at the Retina World Congress about OCS-01

David Almeida, MD, PhD, MBA, a vitreoretinal surgeon and clinician scientist, presented at the Retina World Congress about OCS-01, a new dexamethasone cyclodextrin formulation for diabetic macular edema (DME). The innovative eye drop technology offers promising efficacy and safety outcomes, addressing challenges in medication delivery to the back of the eye. By allowing longer contact times and better penetration, the formulation could potentially reduce treatment burden for patients. 

Almeida highlighted the increasing prevalence of diabetic macular edema and the importance of developing safe, well-tolerated treatments. The next step involves phase three registered trials to further evaluate the medication's potential benefits.

Note: The following transcript has been edited lightly for clarity.

Hi, my name is David Almeida. I'm a vitreoretinal surgeon and clinician scientist at the Erie Retina Research and the Centers for Advanced Surgical Exploration. It's wonderful to be back at Retina World Congress, which is always a very dynamic, collaborative, international meeting, and I've been presenting on one of the topics is the OCS-01 from their DIAMOND program, looking at the 3 times a day, dexamethasone, cyclodextrin, a new formulation for diabetic macula edema, which shows very promising both efficacy and safety outcomes that will then be used for the phase 3 registered trials. 

A drop is challenging, so because it has to last long enough, has to get to the back [of the eye]. So I think the OCS technology allows to have longer contact times, allows better penetration. So I think that's encouraging. Then really beyond that, in terms of, when we think of the prevalence of diabetic macula edema, how those numbers will just keep increasing, to have a really, really safe, well tolerated drop, you know, I think would be really welcome and potential benefit for a lot of patients, hopefully. 

Ideally, you would probably be able to space out visits longer, you know, so that they're just on a drop. And then, when you think of things that are coming down the wire, like OCT, that then could be like nice congruency points to support that, you know, that could support that reduction in treatment burden.

Almeida highlighted the increasing prevalence of diabetic macular edema and the importance of developing safe, well-tolerated treatments. 

RWC 2025: BCVA and CST Improvement over 12 weeks with OCS-01 eye drops for DME

Envision Summit 2025: Patient-centered care and newest treatment strategies in neovascular AMD and DME 

At the Envision Summit 2025 in San Juan, Puerto Rico, Sherrol Reynolds, OD, FAAO, participated in a discussion on patient-centered care and the newest treatment strategies in neovascular AMD and DME. 

My name is Dr Sherrol Reynolds, and I am a professor of optometry at Nova Southeastern University, College of Optometry in Fort Lauderdale, Florida. And it's indeed a pleasure to be here. This is my second Envision Summit, and I think what sets this conference apart from some of the others is that optometry and ophthalmology come together to educate, to inform, and to highlight the latest development in eye care.

And as a person who is in retina and director of our retina service, it was a great opportunity for me to be part of a panel discussion yesterday with noted retinal specialists from Baskin Palmer and other areas, and we talked about patient centered care and the newest treatment strategies in neovascular AMD as well as diabetic macula edema. And what was important to highlight is how we both as retinal specialists on their side and optometrists, can educate our patients about the latest treatment options that are available to these patient. Extended treatment so they don't have to get injections every month. What's new in the pipeline and development of treating patients with neovascular AMD and diabetic maculapathy. So it's exciting times in retina and again, today, we had another opportunity to partner with a retina specialist and my optometric colleagues and further discussion about other conditions that can mimic AMD and how we can differentiate those conditions. What are the latest treatment modalities for these conditions, such as Macular telangiectasia, type two and type one. You know, patients that have polypoidal, choroidal vasculopathy, central serous chorioretinopathy. What's new in the pachychoroid spectrum of diseases.

So in conclusion, you know, emerging therapies, things in retina. Retina is a hot topic. We're seeing new treatment for patients that have geographic atrophy–giving those patients hope. We're seeing treatment modalities where the patients can have an extended treatment. They don't have to get treatment every month, and we're just excited about what's coming down the pipeline.

I think comanagement and collaboration and working together is so critically important. Our patients, especially those that have diabetic retinopathy, diabetic maculopathy and age-related macular degeneration, usually, optometry is that first line, you know, their first entry into eye care. We're seeing a disproportionate number of these patients, so it's important, when these patients have conditions that's vision threatening that not only are we talking about their condition with them, educating them on their condition, but as we're referring them to our colleagues, our retinal specialist, we also want to make sure that they're aware of what the latest treatment option is. A lot of times, our colleagues may have a busy practice, and so these patients go in and, you know, they don't have time to ask their questions. So we, as optometrists, we serve an important role in just getting our patients, not only their diagnosis detected early, but educating them, and then getting them to our colleagues.

Additionally, a lot of times, our patients will come back and may not feel comfortable or have some fears about treatment and may not go back to the retinal specialist. It's important that we again educate our patient and work together well, because the goal is to preserve our patient's sight. So I think it's so important that we work together in doing that.

Canonical

IOP outcomes with intravitreal injection of aflibercept, 8mg and 2mg in patients with diabetic macular edema through week 48 of the phase 2/3 PHOTON

intraocular pressure outcomes with intravitreal injection of aflibercept, 8mg and 2mg in patients with diabetic macular edema through week 48 of the phase 2/3 PHOTON trial.

Mark Barakat, MD, sat down with Ophthalmology Times to discuss intraocular pressure outcomes with intravitreal injection of aflibercept, 8mg and 2mg in patients with diabetic macular edema through week 48 of the phase 2/3 PHOTON trial.

I'm David Hutton of Ophthalmology Times. The Association for Research in Vision and Ophthalmology recently concluded its annual meeting, which was held this year in Seattle. At that meeting, Dr. Mark Barakat, presented intraocular pressure outcomes with intravitreal injection of aflibercept, eight milligram and two milligram in patients with diabetic macular edema through week 48 of the phase 2/3 PHOTON trial. Thank you so much for joining us today. Tell us about your presentation at the ARVO meeting.

Absolutely, thank you so much for having me. So I mean, essentially, we're very fortunate to have both two milligram aflibercept and the higher dose eight milligram aflibercept. One of the key differences is not just necessarily in duration, but it's also in terms of volume. The two milligram is .05 and the eight milligram high dose is .07. So a natural question that arises is, well does that have any deleterious impacts on intraocular pressures with with these repeated injections? So this is basically a post hoc analysis of the PHOTON trial, which looked at all these subjects in these different categories, those that were getting the two milligram, and those who were getting eight milligram at different intervals. And the question that was posed is, is there a difference. And in short, the answer is no, this was actually very well tolerated and safe. That the intraocular pressure in the eight milligram groups was pre dosing was suitable throughout the 48 weeks. 

And similarly, we also looked at the fellow eyes and the fellow eyes remain stable as well whether or not those fellows receive treatment, or otherwise. And then when you actually compare the eight milligram doses to the two milligram doses, there were also very similar both in terms of changes in intraocular pressure, which were actually minute, pretty well tolerated. And also in terms of how many of these eyes, for example, eyes with with no history of glaucoma, were put on on IOP lowering drops, and those those percentages are really small, and 1 to 2% across all categories? And ultimately, the the other question is, well, did any of them meet any procedures to lower the pressure. And in short, there are a rare number of patients that received Pehrson TCS. But vanishingly small across that data set and relatively well balanced. So, the long and short of it is that, yes, we were right to have the theoretical concern about intraocular pressure. The data thus far is encouraging at week 48. And we look forward to having longer data coming out soon to week 96.

How could the results of this research ultimately impact ophthalmology, from ophthalmologists to the patients they treat?

You know, you always wonder a new worry when a new agent comes out. What is the safety profile? What is the safety profile, will it be similar in the clinic as it is in the clinical trials? And while this doesn't answer real world, it does give us some assurance that this was actually well tolerated in the clinical trials. And so the the safety profile of the eight milligrams and two milligrams seemed remarkably similar. And so that's that's encouraging terms of reaching for that medication.

IOP outcomes with intravitreal injection of aflibercept, 8mg and 2mg in patients with DME

Outcomes of patients with diabetic macular edema and baseline best corrected visual acuity of 20/50 or worse, or 20/40 or better

Sean Adrean, MD, FAAO, sat down with Ophthalmology Times to discuss a post hoc analysis of the phase 2/3 PHOTON trial and the outcomes of patients with DME and baseline BCVA of 20/50 or worse or 20/40 or better who were treated with aflibercept 8 mg and 2 mg.

I'm David Hutton of Ophthalmology Times. The Association for Research in Vision and Ophthalmology recently concluded its annual meeting in Seattle. At that meeting, Dr. Sean Adrean presented "Outcomes of patients with diabetic macular edema and baseline best corrected visual acuity of 20/50 or worse, or 20/40 or better, who were treated with aflibercept 8mg and 2mg. A post-hoc analysis of the Phase 2/3 PHOTON trial." Thank you so much for joining us today. Tell us about your presentation.

Thank you for having me. So this presentation had its genesis in Protocol-T. Protocol-T looked at aflibercept ranibizumab, and bevacizumab, quite a few years ago, and looked at how patients did and saw that those patients that had 20/50 or worse vision did quite a bit better with 2mg aflibercept. And those patients that had 20/40 or better vision actually did pretty decently between those three different medication anti-VEGF agents used. So with the onset of 8mg aflibercept, we wanted to look at see how these patients did in the diabetic macular edema population and against kind of splitting their vision into 20/50 or worse, or 20/40 or better. And in this case, we're comparing the 8mg aflibercept with the 2mg aflibercept. The other thing that we're interested in was to see whether or not extended time intervals could be allowed and see how patients would do if they're going longer than that 8 weeks, but maybe going out to 12 or 16 weeks, and would those patients be able to maintain dosing. Either if they're 20/50 or worse, or 20/40 or better.

The other thing that we're curious about is how would their response be for their central macular thickness as well in this population. So at baseline, these patients were pretty well randomized in the different arms between the 2mg aflibercept, the 8mg aflibercept at every 12 weeks, and the 8mg aflibercept every 16 weeks. And the [8mg every 12 weeks], they were randomized, twice as many. So it was one one group would have, at the 2mg aflibercept, it was like one portion of the patient population versus 2 in the 8mg q12 weeks versus one portion of the population in the Aq16 week. And what is also the thing that was interesting with this patient population is that about 40% of these patients had been previously treated for diabetic macular edema. 

So that means that the patient population was a little bit more difficult to treat. And so when we went ahead and looked at the different analysis based on these two different subgroups, we found that those patients that had the 8mg either in the 12 or the 16-week dosing intervals, had just excellent vision compared with the 2mg aflibercept at the every 8 week time intervals. The 8mg dosage got 3 loading doses versus the 2mg that got 5 loading doses. 

And thankfully, those patients had very similar visual outcomes. And there was no statistical difference between those two different groups, which was great. And while those patients had the 8mg done every 12 or 16 weeks, for those patients that were 20/50 or worse, a good 90% approximately of those patients were able to maintain those extended dosing intervals. And when they were 20/40 or better, they were about 98%, were able to maintain those extended dosing intervals, which is great. 

And the other thing that we found was that as you would expect it those patients that had 20/50 or worse vision, they had a bigger visual response. So they gained more letters, about 10 letters in all 3 different treatment arms. Versus those patients that were 20/40 or better, they had about a 6-letter gain. But and you'd expect that because you'd have a little bit of a ceiling effect for those patients that had 20/40 or better. And also the those patients that are 20/50 or worse had thicker retinas. And those retinas thinned out more. So they had a larger reduction in their central macular thickness when compared to the 20/40 group. So, in all these patients did very well with these different treatments as with the extended time intervals.

That's a great question. So this is the one-year data so we look forward to presenting the two-year data at the upcoming American Academy of Ophthalmology meeting looking at these different subgroups. Because we're able to find that these patients are able to go these extended time intervals. And in the two-year data, some of these patients will be out at 20 or 24 weeks, and it'll be exciting to see how these patients do over time with even further extended time interval dosing.

Ultimately, what can this mean for ophthalmologists? And how can it help them give better outcomes for their patients?

Well, as we know, having increased treatment burden for both the patient and for the physician, where patients require, you know, every 4, every 8-week dosing is a large burden on the patients and patients caregiver and on our clinic. So if we're able to start extending these patients out and they can have similar visual outcomes, and do very well controlling their disease process and they're able to go out 16/20/24 weeks, then by reducing that treatment burden, we're going to really be able to help our patients

A post hoc analysis of the phase 2/3 PHOTON trial

post-hoc analysis of the pivotal Phase 2/3 PHOTON dataset

Deepak Sambhara, MD, sat down with Ophthalmology Times to discuss the impact of baseline central retinal thickness (CRT) on vision among patients with diabetic macular edema (DME), as a post hoc analysis of the phase 2/3 PHOTON trial.

I'm David Hutton of Ophthalmology Times. ARVO recently concluded its annual meeting in Seattle. At that meeting, Dr. Deepak Sambhara, presented data on EyleaHD. Thank you so much for joining us today. Tell us about the data you shared in Seattle.

Thanks for having me, David. So ARVO just wrapped up in Seattle. And it was a fantastic meeting, I had the great privilege and opportunity to present a post-hoc analysis of the pivotal Phase 2/3 PHOTON dataset that got 8mg aflibercept its FDA label for the treatment of diabetic macular edema, as well as diabetic retinopathy. Now, as we're all aware PHOTON was a dataset that compared patients who received 8mg aflibercept every 12, or 16 weeks after initial 3 monthly injections against the standard of care, which is 2mg of aflibercept, every 8 weeks after an initial 5 monthly injections. The primary endpoint of that study was non-inferiority of visual acuity at the end of one year. And I'm glad to say that in that dataset, as we're all aware, that both the treatment arms of 8mg aflibercept reached its primary endpoint with a high level of statistical significance.

Now, this presentation that I presented at ARVO–wanted to look a little bit under the hood of the engine at those patients who participated in PHOTON. And in particular, we wanted to look to see what the trajectory of treatment as far as visual acuity and anatomy looked like among PHOTON patients, if you split them up based on disease severity, and the best correlate for disease severity is baseline anatomy or central retinal thickness. So if you go through the exercise, and you split PHOTON patients up, based on baseline central retinal thickness into quartiles, you end up with 4 different slices of patients. With quartile one being patients who have the least swollen retinas at baseline, and quartile four, being patients who had the most swollen retinas, the most severely diseased patients at baseline. To put it in perspective, patients who belonged into quartile four had on average essential retinal thickness greater than 600 microns. So extremely diseased patients at baseline.

Now, what we were looking at was what happened to these patients if you split them up by quartile over that first year of the study. And so looking at treatment burden, visual acuity and ETDRS letters gained as well as anatomical improvement. Now, what I can tell you David, is if you look at the less swollen retinas at baseline, so quartiles one and two, what we found in this post-hoc analysis was that despite your treatment arm, so if you received 8mgs of aflibercept every 12 weeks or 16 weeks, or you are in the standard of care treatment arm receiving it every 8 weeks of the 2mg dose, those anatomical changes and visual acuity changes kind of mirrored themselves over time. These are overlapping lines. As a retina specialist in the real world, what that shows me is this is almost like proof of concept suggesting that patients with less swollen retinas–so those first two quartiles were retinas less than 428 microns in thickness, you could probably conceivably treat these patients with 8mg aflibercept every 12 to 16 weeks immediately following 3 initial monthly injections. Now, the real magic of this data set in this analysis happens when you look at patients in that fourth quartile. Again, quartile four was the most severely diseased retinas, baseline thickness of greater than 600 microns. In that dataset, patients across all treatment arms, were able to achieve very similar absolute letters of ETDRS vision over that first year, and they gained very similar anatomically as well on OCT. What the interesting thing though, is that the folks in the 8mg arm, the q12 or q16 week groups, were able to do it anywhere from two to three injections less than the 2mg group.

Now, the last, and to me, the most interesting part of this dataset was looking at rates of fluid accumulation in that fourth quartile. So there are a couple of places where you can actually compare across all treatment arms, and that would be 8 weeks following the most recent initial monthly injection. So that would be week 16 if you were in the 8mg subgroups. Or it would be week 24 If you were in the 2mg treatment arm. What you're looking at when you're looking at rates of fluid accumulation, is how quickly does the CST shoot back up. And what we found was that in folks receiving 8mg aflibercept, at week 24, they had a very small or modest gain in CST–anywhere from 3.5 to just under 6 microns at that week 16 visit when compared to week 8. Now if you do the same exercise in the standard of care arm and the 2mg aflibercept arm, you actually see a much steeper slope in fluid accumulation that was about greater than 50 microns in CST reaccumulation at week 24 when compared to the most recent initial monthly dose of week 16. What that tells me as a retina specialist, is that folks who have harder to treat retinas that are more burdened by higher circulating levels of VEGF require additional VEGF suppression, more TLC. These aren't the patients that you're going to space out immediately after those 3 initial monthly doses, you're probably going to have them on a shorter leash. And it's probably required. It also reiterates the point that additional VEGF suppression with a higher dose of anti-VEGF medication is beneficial in this particular patient population.

I think that's a fantastic question. I think the next step is really translating what we see in the PHOTON dataset into real world. Meaning looking to see how we can take the principles that I just talked about and apply them to our own patients. We kind of intuitively know patients that come in with more sickly eyes require more frequent follow up and more frequent treatments. But the reassuring thing about looking at this dataset is that the ones that don't necessarily have as swollen retinas at baseline can potentially be fast tracked, to longer intervals of follow up to hopefully help accommodate those harder to treat more frequent flyer patients that do require more timely follow up and a higher level of treatment burden.

And lastly, ultimately, what can this mean for the retina specialist and the patients they treat?

I think that's a great question. For retina specialists and patients alike, if we look at patients and try to figure out how often they actually need to be treated based on how their initial presenting characteristics would call for it. We can potentially figure out who needs more treatment versus who might require a little bit more close follow up with these new second generation agents, which in my hands so far have proven to be very, very effective for our patients.

 Impact of baseline CRT on vision among patients with DME

Hema Ramkumar of Oculogenex talks about mission to treat AMD and sending mice to space

Hema Ramkumar of Oculogenex talks about mission to treat AMD

Hema Ramkumar, an ophthalmologist and founder of Oculogenex, sat down with David Hutton of Ophthalmology Times to discuss their connection with NASA and their experiment on macular degeneration-treated mice in space. 

- This transcript has been edited for clarity.

I'm David Hutton of Ophthalmology Times. Today I'm joined by Dr. Hema Ramkumar, an ophthalmologist and scientist who founded Oculogenex. For more than 17 years, she has focused her research on treatments for age-related macular degeneration. Thank you so much for joining us today. First, tell us about your focus on this insidious disease, and what drove you to form Oculogenex.

Thank you so much for having me here today, David. So dry macular degeneration is very prevalent. And as a practicing retina specialist in Orange County, I see many patients suffering with this diagnosis. Many of whom may also have family members who are getting injections or slowly had to lose some of their ability to care for themselves or drive because of this devastating, persistent disease. I also have the opportunity to provide care for patients with wet macular degeneration, and see the improvement in vision that they get with treatment, but also understand the burden of needing monthly or bi-monthly injections on the patient, the caretaker, and the family. So there are two things that really drove me to found Oculogenex. One, I really believed to change the prognosis and the natural history of dry macular degeneration, or even of advanced disease, we need to intervene in the disease early. Before we have tissue loss before we have many of the symptoms of advanced disease. If this were possible, it might be that we don't have severe tissue loss from geographic atrophy or wet macular degeneration. And this would allow patients to preserve their vision and independence for much longer. Also, I understand that developing a therapy that only lasts a month or three months, comes with it all the burdens of chronic intravitreal injections. And so that's why Oculogenex is developing gene therapies that will allow for a much more durable and consistent response to therapy, so that patients can still have continuous treatment without needing to see their retina doctor every month or every other month. So those two are what led me to form the company. And we're really focused on helping patients with macular degeneration improve vision from all the other parts of the disease that cause vision loss, other than excitation, which we see in wet [AMD].

You've developed an interesting connection with NASA. Could you tell us a little bit about that?

Yeah, that was an exciting connection. Oculogenex was in the 2021 mass challenge incubator. And during the course of this incubator, we were offered, actually reached out to by the International Space Station National Laboratory. And they asked us if partnership with NASA and ISSNL would help hasten our technologic development and bring us to the clinic faster. And so we looked into it. And one of the challenges that we were having and many other companies in the space are having is developing a good animal model of intermediate AMD. You know, there are many transgenic models and many models that take years to develop. And that's one of the limitations in developing a good therapy for these patients. And so I found that there was some recent work by other groups showing that there was increased retinal oxidative stress, and some loss of retinal photoreceptor function and a small amount of retinal tissue loss after a 35 day mission to the International Space Station. And also, there was an increase in AMD related gene expression. So I found based on the limited data that there was that this might be an excellent quick model for dry AMD. Since the therapy we're developing, inhibits oxidative stress induced tissue loss and enhances mitochondrial function. We believe that our therapy might be able to mitigate that oxidative stress and damage that you see in a quick spaceflight mission.

Tell us a little bit about the experiment that was recently sent to the space station.

Sure, all the previous other missions, looking at the retinal function, were mostly observational. There was one other that involved a systemic therapy. But what our experiment is, the first mission that has ever sending any ophthalmic treated or eye treated animal to space. So the way we're doing this experiment is that we've collected mice from Jackson labs. We treated half of them with our investigational therapy and half of them with a control with the suprachoroidal injection. And then we did baseline ERG, OCT, and fundus photos. And then one month after drug levels have stabilized after the injection, they're being then flown to the space station, and that launch occurred a couple of weeks ago. And so they docked at the space station and they're exposed to normal, you know, microgravity. They're not having any treatments there and they're being cared for with usual animal husbandry by the astronauts. And when they come back, shortly after we'll be measuring their OCT thickness and their ERG. In this way, we also have a ground control. So the purpose of this experiment is twofold. One, we'll be collecting biomarkers from the RPE and retinal tissues of the mice that are going to space and coming back to further validate the use of spaceflight as an intermediate AMD marker. And second, we'll assess if our therapy is able to inhibit oxidative stress and tissue damage and function loss by using ERG and OCT. And we'll be taking the first images of mouse retinas immediately after spaceflight.

How could the retinal scans of these mice ultimately help ophthalmologists provide better outcomes for patients diagnosed with AMD.

So the entire purpose of this mission is to help patients see better with dry AMD, not just prevent tissue loss or lose vision. And so if these scans show that we're able to mitigate the diffuse retinal thinning, that we see with spaceflight, with our therapy, this would be additional proof of concept that our epigenetic gene therapy could prevent that chronic oxidative stress related to age and genetic predisposition in patients with AMD.

Then, as you mentioned, this is certainly a first amongst studies like this being the first ophthalmic treatment study on live animals in space. Could it also yield information about other eye issues?

Yes, that is possible. So in addition to being the first ophthalmic treatment on live animals in space, we recently found out it's also the first gene therapy in live animals to ever be in space, of any type. So two firsts, one for ophthalmology, and one for gene therapy. And so we are definitely going to be evaluating everything related to these eyes coming back, as you may know, fluid shifts associated with a globe change is also a problem with spaceflight. And with astronauts, and so we'll be doing a retinal thickness scans and evaluating if there is any impact of our therapy on that. The we will be looking at taking a global approach to all to all the gene expression and biomarkers that we see. And so there are many retinal diseases that get worse with age and even ocular diseases, including, you know, glaucoma. And so what we are going to be looking at is all all the tissues and you know, their oxidative stress plays a role in age-related diseases, but also even diabetic retinopathy. So we'll be looking at all the different biomarkers that are changed with spaceflight that we know lead to retinal degeneration. And we'll be seeing how our therapy influences that.

After the mice have returned, what are your next steps in this research?

So we are planning and in the process of submitting a package to the FDA to start IND enabling studies and to get concurrence with them on our Phase 1/2 clinical trial plan. So this is our next step. We're planning to get an IND by next year, and hopefully, be into the clinic by the following year. And so that is our goal. And this work, and this research will help contribute to our regulatory package.

And that kind of segues into my next question, ultimately, how will you measure success of this research?

So we'll measure success if we're able to accurately describe the retinal pigment epithelial function and retinal function on these very detailed and sensitive tests. And if we're able to see any changes in oxidative stress related pathways, and retinal function of photoreceptors, with our therapy compared to control.

Lastly, are there any other areas of this research maybe that we haven't yet touched upon?

So I think there are a couple of things that make our investigational therapy different from others that are in development. One is that it is a gene therapy. So that will be more durable. And second is that it is the mechanism is by enhancing mitochondrial function, and in this way, attacking the disease more upstream. So this is a very exciting approach because other therapies that have improved mitochondrial function have also resulted in improved vision in patients with intermediate AMD. So we're going after an area that we know has a promise to improve vision. And I think that our therapy is unique and well positioned and targeted to address dry AMD and potentially other age related diseases relating to mitochondrial dysfunction.

Hema Ramkumar, an ophthalmologist and founder of Oculogenex, sat down with David Hutton of Ophthalmology Times to discuss their connection with NASA and their experiment on macular degeneration-treated mice in space.  

Oculogenex founder talks about collaboration with NASA and ISS on experiment in macular degeneration

Jeffrey Cleland discusses the year for Ashvattha Therapeutics

David Hutton of Ophthalmology Times talks with Jeffrey Cleland, PhD, President and CEO of Ashvattha Therapeutic, about the company's D-4517.2, a unique nanomedicine technology for the treatment of wet AMD and DME.

I'm David Hutton of Ophthalmology Times. Joining me today is Jeff Cleland, CEO of Ashvattha Therapeutics. Thanks for joining us, Jeff. First off, the company had a great year in 2023. Tell us a little bit about D-4517.2 for wet AMD and DME.

Yeah, thanks, David, I appreciate the opportunity to speak with you again. Really, what we're focused on is trying to remove the need to have intravitreal injections, and have an at home administered product. Which is very unusual for treating retinal disease, because as you know, right now, everyone has to have an injection directly in the eye. And so what we're working on is the unique nanomedicine technology that was developed by our founders at Johns Hopkins University in the Wilmer Eye Institute. What they've done is taken what we call a hydroxyl dendrimer, and what it does is very uniquely targets inflammation, specifically in the back of the eye. 

And is taken up after systemic administration, by those activated cells in the back of the eye that are causing the retinal disease. And so what we've been able to show is that in animal studies, by putting on a drug that actually blocks VEGF signaling and blocks, the VEGF expression by those cells on this nanomedicine, we're actually able to shut down that neovascularization, that happens in the back of the eye that cause wet AMD, and DME. And so what we've been able to show in patients so far, is that it's very safe, very well tolerated, no systemic adverse events, which is very unusual for a lot of these drugs that, as you know, block VEGF, who often have systemic side effects. We've seen no systemic side effects, we're now on repeat dosing studies. Again, no systemic side effects have been noted so far. And in animals also, we've only seen a localized effect on the kidney when we give very, very high doses, because that's [inaudible] for this molecule. So now what we've done is a study where we're comparing directly in the same patients, and intravitrial dose of aflibercept. So giving them intravitrial aflibercept, then waiting to see how long it is before the fluid comes back by OCT. 

And when fluid comes back, we gave a single subcutaneous dose of our drug primarily at either one or two milligrams per kilogram, in wet AMD and DME patients. So 7, wet AMD and 5 DME patients. And those data were pretty encouraging to us, saying that even just a single administration, we were able to stabilize fluid in 11 out of 12 patients for at least 2 weeks, and then in 9 out of 12 patients for 4 weeks, and actually 4 patients remain stable with no change in fluid or BCVA out to 12 weeks from just a single administration, subcutaneous administration, so not intravitreal. So now the question is, can we prolong that and do a treat and extend and really treat the maintenance phase of this disease, these diseases. And really, what we're doing now is exactly that. 

David Hutton of Ophthalmology Times talks with Jeffrey Cleland, PhD, President and CEO of Ashvattha Therapeutics, about the company's D-4517.2, a unique nanomedicine technology for the treatment of wet AMD and DME.

DME

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