At the Angiogenesis, Exudation and Degeneration meeting, Dr David Brown presented his talk, “CANDELA: High Dose Aflibercept for Neovascular AMD.” Dr Brown is the Director of Clinical Research at Retina Consultants of Texas.

I'm David Hutton of Ophthalmology Times, and our team is providing virtual coverage of Bascom Palmer's Angiogenesis conference held in Miami. Joining me today is Dr David Brown, Director of Research at Retina Consultants of Texas, who will discuss Phase 2 results for high dose aflibercept 8 milligram in wet AMD. Thank you for joining us today, Dr Brown. Tell us about these exciting results.

Thanks, David. This is the first presentation of the 44-week results of the CANDELA study. And if you go through time, in almost every anti-VEGF trial we've done, we've seen a dose response curve: Half milligram did better than 0.3 in ANCHOR and MARINA, bevacizumab did better than ranibizumab in CAT, higher molar blockade you saw aflibercept did better than ranibizumab and, in the head-to-head trials, more anti-VEGF blockade.

So the big question is, can we do better with a higher dose of what's currently the market leader, aflibercept?

We tested 8 milligrams versus 2 milligrams in 106 patients, 53 patients in each arm. You know, there was some question whether this would make a difference. If you look at the HARBOR data with ranibizumab. There wasn't a difference when you made it four times higher dose. This is a different molecule though aflibercept is bispecific, right? It gets placental growth factor and anti-VEGF; it's also a larger molecule than ranibizumab.

What did we find? We found that in a population that was not a strict monthly, although it wasn't what I call the criminal retreatment criteria of many of the other trials, you had physician discretion on when to treat based on fluid.

It was masked, so it's head-to-head. At every time point, there was better anatomy with 8 milligrams. In other words, you dried up more of the retina. That was statistically significant. If you looked at fluid in the entire macular scan, almost double the amount of dry patients.

And more importantly, we actually saw a visual acuity benefit with this treatment paradigm in this population. 7.9 letters gained with the 8 milligram aflibercept versus 5.7 in the 2 milligram, and these time points were pretty consistent throughout that the higher dose, dried out more retinas, and improved the visual acuity.

It certainly shows us that it's probably a better drug, especially in a population where you're not treating monthly—and that's more real world because things get in the way, right? Christmas, Hanukkah, gallbladders—you miss appointments. And so in the real world, I'm hoping we can get this molecule.

Currently, it's being tested in a Phase 3 DME and AMD. That's a little different. When you do something for registration, you'd have to go against labelling, so it's going against aflibercept load and then every eight weeks, but we'll see. We're doing extended dosing out to 16 weeks, and I think it may be a decent competitor for the new faricimab and upcoming Kodiak molecules.

You mentioned that Phase 3 trials. Really what's the next step for this?

Basically, they're fully recruited. There'll be one-year trials. You know, they'll have to do some more studies to try to get the kind of label that faricimab got, the 4-week to 16-week, but we'll see.

We were concerned about a couple of things. I'm always worried about systemic safety when you're using an anti-VEGF that strong in the eye. We didn't see anything in this trial. We had two patients with increased hypertension. Fortunately, one was 2 milligram and one was 8 milligram, and we saw one patient with mild inflammation in the 8 milligram arm.

You know, as we get bigger, we got to make sure that we're not causing inflammation like a, you know, brolucizumab was a lot of protein in a molecule; this will be certainly more protein. So they're not out of the woods, but it's a promising start.

 This transcript has been lightly edited for clarity.

Videos

At Angiogenesis, Dr David Brown presented the Phase 2 results of the CANDELA study for high dose aflibercept 8 milligram for wet AMD; here, he discusses those results.

High dose aflibercept shows improvement for wet AMD patients in CANDELA

The 19th Angiogenesis, Exudation and Degeneration annual meeting, hosted by Bascom Palmer, was held February 11 and 12, 2022. The event was completely virtual, and it highlighted findings discussions about understanding and treating neovascular and exudative diseases of the eye.

Scientists, clinicians and healthcare experts gathered online to discuss developing pharmocotherapies as well as clinicial practice for management of neovascular AMD, macular edema, diabetic retinopathy, retinopathy of prematurity and additional exudative diseases of the eye.

Exploring the link between choriocapillaris, atrophy and neovascular AMD

At Angiogenesis, Dr SriniVas R. Sadda discusses how choriocapillaris may predict the rate of progression of atrophy.

Portal extension trial: PDS maintains visual and anatomic benefits over long term

Most patients who had received monthly injections, that is, 92%, preferred the PDS after switching, with 88% having a very strong preference.

Safety results for DAVIO trial: Positive outcomes for EYP-1901 for wet AMD

Previously treated patients showed significantly reduced treatment burden.

Updates on FOCUS trial: CFI supplementing gene therapy in GA

Dr Nadia K. Waheed reviews the latest updates on the FOCUS trial, evaluating AAV-based viral vector GT005 for the treatment of geographic atrophy.

Subretinal implant for advanced dry AMD determined to be safe, well-tolerated

This study showed that an investigational subretinal implant, CPCB-RPE1, containing allogeneic human embryonic stem cell-derived RPE cells, was safe and well-tolerated by patients with dry AMD.

Investigating Stargardt: RNA, gene therapy options for patients

Dr Carel Hoyng divulges the main takeaways from his Angiogenesis presentation, including the origins of Stargardt disease, correct diagnosis, ongoing gene therapy trials and the future of therapy.

Hope for Stargardt on the horizon: RNA therapy holds promise

Investigators in the Netherlands have developed an RNA therapy to halt the progression of Stargardt disease.

Leveraging deep learning for diabetic retinopathy detection with ultra-wide field imaging

During her talk at Angiogenesis, Dr Anat Loewenstein outlines how artificial intelligence could revolutionize diabetic retinopathy screening.

Blocking Connexin-43 may improve diabetic retinopathy, AMD

Dr David S. Boyer describes how blocking Connexin-43 may improve the retinal vascular system function in patients with diabetes, potentially creating a future of oral medication for treatment of diabetic retinopathy and AMD.

KESTREL, KITE studies: 100-week results of brolucizumab investigation

Dr Carl Regillo discusses the 100-week results of KESTREL and KITE, two pivotal Phase 3 studies for brolucizumab for the treatment of diabetic macular oedema.

Faricimab for DMO: Safe, durable treatment over the long term

Faricimab is the first bispecific antibody designed for intraocular use that blocks 2 pathways, the angiopoietin-2 (Ang-2) and the vascular endothelial growth factor (VEGF) A pathways.

Once-daily oral dosing: a future boon for patients with DMO, GA, kidney disease

A once-daily oral drug targets inflammatory processes and thus far has been found to be well tolerated in a Phase 2 safety trial.

THR-149 demonstrated to be safe, well-tolerated for treatment of DMO

KALAHARI study finds THR-149 to be safe, well-tolerated with preliminary efficacy as treatment for DMO patients who respond suboptimally to anti-VEGF.

KALAHARI results indicate BCVA increase, stable CST in high-dose group

Dr Arshad M. Khanani reviews the Phase 2 part A results of the KALAHARI study of THR-149 for the treatment of DMO.

Articles

A brief overview of findings presented at the 2022 Angiogenesis, Exudation and Degeneration meeting hosted by Bascom Palmer.

Angiogenesis 2022 review: Research makes strides in geographic atrophy, diabetic eye disease

Investigators in the Netherlands are focused on finding a treatment for Stargardt disease, an inherited progressive retinal disorder that affects about 1 in 10,000 individuals worldwide. They have developed a unique therapeutic approach, an RNA therapy, to stop the progression of the disease, which ultimately leads to legal blindness, according to Dr Carel B. Hoyng, professor of ophthalmology and shareholder and cofounder of Astherna with Dr Rob Collin, professor of Molecular Therapy for Inherited Retinal Diseases, both from Radboud University Centre, Nijmegen, Netherlands.

Dr Hoyng explained at the annual Angiogenesis, Exudation, and Degeneration 2022 conference that mutations in the 

 gene interrupt the visual cycle in Stargardt disease, which usually affects people in the first or second decade of life. That disruption in the visual cycle affects production of proteins and ultimately leads to lipofuscin accumulation in the retinal pigment epithelium (RPE). The goal is to restore the appropriate protein production in the visual cycle of these patients.

Stem cell, gene, and pharmacologic therapies have been considered for Stargardt disease. Among these, hESC-RPE cells are in trials as is the gene therapy SAR422459 in the StarGen trial. Numerous pharmacologic therapies are also being evaluated.

AONs, a new area of drug development, can prevent the gradual decline in vision that characterizes Stargardt disease by binding to the targeted RNA. These synthetic RNA molecules work to restore the proteins that are affected by the disease. This approach has already been shown to be promising in Leber congenital amaurosis, another inherited retinal disease. In these patients, eight intravitreally AON-treated eyes had a clinically meaningful (p = 0.001) improvement in vision compared with the untreated contralateral eye 3 months after treatment,

This therapy is advantageous in that it gets to the inherited root of the disease, i.e., the flaws in the RNA, and the small size of the molecules allows them to access the targeted retinal cells.

 in which Dr Hoyng participated, the investigators sought to identify missing heritability in these patients. They sequenced ABCA4 in eight cases with one variant and p.Asn1868Ile in trans, 25 cases with one variant, and three cases with no ABCA4 variant. In two-thirds of cases, they identified one known and five novel deep-intronic variants. AONs introduced to correct splice defects resulted in partial correction of the defects in the 

 gene, thus demonstrating the potential of this therapy.

“The importance of this research is that it tackles the root cause of Stargardt disease,” Dr Hoyng concluded.

1. Cideciyan AV, Jacobson SG, Drack AV, et al. Effect of an intravitreal antisense oligonucleotide on vision in Leber congenital amaurosis due to a photoreceptor cilium defect. Nat Med published online Dec 17, 2018; doi: 10.1038/s41591-018-0295-0

2. Sangermano R, Garanto A, Khan M, et al. Deep-intronic ABCA4 variants explain missing heritability in Stargardt disease and allow correction of splice defects by antisense oligonucleotides. Gen Med 2018; DOI: 10.1038/s41436-018-0414-9

Dr Carel Hoyng discusses his presentation at the Angiogenesis, Exudation and Degeneration meeting hosted by Basom Palmer. Entitled “Stargardt Disease, Towards Therapy,” Dr. Hoyng’s presentation explored the origins of Stargardt disease, proper diagnosis, current gene therapy trials and RNA therapy options.

Thank you for joining me today, Professor Hoyng, to discuss your presentation at the upcoming Angiogenesis meeting. Firstly, what are the main takeaway points from your upcoming presentation?

The main takeaway points from my presentation are that Stargardt's disease is the most common inherited retinal disease caused by a single gene. However, due to the difficulties of this gene—it's very large, it doesn't fit into an AAV virus—gene therapy until now, has not been undertaken at this moment. No trials in gene therapy.

There are a few trials that have a pharmacological approach by, for example, slowing down the visual cycle, which has a lot of times possible side effects. And we have undertaken now the efforts to make an RNA therapy, which is now called in United States ASO, antisense oligonucleotide, therapy to—with small molecules to repair the RNA. We are now in preclinical phase of research.

That's very interesting and how might the topics from your presentation be applied day to day?

One topic—subtopic—of my presentation, but very important, is that a lot of Stargardt's disease are not recognized properly.

So we know that the traditional picture of Stargardt's disease by a flecked retina and in children, but there is a part of Stargardt's disease that occurs in adults and is not recognized properly always. And is diagnosed mostly as dry AMD, which it is not. It's Stargardt's disease, and we have solved nearly all the genetic mutations in these patients.

So about 1/3 of patients with Stargardt’s disease are late-onset Stargardt's disease and should be recognized as that.

 What are the next steps for this research?

 In our research in where we try to repair the RNA mutations, the next step is that we will go into clinical Phase 1/2, and probably in about a year. And so that are the next steps at this moment. We are in talk studies. And the next step is to go to in-patients.

That's excellent. And finally, what are you most excited about in this field?

 In the total field of inherited disease, I am very excited that therapies are really coming on the market now. So all these kids that get blind by all different kinds of inherited retinal diseases. Now, in the near future, there will be therapies. And that's very exciting. I think one of the most exciting fields at this moment in ophthalmology.

 Indeed. Well thank you very much for that short interview. It was most interesting.

This transcript has been lightly edited for clarity.

At the Angiogenesis, Exudation and Degeneration meeting, Dr Carl D. Regillo presented his talk, “Brolucizumab for the Treatment of DMO: 100-Week Results from the Two Pivotal Phase III KESTREL and KITE studies.”

I'm David Hutton of Ophthalmology Times. The Bascom Palmer Eye Institute at the University of Miami is hosting its Angiogenesis, Exudation and Degeneration 2022 virtual edition. Joining me today is Carl Regillo, MD, who is presenting brolucizumab, for the treatment of DMO: 100-week results from the two pivotal Phase 2 KESTREL and KITE studies. Thank you for joining us today. Tell us about your presentation.

Thanks, pleasure to join in here. I had the privilege of presenting the 100-week, or essentially two-year, results of the two pivotal Phase 3 KESTREL and KITE studies, which is for brolucizumab for the treatment of diabetic macular oedema.

KITE and KESTREL are very similar global Phase 3 randomized clinical studies that compared brolucizumab to aflibercept for the treatment of DMO. We’re all aware of the favourable one-year primary endpoint results. And what I presented here were the two-year results.

The KESTREL was very similar across the entire two-year timeframe. In this study, it was 3 or 6 milligrams of brolucizumab compared to aflibercept, on-label, with the brolucizumab having a loading phase of five injections dosed every six weeks, and then in the maintenance phase dosed either every eight or 12 weeks through Week 100, depending on disease activity. And then the aflibercept arm, of course, the standard five loading doses monthly. And then every eight weeks thereafter, and that stayed through the 100-week endpoint.

The KITE study was a little different. It started the same, in many ways, as KESTREL did. It was only 6 milligrams of brolucizumab versus aflibercept on-label; the aflibercept arm was the same. But here in the second year, starting week 72. In the KITE study design, there was the option based on the presence or absence of disease activities potentially, re-extend the treatment interval from eight to 12 weeks or 12 to even 16 weeks. So there's an extended dosing in the KITE by design in year two. Baseline characteristics among the arms of both studies were well balanced with no significant differences, as was the baseline diabetic retinopathy severity. Again, between the studies and between the treatment arms.

We know that brolucizumab was found to be non-inferior to aflibercept at the primary endpoint, which is 52 weeks, but now we have extended the two-year data out to week 100 for both studies, and the visual gains are well maintained compared to aflibercept over the entire study timeframe of both studies.

And that meant within just a couple letters, brolucizumab 6 milligrams versus aflibercept 2 milligrams all the way up to week 100.

And the same goes for disease control as measured by central subfield thickness. Looking at the OCT change from baseline, we see brolucizumab at 6 milligrams performing comparatively to aflibercept 2 milligrams throughout the entire study timeframe through year two. And this is with reduced dosing in the brolucizumab arm compared to aflibercept again in both studies.

In fact, there's trends particularly with the KITE study to have better drying. And in fact looking at the proportion of patients with effectively a dry macula, defined as central subfield thickness of less than 280 microns at week 52 and week 100. Despite lower numbers of injections with brolucizumab 6 milligrams, there's actually a higher percentage of patients, so numerically favouring brolucizumab compared to aflibercept at both weeks 52 and weeks 100 of both studies.

What we observed in terms of treatment intervals. Again, KESTREL was just the option of eight weeks versus 12 weeks, and at end of study week 100 in KESTREL, about 1/3 of patients on brolucizumab were being treated every 12 weeks. And in the KITE study nearly 50% were either 12 or 16 weeks with about a quarter, 24.8%, achieving in every six-week dosing interval. So extended even more in the second year in KITE for the 6 milligram arm.

We're looking at DRSS of course in these diabetic retinopathy studies, and again brolucizumab 6 milligrams compared favourably to aflibercept in terms of the proportion of patients gaining two or more steps in DRSS score at weeks 52 and weeks 100. In fact, some trends again with brolucizumab showing slightly higher percentages of two or more step improvement.

And then when it came to safety, brolucizumab’s overall safety profile at week 100 in both studies was very similar to what we've known in how brolucizumab has looked previously at the primary endpoint in both of these DMO studies, and also comparable to the wet AMD studies. What we didn't see though were a lot of new cases of retinal vasculitis; there were some cases of vascular occlusion, but not related to inflammation or retinal vasculitis.

And so the year-two safety profile actually looked a bit more favourable compared to year one. Rates of interactive inflammation was about the same again; not a lot of new cases in year two. Came out to, in the 6 milligram arms, 4.2% for intraocular inflammation in the KESTREL study and 2.2%, in KITE, and that was compared to aflibercept at 1.1% in KESTREL to 1.7% in KITE. So there's actually very little difference in the IOI rates in the KITE study.

So in summary, the vision gains achieved with brolucizumab 6 milligrams in both KITE and KESTREL were very comparable to aflibercept all the way out now to week 100, despite fewer injections. Atomically, the 6 milligram dose performed very well; in fact, yielded higher percentages of patients with complete macular drying in these DMO patients. And this was achieved with less dosing. In KITE 25% of patients approximately were able to be extended to 16-week treatment animals by the 100-week endpoint.

And with regards to overall safety, safety profile is similar to previous studies, both DMO and wet AMD intraocular inflammation imbalance with higher rates, of course, brolucizumab that we’ve seen before, but very few new cases of inflammation and no new cases of retinal vasculitis or vascular occlusions.

Both of these are Phase 3, so what's the next step?

So the next step is potential FDA approval. So these are registration studies for the indication of DMO. Brolucizumab is FDA approved for the treatment of neovascular AMD, and this would sort of complete that process, potentially to be improved for this disease state.

Well, what brolucizumab looks to be doing here for DMO is a bit better drying, which is important because that is correlated to better vision outcomes for some patients at least. So we had to have a drug that dries better for DMO for our patients is potentially important as a way to get better vision gains. And it also looks to be a little more durable. And so potentially we can get better outcomes with less treatment.

At the 2022 Angiogenesis, Exudation and Degeneration meeting hosted by Bascom Palmer, Dr Arshad M. Khanani presented his talk, “Phase 2 Results of THR-149 in Patients with DME: KALAHARI Study Part A.”

I'm David Hutton of Ophthalmology Times with our coverage of the Bascom Palmer Eye Institute's 19th Annual Angiogenesis, Exudation and Degeneration 2022, virtual edition. Arshad Khanani, MD, presented data on part A of the KALAHARI trial. Thank you for joining us today. Tell us about your presentation.

Thanks for having me here, David. At Angiogenesis, I presented the results of the part A of the Phase 2 KALAHARI study looking at efficacy of THR-149 In patients with diabetic macular oedema.

THR-149 is a highly potent plasma kallikreininhibitor that is designed for DME. P-kal is clinically validated target for oedema inflammation and prevention of micro haemorrhages, and we know that P-kal is a key driver in patients with DME, in a subset of patients independent of VEGF. So THR-149 is a selective P-kal inhibitor having the potential to treat 40 to 50% of patients with DME that have suboptimal response to anti-VEGF treatment. 

Looking at the study design, this study included patients with suboptimal response to prior anti-VEGF and who can benefit from new mechanism of action. They had to have CST of greater than equal to 320 microns as well as visual acuity between 39 and 73 letters. They had to receive an aflibercept injection three to six weeks prior to screening, and if they met the criteria, they're enrolled in the study.

The part A of the study was dose selection for THR-149. Here we had three different doses: 0.01 milligram, 0.04 milligram and 0.13 milligrams, and patients receive three injections once a month—so day one, month one, and month two—and then the dose level selection for part two was done a month after the last dose.

Here are the results. We found that the multiple intravitreal injection up to three injections of THR-149 were safe and well-tolerated in all treatment groups. There was no events of intraocular inflammation. Also, we found that in the high-dose group, which is the dose that has been selected to go forward, we saw mean BCVA gain of 6.1 letters at month three with gains observed up to six months, as well as CST stabilization over the six-month study period compared to baseline.

Remember that after the three doses, patients were followed, and not treated up to six months in this part A.

There was no need for rescue treatment in the high dose. Also a postdoc analysis was done by the reading centre, and what they looked at was the inclusion criteria on imaging and excluding two subjects with abnormalities and OCT. A mean gain in BCV of 9.3 letters was observed at month three in the high dose group, and it was maintained up to month six.

And so based on the results of the Part A, the high dose of THR-149 was selected for the part B of the KALAHARI study. Part A learnings have been implemented in Part B using an amended study design, and part B is currently enrolling globally. So we are looking forward to have the Part B of the trial enrolled and have data in the near future. Thank you for having me here, David.

The Phase 2 part A results of the KALAHARI Study that assessed the effects of THR-149 (Oxurion), a plasma kallikrein (PKal) inhibitor, found that up to 3 intravitreal injections were safe and well-tolerated in patients with diabetic macular oedema (DMO), according to Dr Arshad M. Khanani, who reported the results at the Angiogenesis, Exudation, and Degeneration 2022 conference. He is from Sierra Eye Associates, Reno, NV.

PKal is a principle driver of DMO pathology apart from vascular endothelial growth factor (VEGF) and is a validated target for oedema, inflammation, and prevention of microhaemorrhages, Dr Khanani explained.

The value of a PKal inhibitor lies in the fact that it can potentially treat 40% to 50% of patients who do not respond well to anti-VEGF therapies.

In this study, 20 patients were randomized to 1 of 3 doses of THR-149, 0.01, 0.04, or 0.13 mg, to evaluate the systemic/ocular adverse events, serious adverse events, and the mean changes in the best-corrected visual acuity (BCVA) and central subfield thickness (CST).

Patient inclusion was based on a suboptimal response to 5 or more anti-VEGF injections and a CST of 320 microns or more and a BCVA of 73 Early Treatment Diabetic Retinopathy Study letters or fewer and 39 letters or more. Patients who were included also had had a last injection of aflibercept (Eylea, Regeneron Pharmaceuticals) 3 to 8 weeks before study screening.

The mean age of the treated patients was 63.4 years; 95% were Caucasian, and 60% were male. The demographics of the patients in the 0.01-, 0.04-, and 0.13-mg groups were similar at baseline. The groups included 6, 6, and 8 patients, respectively.

Most patients had mild-to-moderate diabetic retinopathy (DR). Two patients randomized to the 0.01-mg dose had more severe DMO and DR for a longer time. During the year before screening for this study, 80% of patients had received more than 5 anti-VEGF injections.

The CST in the group treated with the 0.13-mg dose was slightly thinner (421 microns compared with 465 and 470 microns in the 2 lower doses).

No serious adverse events or intraocular inflammation developed. Any adverse events that did develop were mild to moderate; one adverse event (worsening of DMO) was associated with the treatment and one (IOP increase) with the injection procedure in the lower dose groups. The number of adverse events did not increase in association with the increasing dose or number of injections.

Dr Khanani reported, “In the high-dose group, at month 3, 1 month after the third injection, the BCVA increased by a mean of 6.1 letters. The gain in BCVA was maintained out to month 6 with no need for rescue treatment.”

In addition, in the same group, the CST was stable out to month 6.

A post-hoc analysis of the BCVA changes found that 2 patients had abnormalities on optical coherence tomography (OCT). Their exclusion from the analysis showed a mean letter gain in BCVA of 9 or more letters that remained out to month 6.

In the high-dose group, 50% of subjects had a 2-line or more improvement in BCVA up to month 6, 4 months after their last THR-149 injection, without needing rescue therapy.

The take-home messages from part A are that up to 3 intravitreal injections of THR-149 were safe and well-tolerated. A mean gain of 6.1 letters of BCVA was seen at month 3 that was sustained out to month 6 accompanied by a stable CST.

Following the review of the results in part A, the high dose was selected for evaluation during part B when the dose will be compared with aflibercept. Based on the post-hoc analysis, the target population was refined and patients with imaging abnormalities were excluded.

Based on the results in part A, the high-dose was selected for evaluation during part B when the dose will be compared with aflibercept. Patients are currently being enrolled in part B.

Dr Khanani stated, “The data from the part A of the KALAHARI trial is encouraging. It shows that THR-149 has the potential to improve vision in patients with DMO who have a sub-optimal response to anti-VEGF therapies.”

Dr Anat Loewenstein discusses her presentation at the Angiogenesis, Exudation and Degeneration meeting. Her talk, “Detection of Diabetic Retinopathy from Ultra-Wide Field Scanning Laser Ophthalmoscope Images: A Multi-Centre Deep-Learning Analysis,” delves into how artificial intelligence can aid in patient screening. In testing, the deep learning model scored well in sensitivity, specificity and accuracy.

I'm David Hutton of Ophthalmology Times. The Bascom Palmer Eye Institute at the University of Miami is hosting its Angiogenesis, Exudation and Degeneration 2022 virtual edition. Joining me today is Anat Lowenstein, MD, who is presenting “Detection of Diabetic Retinopathy from Ultra-Wide Field Scanning Laser Ophthalmoscope Images: A Multi-Centre Deep-Learning Analysis.” Thank you for joining us today. Tell us about your presentation.

 Thank you, David. I'm very happy to tell you about my presentation on diabetic retinopathy detection from ultra-wide field scanning laser ophthalmoscope images.

So we all know that usually diabetic retinopathy screening uses a limited field of view, 45 to 50 degrees. And theoretically, ultra-wide field imaging can be an alternative to the existing model. But interpretation of these images does require expertise of human graders that are very knowledgeable in diabetic eyes.

We're suggesting models of deep learning to detect variability and assess the referral and vision-threatening diabetic retinopathy, which are important parameters that we want to use.

So in order to do that, we develop models to assess both ability to evaluate a referral diabetic retinopathy and vision-threatening one. And we use the transfer learning procedure for each such a model.

Basically, we looked at almost 10,000 images from almost 2,000 eyes with diabetes. And we had sets for training and validation, the primary set and external testing the external data sets. And when we looked at the sensitivity, specificity and accuracy, we could see that they're pretty high for the primary dataset, 86.5% 82.1% and 83.1%, respectively. So pretty high sensitivity, specificity and accuracy, which were shown by our model.

Also, we were able to show on the receiver operating curves that the performance of the deep learning is on referable diabetic retinopathy were pretty high. So pretty good results on that front as well.

And also for vision-threatening diabetic retinopathy. Again, the area under the receiver operating curve, it was able to show us the rate of accuracy pretty high with our model.

Basically, we were able to show that the diagnosis performance of the deep learning system for detecting referrable diabetic retinopathy and vision-threatening diabetic retinopathy in both primary and external validation sets were pretty high with the ratio of sensitivity, specificity and positive predictive value for both was around 90%. So pretty high and good performance.

And we will show some examples of AI with diabetic retinopathy with referral that the current neuropathy and so forth. So basically, we are able to show high performance in both variability and severity of diabetic retinopathy. And we suggested as a model to facilitate screening of patients with diabetes, for referrable and vision-threatening diabetic retinopathy.

We believe that such readability is crucial for the screening of this disease, it can identify hidden lesions and allows for objective identification of diabetic retinopathy severity.

Of course, our study has advantages and limitations. One of the advantages is that we have multiple ethnicities and geographical location.

But of course, there are also limitations such as the fact that some lesions cannot be captured by the system, maybe artifacts that do affect the prediction. And in the proliferative diabetic retinopathy primary data set, we had a limited number of images.

Of course, the fact that OCT imaging was not used to evaluate the ground truth of diabetic macular oedema is a major limitation of our trial. But I think I can conclude that the deep learning system did demonstrate their high rate of identifiable referable diabetic retinopathy cases and that the model has the potential to be implemented in clinical settings, and therefore reduce the burden of both patients and clinicians. Thank you very much, David.

Interim long-term safety and efficacy data for the Port Delivery System (PDS) with ranibizumab (Susvimo, Genentech) indicate that the device maintains the visual and anatomic outcomes over 3 years and beyond.

Moreover, patients with neovascular age-related macular degeneration (nAMD) prefer this treatment over monthly injections of anti-vascular endothelial growth factor drugs, according to David Eichenbaum, MD, who reported the findings of the Portal Extension Trial at the Angiogenesis, Exudation, and Degeneration 2022 virtual meeting. He is Director of Research, Retina Vitreous Associates of Florida, and Collaborative Associate Professor of Ophthalmology, Morsani College of Medicine at the University of South Florida, St. Petersburg.

A caveat is that 2% of patients in the extension study developed endophthalmitis associated with conjunctional erosion.

The PDS provides continuous delivery of 100 mg/ml of ranibizumab into the vitreous. The previous phase 2 Ladder and phase 3 Archway studies provided results that were comparable to monthly injections but without the enormous treatment burden.

The Portal Extension Trial includes patients with nAMD from the Ladder and Archway studies to determine the long-term safety of this treatment.

In the Ladder study, patients received the PDS and 1 of 3 doses (10, 40, or 100 mg/ml) that were refilled as needed or monthly injections. Archway patients were treated with PDS 100 mg/ml with fixed 24-week refills or exchanges or monthly injections. In the extension study, the patients are treated with the PDS every 24 weeks. The treatment efficacy was assessed for those who moved from the Ladder study to the Portal Extension Trial. Patients also completed a questionnaire regarding treatment preferences. The safety was determined by analysis of pooled data from all randomized to the PDS in the 3 clinical trials.

Eichenbaum reported that the mean center point thickness and the best-corrected visual acuity (BCVA) remained stable in the patients treated with PDS 100 mg/ml and in those who had been treated with monthly ranibizumab injections from baseline to month 48. The mean BCVA letter change was 0.1 in the PDS group and 2.3 in the monthly injection group.

The vast majority of patients, 95%, implanted with the PDS did not need supplemental treatment before the refills, indicating the persistence and durability of the treatment.

Between 22% and 24% of patients had an adverse event of special interest. The most frequently seen events of special interest, about 50%, were development of cataract; 2% of cases in the PDS population developed endophthalmitis. The patients who developed endophthalmitis had an association with conjunctival erosion and conjunctival retraction. Eight of the 11 patients who developed endophthalmitis had a concurrent conjunctival erosion; 7 of the patients maintained vision over 20/40 or better at the last follow-up and 4 had substantial visual loss. Seven of the 11 had the implant removed.

Most events of special interest occurred during the first 1 to 2 years of the study. However, conjunctival erosion continued throughout the study.

“The conjunctiva must be watched over the long term as well as being recognized and managed,” Eichenbaum emphasized.

Patients who had substantial vision loss, defined as 15 letters or more, had conjunctival erosion throughout the study.

He concluded, “The efficacy outcomes over the long term in the Portal Extension Trial are maintained, with the PDS 100 mg/ml demonstrating stable vision and anatomy. Every-4-week treatment durability and reduced treatment burden persist beyond the results of the phase 3 trial and the results in the extension study are similar. Long-term safety is well characterized and manageable; 2% of patients had endophthalmitis in the PDS population that was most often associated with conjunctival issues and exposure. Patients preferred the PDS, with 92% who switched from injections expressing a strong preference or fairly strong preference for the PDS at week 48.”

Positive safety results from the Phase 1 DAVIO clinical trial were seen for the DuraSert implant (EYP-1901, Vorolanib, EyePoint Pharma), a bio-erodible implant for previously treated wet age-related macular degeneration (AMD), according to Dr Jay S. Duker, Chief Operating Officer, who reported the 8-month results at the Angiogenesis, Exudation, and Degeneration 2022 Conference.

“The major unmet need in current wet AMD therapy is longer term therapies, in that the currently approved therapies typically need to be reinjected very 1 to 2 months in most patients,” Dr Duker explained. EYP-1901, is an anti-vascular endothelial growth factor (VEGF) treatment that may meet that need. It is delivered as an in-office intravitreal injection with the potential for every six month dosing intervals in most patients.

The key safety findings with EYP-1901, a tyrosine kinase inhibitor (vorolanib) in a bio-erodible form of DuraSert, with a minimum of 8 months of follow-up of all eyes were that no ocular serious adverse events (SAEs) were reported in any eyes. The majority of ocular AEs were mild and to be expected from intravitreal injections.

“Specifically, there were no reported SAEs related to significant intraocular inflammation, best-corrected visual acuity [BCVA] reduction, intraocular pressure elevation, and no endophthalmitis, vitritis, retinal detachment, migration of the inserts into the anterior chamber, or retinal vasculitis,” he commented. In addition, there were no drug related systemic SAEs reported

The results also showed stable VA and central subfield thickness (CST) on optical coherence tomography (OCT) over 8 months. The median time to the first supplemental anti-VEGF treatment after EYP-1901 was 6 months. Specifically, the study showed that 76% of eyes did not require a supplemental anti-VEGF treatment up to 4 months, 53% of eyes did not require a supplemental anti-VEGF treatment up to 6 months, and 41% of eyes did not require a supplemental anti-VEGF treatment up to 9 months, Dr Duker reported.

These results lead to clinically significant reductions in treatment burden: a 79% reduction in treatment burden at 6 months and a 75% reduction at 8 months.

This is a Phase 1, open-label, dose-escalation, clinical trial of EYP-1901 that enrolled 17 patients all of whom had previously treated wet AMD. One week after screening and a standard-of-care anti-VEGF injection, the patients received 1 injection of EYP-1901. No retreatments with EYP-1901 occurred in this trial.

The primary study endpoint was safety; the secondary endpoints were BCVA and CST measured by OCT.

The investigators also looked at both the number of eyes that did not require rescue treatment at various time points and the degree to which the anti-VEGF treatment burden was reduced after administration of EYP-1901.

The study included four dosing cohorts: low dose (440 ug, single dose), low medium dose (1,030 ug, single dose), mid dose (2,060 ug, single dose), and high-dose (3,090 ug, single dose).

The patients included in this study had diagnosed wet AMD in the study eye for at least 4 months prior to the screening visit. All patients had to have received at least 3 previous injections with an anti-VEGF product in the study eye, such as bevacizumab (Avastin, Genentech), ranibizumab, (Lucentis, Genentech), or aflibercept (Eylea, Regeneron) during the previous 6 months and a BCVA between 25 letters (20/320 Snellen equivalent) and 75 letters (20/32 Snellen equivalent).

The future for EYP-1901 includes advancing into three Phase 2 clinical trials by 2023, start of a wet AMD Phase 2 trial expected in the third quarter of 2022 (3 arms: 3 mg EYP-1901, 2 mg EYP-1901; Eylea control), start of a study to treat diabetic retinopathy expected in the second half of 2022, and a study to treat retinal vein occlusion beginning expected by Q1 2023.

“With EYP-1901, the sustained, stable release over 6 months or longer may lead to fewer patient visits, fewer injections, and possibly better visual outcomes through uninterrupted receptor blockade. In addition, EYP-1901 has the potential for up to every 6-month dosing, which would address adherence issues and, therefore, possibly treat wet AMD more effectively,” Dr Duker concluded.