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High-Frequency Deep Sclerotomy A MIGS Procedure for Mild-to-Moderate Glaucoma

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Session moderators, speakers and audience members all will examine and analyse the most relevant and controversial issues within the field of ophthalmology. 



Countdown to COPHy 2023: Let the evidence-based debates and discussions begin

EMBL-EBI researchers use UK Biobank data to uncover new information about rare diseases of the eye.

Large-scale study focuses on new insights into rare eye disorders 

A look at what’s in the therapeutic delivery pipeline for these disorders.

The ins and outs of gene therapy for inherited optic neuropathies

Yusuke Oshima, MD, PhD, in a presentation at the 38th Asia-Pacific Academy of Ophthalmology Congress, Kuala Lumpur, Malaysia, discussed the advantages of using a beveled-tip ultra-speed probe for complete vitreous shaving during retinal detachment vitrectomies.

APAO 2023: Probe with beveled tip offers surgeons an all-in-one instrument for retinal detachment vitrectomy

Further research is needed before dietary nitrate intake can be recommended as a therapy for age-related macular degeneration, according to the study authors.


Cohort study: Considering if dietary nitrate intake is associated with progression of AMD

Arun Singh, MD, discusses Retinoblastoma in 2023 and the advancements of tumor chemotherapy from his presentation at the Asia-Pacific Academy of Ophthalmology (APAO) 2023 conference with David Hutton, Managing Editor, Ophthalmology Times®.

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


Hello, I'm David Hutton of Ophthalmology times. I'm joined today by Dr. Arun Singh. During the Asia Pacific Academy of Ophthalmology conference in Malaysia, he participated in a panel discussing retinoblastoma in 2023. Tell us a little bit about the presentation and some of the key takeaways.

Well, thanks for having me. This is a regional meeting Asia Pacific Academy of Ophthalmology meeting. And at the symposium, there were speakers from Thailand, Malaysia, Hong Kong, China, India, Indonesia. And of course, Dr. Eagle from United States. I was the chair of the symposium, which covered several aspects of retinoblastoma.

So, just to summarize the key findings, first of all, there's a lot of interest and research in the genetics of retinoblastoma, particularly in the genes that are altered in the tumor that can be accessed through aqueous humor biopsy. So we do not need a tumor sample, we do not need a blood sample, we can actually get the genetics from the cells that are floating or dead in the anterior chamber. And from that, we are able to prognosticate to some extent, what the tumor response will be to chemotherapy. So that's one exciting area.

Second is of course, advancements of tumor chemotherapy delivery to the tumor. And we are familiar with the newer methods that include intra-arterial chemotherapy, which is now being expanded to the developing nations. And we have Dr. Hamzah, talking about this treatment that is being used in Malaysia.

And then the old topics like extraocular extension, how the pathology identifies the prognosis, which patients can benefit from adjuvant chemotherapy. All that is highlighted by the presentation from Dr. Renbing Jia from China. As you might know, China and India are the countries with the largest number of retinoblastoma in the world. And therefore, speakers from these countries have tremendous experience because they see large number of cases.

And in the last one, I would like to point out that in addition to these high tech innovations in drug delivery and genetics, there's also an aspect of access to care. Again, this happens in developing nations, there are several barriers – social, cultural, and financial. And people are coming up with innovative methods of delivering health care, or specifically to this complex treatments that children with retinoblastoma need. And this is how it was highlighted by Dr. Rita Sitorus, from Indonesia. 

So overall, it's a new look at old problems. And that keeps us excited, and takes us, gives us incentive to do more work in this field. Thank you.

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Arun Singh, MD, discusses Retinoblastoma in 2023 and the advancements of tumor chemotherapy from his presentation at the Asia-Pacific Academy of Ophthalmology (APAO) 2023 conference.

APAO 2023: Looking at retinoblastoma in 2023

Carl D. Regillo, MD, highlights the Talon Phase 3b results for brolucizumab vs aflibercept in a matched treat-and-extend superiority study for neovascular AMD at the virtual 2023 Angiogenesis conference.

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

 We're joined today by Dr. Carl Regillo of Wills Eye Hospital. We're delighted to have you at this year's virtual Angiogenesis meeting. Could you take a couple minutes and tell us about the results of the Talon Phase 3b study?

 Sure. Thanks, Sheryl. Glad to be here. The Talon Phase 3b study is a unique study. In fact, it's the first of its kind to have identical, variable, individualized treatment regimens. We call it treat and extend.

This study was designed to mimic, to be most accurate as possible, to create what we do in clinical practice: treat and extend but to maintain the macula in the driest possible state. That's what we do in practice. What we did here was randomize patients in 1: 1 fashion in this double-masked, prospective, large-scale international clinical study, where patients were getting either the brolucizumab standard 6 milligram FDA-approved dose, or the standard 2-milligram aflibercept dose, with some loading doses monthly and then every other month, and then by 4 week extensions treat and extend all the way out to 16 weeks. There were two endpoints: the primary endpoint at 32 weeks, and the final endpoint or final study assessment at 64 weeks. That's the new data that I presented.

 Were the results what you expected them to be? Were there any surprises or any other discoveries that came out along the way?

 Well, actually, the study really has very interesting results. It says, with certainty, proven that brolucizumab does indeed last longer, has greater durability than aflibercept. Now, we knew that at the primary outcome when I first presented this at the ASRS meeting in 2022. This held true all the way to the final outcome where patients were allowed to be extended up to 16 weeks.

What we're seeing here is a much smaller proportion of patients being treated with brolucizumab compared with aflibercept, frequently, every 4, 8 weeks or so and a much larger percentage of patients being extended out 12 and 16 weeks. In fact, over double the amount of patients were successfully managed; that is, maintained in a dry macular fashion at 16 weeks compared with aflibercept.

Previous studies gave us the suggestion that brolucizumab might last longer but this is actually the proof. They're identical treatment regimens and held all the way into year 2, the final outcome at 64 weeks. Keep in mind though not only is it more durable; of course, durability means nothing if it doesn't maintain the vision gains. In fact, brolucizumab was visually noninferior to aflibercept with essentially identical like vision gains, all the way through the entire course of the study up to 64 weeks.

 What does this study mean long range for clinicians and their patients?

 Well, you know, we knew brolucizumab was an effective medicine. We had that sense it lasted longer. Now we have that proof. I think the study design is a good one for future studies and future comparisons of other therapeutics. Brolucizumab has been on the market and FDA approved now for several years with the treatment of neovascular AMD. It's been held back because of a safety profile with higher rates of intraocular inflammation and certain adverse event rates that are higher than the drugs we had been using. That was also seen in the Phase 3b Talon study. That's not a surprise. The safety profile was similar to what we saw in the brolucizumab Phase 3 pivotal studies. And that holds back its particular usage in the setting of neovascular AMD so when you think: Oh, if it works as well, but lasts longer, we'd be using that first line. Unfortunately, because the safety is not quite as good, it's not really going to be used first line.

Nonetheless, it gives us confidence that we might be able to use it accepting those higher risks if we want to get greater durability for our patients. And then, of course, newer drugs being introduced, such as faricimab and maybe even later this year high-dose aflibercept may also show similar durability.

Angiogenesis 2023: What the Talon Phase 3b study results mean for neovascular AMD

This transcript has been lightly edited for clarity.

 We're joined today with Dr. Justis Ehlers, who is presenting this year at the American Academy of Ophthalmology. Welcome. Dr. Ehlers, could you tell us a little bit more about your talk this year?

 Sure, Sheryl. Thank you so much for having me; it's a pleasure to be able to share a little bit about the data that we're presenting at the Academy meeting.

The focus of the talk, and as some of the research that we're presenting is really around the importance of understanding what's going on from a fluid dynamics standpoint in wet macular degeneration, and how that may impact visual outcomes. There's been a lot of research that suggests that the presence of different fluids may have different impacts on overall visual acuity. In particular, some of the early data has said that subretinal fluid may be associated with better visual acuity and intraretinal fluid may be associated with more significant visual acuity loss.

Interestingly, in some of these studies, they've actually demonstrated that the presence of subretinal fluid may actually be better than not having any fluid in terms of vision. And we wanted to dive into that a little bit more in terms of evaluating ways to look at the OCT, that may have a better understanding for us as clinicians.

And what we were able to do is, using some advanced image processing, is look at the overall intact aspect of the ellipsoid zone and the integrity that's there. And really judging whether or not there may be underlying atrophy.

And what we found was interesting, and that was was that if the outer retina was intact, the retina being dry was clearly the best visual acuity outcome, really suggesting that that really is what we should push for, as clinicians. Subretinal fluid being present was the second in terms of overall visual acuity outcomes, and then intraretinal fluid, and then actually underlying atrophy being the overall worst visual acuity outcomes.

And so you can see how understanding that key feature of the outer retina really drives the difference that may push outcomes towards more limited visual acuity when you sum the entire population together.

The last piece that we looked at was this concept around volatility. And that is, is that if the fluid is changing significantly, does that have an impact overall? And one of the things that we did find that I think was sort of unexpected, was that dynamic subretinal fluid, so that is that fluid that's changing from visit to visit, appears to have a more deleterious effect on visual acuity than fluid that's static.

And so again, really understanding and as we have more and more therapeutics available to us to understand what's happening on a really monthly, and really weekly basis, for these patients will be helpful to understand how we can optimize their outcomes overall.

 Excellent. And what would be the take-home message for the clinician in their daily practice?

 I think you'll one of the key take-home messages is just use caution in terms of how quickly you extend patients, and really understanding early on--is fluid resolving? And you're not just capturing that. And I think you know, striving for the best fluid outcome early on in treatment, in terms of resolution are really the things that I've taken away from this.

 Well, thank you so much for sharing that. We look forward to learning more about your presentation.

At AAO 2022, Dr Justis Ehlers presented a talk entitled, "Defining the Fluid Problem in Neovascular AMD: To Dry or Not to Dry?"

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Fluid dynamics in wet macular degeneration: How fluid type affects visual acuity

Dara Conlon, Executive Vice President of EURETINA, and Prof. Anat Loewenstein, General Secretary of EURETINA, discuss some key features of this year's Congress.

EURETINA leadership discusses what to expect at the 2022 Congress, outlines Women in Retina programme

My name is Sally Ong. I'm an assistant professor of ophthalmology at the Wake Forest University School of Medicine as well as an adjunct professor of ophthalmology at Wilmer Eye Institute.

At the Wilmer Eye Institute, we completed a multicentre, retrospective cohort study looking at giant retinal tear related retinal detachments that were surgically repaired with vitrectomy versus vitrectomy and scleral buckling. And we examined surgical, anatomic and functional success between the two groups.

We found that there were really no differences in baseline demographics between the two groups, except for a higher preponderance of patients with developmental abnormalities in the vitrectomy and scleral buckling group versus the vitrectomy alone group.

We also found there were no differences in the use of surgical adjuncts between the two surgical groups. There were no differences in rates of retinectomy, drainage retinotomy, and no differences in the use of surgical tamponade between the two groups.

When we looked at anatomic success rates, we found that there was no difference in single surgery anatomic success at six months or one year between the two surgical groups. The single surgery anatomic success for vitrectomy-only eyes was 77% versus for vitrectomy and scleral buckling eyes, it was 86%.

Next, we stratified the eyes by age. And we found that in children less than 18 years of age, there was a difference in single surgery anatomic success at one year. Specifically, the success rate was higher in vitrectomy and scleral buckling group: it was 89% versus in the vitrectomy-only group, the success rate was 56%.

However, when you looked at adults, there was no difference in single-surgery anatomic success between the two surgical groups.

We also looked at visual functional outcomes. And in adults, again, there was no difference in visual outcomes at one year between the two surgical groups; however, in children, there was a difference in the two surgical groups. Visual outcomes were better in the vitrectomy and scleral buckling group, versus vitrectomy-only group for children.

So in conclusion, we found that in eyes with giant retinal tear-related retinal detachment, for adults at least, there was no difference in anatomic or visual, functional success at one year between vitrectomy alone versus vitrectomy and scleral buckling. However, in children, we found that anatomic and visual outcomes success was higher in the group that was treated with vitrectomy and scleral buckling versus vitrectomy alone.

And we hypothesize that is because when you have a giant retinal tear, it looks almost like a relaxed retina to me. And that may be sufficient for adults, but in children, where the vitreous is still very formed, having that scleral buckle as an adjunct, it's really helpful to increase your surgical anatomic and functional success.

At ASRS 2022, Dr Sally Ong presented a talk entitled, “Vitrectomy vs Vitrectomy With Scleral Buckling in the Treatment of Giant Retinal Tear Related Retinal Detachments: International Multicentre Study.” Here she shares the biggest takeaways.

Paediatric eyes repair better with scleral buckling, adults need vitrectomy only for giant retinal tear-related detachments 

In Fort Lauderdale, Florida, United States, Dr Justis P. Ehlers presented a talk entitled, “The impact of compartmental exudative volatility on visual acuity and ellipsoid zone integrity in neovascular AMD.”

So it's my pleasure to share some of the results from our research today. As many of you know, there's been a lot of work done recently examining the impact of central subfield thickness, volatility and the overall impact on visual acuity in clinical trials in wet AMD.

One of the big questions that remains is: What's driving that volatility in retinal thickness changes, and do those changes actually end up with important anatomical sequela that we can understand and strive to minimize as clinicians?

For this study, what we did is we looked at the Phase 3 Hawk clinical trial, we're able to use machine learning augmented, multilayer segmentation, as well as feature extraction to pull out specific fluid compartments including intraretinal fluid and subretinal fluid, as well as subretinal material.

Using this, we're able to look at volatility from week 12, after the loading phase all the way to the end of year one and to evaluate the impact of high volatility in each of those compartments on visual acuity outcomes and on anatomic sequela.

What we found was that each of those compartments intraretinal fluid, subretinal fluid, as well as subretinal material all had a negative impact on visual acuity if it was in the high volatility group, whereas eyes that were in the low volatility group continued to improve vision over time. When we looked at the anatomic sequela, what we found was, in fact, the subretinal fluid compartment had the biggest driver towards negative anatomic outcomes, particularly increase in subretinal fibrosis and subretinal material, as well as poor maintenance of ellipsoid zone integrity.

Interestingly, this flies a little bit in the face of what we know in terms of subretinal fluid. We've seen in the past that this can be linked with overall better visual acuity at specific time points, but what this shows is that potentially overall activity and the volatility of that compartment is an important discriminator between eyes that may do well with tolerating subretinal fluid, that static, versus really minimizing that subretinal fluid that may be volatile and dynamic. So overall, more work needs to be done in this area. It's really an exciting opportunity given the new and advanced image analysis techniques that we have, and we're excited to share it here at Retina World Congress.

Dr Justis P. Ehlers dissects the revelations from the data in the Phase 3 Hawk clinical trial regarding the impact of central subfield thickness, volatility and the overall impact on visual acuity.

Clinical trials in wet AMD: Impact of central subfield thickness, volatility on visual acuity

In Fort Lauderdale, Florida, Dr Dilsher Dhoot gave a presentation: “Effects of Time Since Diagnosis to Intravitreal Aflibercept Injection and Baseline BCVA on Outcomes in CRVO: Post Hoc Analysis of the COPERNICUS and GALILEO Trials.” The study found that treatment soon after diagnosis resulted in better visual acuity gains.

So we did a post hoc analysis of the Copernicus and Galileo trials. These are the Phase 3 registration trials for macular oedema in central retinal vein occlusion.

In this trial, patients are randomized to receive either aflibercept or sham injection. Aflibercept patients were treated every four weeks for 24 weeks, at which point primary end point, which was loss of three lines or more, was read out.

In this post hoc analysis, we were very interested to see if a delay in treatment resulted in differences in anatomy or visual acuity gains. And so patients were divided into one of three groups: patients who were enrolled in the trial within one month of diagnosis, one to three months of diagnosis, or greater than three months from diagnosis.

So the interesting part of this trial was that there was visual acuity differences. Patients who had the best visual acuity gains were those patients who were treated within one month of their diagnosis, compared to those patients who were treated after three months of diagnosis were the worst visual acuity cases. Interestingly, their anatomy was the same. So the anatomy improved in all groups, and there was no difference.

The second part of this analysis was looking at baseline visual acuity. And the baseline vision acuity had any bearing on final visual acuity. And in fact, those patients with the best baseline visual acuity have the greatest vision at the end of the trial. The greatest gain was in those patients with the worst baseline visual acuity. And this may have to do with ceiling effect. But it turns out that their final visual acuity were not as good as your counterparts who started off with good vision.

And so I think this trial provides information for our patients and physicians and helps manage expectations; namely, that if a patient is seen with macular oedema secondary to central retinal vein occlusion, it really is important to get started on treatment right away.

Dr Dilsher Dhoot discusses the post hoc analysis of the Copernicus and Galileo trials, which investigated if a delay in treatment would affect visual acuity gains or change in anatomy.

Post hoc analysis of Copernicus, Galileo trials find time since diagnosis affects BCVA outcomes in CRVO

In Fort Lauderdale, Florida, Dr Steven Yeh, dives into his presentation, “Front-line therapies and novel drug delivery for uveitis.” He outlines a few common therapies, such as methotrexate, mycophenolate mofetil (CellCept; Genentech), adalimumab, and fluocinolone acetonide via suprachoroidal delivery (Xipere; Bausch + Lomb).

I have the privilege, at the Retina World Congress, to speak to frontline therapies and novel drug delivery for the treatment of noninfectious uveitis. Within the field of uveitis, we're very excited about the different possibilities and the therapeutic alternatives in our armamentarium — both systemic therapies that have been shown through randomized controlled studies to be effective for the treatment of noninfectious uveitis. These include medications like methotrexate as well as mycophenolate mofetil, or CellCept, for the treatment of steroid-sparing agents for noninfectious uveitis. We also have level-one data related to adalimumab, which is a tumor necrosis factor alpha inhibitor, that's also helpful for the treatment of noninfectious uveitis.

Now, when we think about uveitic macular oedema, which is the leading cause of vision loss in uveitis, we also know this is very important to target these as well, both from the standpoint of reducing complications related to structural deficits as well as improving visual acuity.

And there have been other randomized controlled studies that have also looked at both intravitreal therapies as well as suprachoroidal drug delivery for the treatment of noninfectious uveitis. Within the realm of intravitreal therapies, the fluocinolone acetonide 0.18 milligram dose has been shown to be effective for reducing the rate of recurrences of uveitis in randomized controlled studies and two large phase 3 studies.

Now with regards to other treatments in uveitis, suprachoroidal drug delivery is a nuanced innovative drug-delivery platform that allows the treatment of macular oedema due to noninfectious uveitis. Xipere, which is administered via the suprachoroidal drug-delivery platform, delivers high levels of medication within the retina to the choroid for reducing levels to anterior segment structures. Within the PEACHTREE study, which evaluated suprachoroidal drug delivery compared to sham control, patients who received Xipere experienced a greater visual acuity gain with about 47% of individuals getting three lines or greater visual acuity over the 24-week endpoint. In addition, rates of cataract were comparable between sham control, as well as suprachoroidal drug delivery and intraocular pressure rates were favorable as well.

So, in summary, there's a lot to be excited about within the realm of treatment for noninfectious uveitis both within systemic therapies, we have randomized controlled studies with level-one evidence about their efficacy signals for the quality of life and the patient's visual acuity with noninfectious uveitis. And within the realm of local therapies, both intravitreal and via the superchoroidal route, there's a lot to look forward to with regards to drug delivery to improve visual acuity and the quality life of our patients.

 This transcript has been lightly edited for clarity.

Dr Steven Yeh provides a brief overview of available therapies for noninfectious uveitis and uveitis macular oedema.

Noninfectious uveitis, uveitic macular oedema: A synopsis of frontline therapies

In Fort Lauderdale, Florida, United States, Dr Aleksandra Rachitskaya presented, “End-of-Study Results from the Phase 3 Archway Trial of the Port Delivery System With Ranibizumab in Neovascular Age-Related Macular Degeneration.” The Port Delivery System (Susvimo, Genentech) received US FDA approval in October of 2021.

Well, thank you so much for having me. And it's a pleasure to talk to you today about the presentation that I delivered at the Retina World Congress in Fort Lauderdale, Florida.

So what I focused on was the results of the end of trial for Archway. Archway, as you might know, is a study that focused on the Port Delivery System. And it's really a pivotal trial that compared the Port Delivery System for the treatment of neovascular AMD to monthly ranibizumab.

The way this trial was structured, it had the Port Delivery System that was surgically implanted, and then refilled every 24 weeks and the control group were the patients who received ranibizumab monthly. We know that the primary outcomes were at week 36 to 40, and those results have been released and showed that Port Delivery System is noninferior and equivalent to monthly ranibizumab.

So in this presentation, we focused more at the secondary outcomes. So we looked at the visual acuity outcomes at 60 to 64 weeks as well as 88 to 92 weeks. And we also looked at anatomic outcomes, patients who required supplemental ranibizumab in Port Delivery groups and also at the safety. So that's kind of the big picture of what we looked at.

And the Port Delivery System is a surgically implanted reservoir that allows for continuous delivery of ranibizumab in patients with neovascular AMD. In fact, based on the Archway results, we have approval, FDA approval, for patients with neovascular AMD to receive the Port Delivery System. And those are patients who have been treated with two or more anti-VEGF agents.

So looking at the results of—end-of-trial results showed that in terms of visual acuity, the Port Delivery System was noninferior to monthly ranibizumab. We also saw very nice OCT findings, they were consistent and showed drying of the retina.

The other interesting aspect that we saw is by the end of the trial patients were eligible for 4 refills, so refills occurred every 24 weeks. So they were able to get 4 refills. Before each of these refills, at several visits before, patients were eligible to receive supplemental ranibizumab if they needed it, based on particular criteria. And so the study showed that 95% of patients did not require any supplemental ranibizumab. So that's interesting information in terms of efficacy of the Port Delivery System.

And then finally, we looked at the safety because this is a surgical procedure. So safety, of course is extremely important. And we didn't see any new safety concerns compared to the primary outcomes. In particular, we looked at the conjunctiva retraction and erosion, endophthalmitis, implant dislocation and septum dislodgement.

So, in summary, the end-of-trial results showed that when it comes to Port Delivery System, it is noninferior to monthly ranibizumab in terms of visual acuity and OCT outcomes, and the adverse events were manageable, and we continue to learn how to improve this surgery and make this successful for our patients.

Dr Aleksandra Rachitskaya discussed the Phase 3 Archway end-of-trial results for the investigation of the Port Delivery System with ranibizumab in neovascular AMD.

Archway: Phase 3 end-of-trial results show Port Delivery System is noninferior to monthly ranibizumab

At Retina World Congress in Fort Lauderdale, Florida, United States, Dr Carl Regillo presented a talk entitled, “Results of the KSI-301 Dazzle Neovascular AMD Pivotal Clinical Trial.” While the study failed to meet its primary endpoint, KSI-301 demonstrated good initial visual gains and anatomic effects as well as positive durability.

Dr Regillo is the director of retina service at Wills Eye Hospital.

I had the opportunity to present the top line results of the Phase 2/3 pivotal study on the use of KSI-301 to treat neovascular AMD.

This is all very new information, so a lot of people are probably not aware of the results. Unfortunately, the study did not reach its primary endpoint in terms of KSI being noninferior in mean change BCVA from baseline to the primary endpoint compared to aflibercept.

So, we saw some initial visual gains that look good, in addition to some good anatomic effects early on during the induction phase, the monthly injections of the therapeutic, but some loss of vision over time. And so the amount of vision gain at the primary endpoint was not as much as aflibercept.

What we saw was very good durability, actually. And there's the positive aspect to the way KSI performed. Sixty percent of patients were able to be extended out or be treated as infrequently as every 5 months. So that is impressive, with 60% of patients going 5 months and doing very well, visually, anatomically, on par with aflibercept. It was the 30% of patients that were getting KSI-301, every 12 weeks or three months that didn't perform as well.

It is pretty clear from case studies in further analysis that those patients probably need to be dosed more frequently than every 3 months, because we saw a good initial drain 1 or 2 months after a given KSI dose. But then disease activity recurred significantly and that accounted for vision loss. It was that 30% of KSI patients getting treatment every 3 months that sort of brought the whole population visual acuity down over time to the primary endpoint.

While the DAZZLE trial failed to meet its primary endpoint, KSI-301 demonstrated good initial visual gains and anatomic effects as well as positive durability.

Clinical trial offers insight into development of KSI-301

 I think the port delivery system [PDS] can have a very significant clinical impact on the treatment of wet AMD [age-related macular degeneration]. We’re all aware of the treatment burden patients have with frequent intravitreal injections. In addition, we know the peaks and troughs of anti-VEGF injections can affect the recurrence of wet AMD. Given that it is a continuous delivery of anti-VEGF therapy, not only can this potentially reduce the treatment burden for patients, there is also a possibility for disease modification with the port delivery system.

The fact that many patients in the LADDER study did not even meet refill criteria, and that 98% of patients in the ARCHWAY trial did not need any additional treatment before the first refill, implies that we may be actually modifying the disease to the point of even potential quiescence for some of these patients.

Now that we have the port delivery system as an approved option, it’s important to consider how it can fit into our treatment plan. I have plenty of patients who require monthly or Q2 monthly [every 2 months] intravitreal injections. I think these are the patients I will first have a discussion with, and talk to them if they’re interested in potentially having a longer-term delivery of intravitreal anti-VEGF. Reducing the treatment burden will be very appealing for many of these patients. Of course, the risk and benefits of surgery need to be weighed carefully for such patients. One of the factors that I consider for PDS is the frequency of injections that the patients have. I also will look at the stability for these patients. If these patients can be stable on a monthly or every 2 months setting, we may still discuss it. However, if they’re having recurrent fluid, I think I’ll be much more likely to discuss the port delivery system. If a patient happens to be very stable with injections only every 3 or 4 months, the port delivery system may not be as appealing for some of these patients, unless they’re against getting transscleral intravitreal injections. With respect to insurance approval, of course many of these questions are yet be answered. However, we certainly hope and anticipate for insurance to cover this procedure. It is yet to be determined if it will be a step-wise approach, but I surely hope these critical patient-care decisions are left up to the physician, with explanation and discussion with the patient, and not mandated policy.

Having performed many of these surgeries already during the clinical trials, I can say that the patients who have received the port delivery system are quite happy. They do notice a stability of their disease. In addition, with the refill procedure, although technically it is very different from an intravitreal injection, and the surgeon has to be very aware of the different techniques, for the patient experience, it’s quite nice. It’s more tolerable because there’s no transscleral penetration of a needle. Patients often report that this was a much more comfortable and easier process to do. In terms of the implantation, it’s also considered to be quite painless. Most patients may have a little bit of itchiness or mild irritation immediately in the first 1 to 2 days of the postoperative period. Otherwise, it is a very well-tolerated procedure, and patients seem to have a very good experience.

With the approval of the port delivery system for neovascular AMD, I think the future for this platform is quite interesting; it has a lot of great potential. Studies are underway for both diabetic macular edema, as well as diabetic retinopathy. In addition, as we develop better compounds that may be more efficacious, such as bispecific molecules, marrying the PDS platform with these new molecules may yield even better results for our patients. I think there are a lot of exciting possibilities for the PDS platform.

As our retina specialty embarks upon a new era for the treatment of wet macular degeneration, I think as colleagues, it’s important that we utilize all the resources available. I highly encourage you to use all of the information, as well as surgical device liaisons, for example, in order to help maximize our patient outcomes.

Closing out his discussion on the port delivery system in retinal diseases, Chirag Jhaveri, MD, considers how this approach has impacted the treatment landscape. 

Clinical Implications of Port Delivery System in Retinal Diseases

As we all start performing more of these surgeries, since it is now approved for the use of neovascular AMD [age-related macular degeneration], it is going to be very important to review videos prior to implantation of the PDS [port delivery system] in our patients. In addition, there are surgical simulators that can give you great hands-on experience. I anticipate many of these simulators to be available at many of our meetings, including ASRS [the American Society of Retina Specialists] and AAO [American Academy of Ophthalmology]. It’s also very important to have a good relationship with your surgical device liaison. These individuals are going to be very helpful in guiding you through your first few surgeries. They will be present as needed in your operating room, and they will definitely be there for your first few cases. I highly recommend utilizing them, as they’re wonderful resources to help guide you through your first few cases.

The surgical device liaisons are individuals who you can get in touch with through the company representatives. They are individuals who are there for your resource, and to help guide you in learning any of the tips, pearls, and steps that you would like to discuss for the PDS implantation.

A detailed description of both the implantation and the refill is going through publication approval. These will also have associated videos. In addition, if you would like more videos, you can also discuss this with your surgical device liaison, and they’re happy to provide additional teaching techniques and videos.

Concise insight on education and training strategies that will optimize use of the port delivery system in retinal diseases.

PDS in Retinal Diseases: Practical Advice on Education and Training 

The LADDER trial was a phase 2 trial that showed overall good safety and efficacy for the port delivery system [PDS] for the treatment of neovascular AMD [age-related macular degeneration]. It looked at varying doses of ranibizumab in the PDS implant. Patients were dosed at 10-mg, 40-mg, and 100-mg concentrations. Interestingly, and this is different than the ARCHWAY study which we’ll talk about shortly, patients were only given a refill of ranibizumab if they met criteria of worsening fluid, vision, or new submacular hemorrhage. The 100-mg concentration, which is what is approved, showed that about 80% of patients were able to go 6 months or longer before needing a refill; the median time for needing the first refill in the 100-mg group was nearly 16 months.

Overall, the port delivery system procedure was very well tolerated. As mentioned before, after the modification of the technique, patients did not have any vitreous hemorrhage within the first month. The refill procedure was also very well tolerated, and was able to be done in an in-office setting.

Coming from very good results from the LADDER trial, ARCHWAY was the phase 3 trial, which was a 2-year study comparing monthly ranibizumab to the PDS implant with 100 mg ranibizumab and refills [every] 6 months. The patients enrolled in this study were patients who had wet AMD, were diagnosed within 9 months of screening, and who were responding to anti-VEGF treatment. The ARCHWAY trial showed that 98% of patients were able to go without any additional treatment in the PDS group. The PORTAL trial is an extension study that will be looking at how patients do beyond 2 years. The safety and tolerability of the procedure were also consistent with the LADDER study, particularly with respect to very low incidence of vitreous hemorrhage, as well as the procedure being very well tolerated.

The patients who were included in the ARCHWAY study were recently diagnosed with neovascular AMD. All the patients had to be diagnosed within 9 months of their screening visit, and they all had to show a good response to anti-VEGF therapy.

The ARCHWAY study so far shows that patients are tolerating the port delivery system very well, even in a long-term manner. We’re also showing that patients have good, consistent visual recovery, as well as good stability of their macular thickness. We also analyzed patients with fluid fluctuations, and showed that patients with the port delivery system have good minimization of fluid fluctuations, similar to having monthly ranibizumab injections. I’m also excited about learning what longer-term data are going to show in the PORTAL study. The PORTAL study is looking at patients well beyond 2 years, as well as multiple refills beyond 2 years.

Chirag Jhaveri, MD, reviews the trial design and results of the LADDER and ARCHWAY studies, which tested the port delivery system in neovascular AMD. 

PDS in Retinal Diseases: Interpreting the LADDER and ARCHWAY Studies

The port delivery system is an ocular delivery system that is surgically inserted via the pars plana area in the superotemporal quadrant of the eye. It provides continuous delivery of ranibizumab to the posterior segment. It has a reservoir chamber where a higher concentration of ranibizumab is held, and there is slow release into the vitreous cavity. It has been approved for use in patients with neovascular AMD [age-related macular degeneration], although other indications, including diabetic macular edema, are also being investigated.

With the approval of Lucentis [ranibizumab] for the indications of neovascular AMD, the treatments for neovascular AMD were revolutionized. However, there still is a significant treatment burden for many of our patients who require frequent, often monthly, injections. The treatment burden for both the patients and the family can be quite high. In addition, although we’re delivering a nice bolus of anti-VEGF treatment, there is a waning of the amount of medication in the vitreous cavity. Therefore, a more sustained, endurable treatment modality was needed. Like most devices, the port delivery system was started in the preclinical stages, where it was developed and then tested in nonhuman subjects. Once its safety was verified, it went on to trials to verify safety in human patients, and then to look at the efficacy.

In the phase 2 LADDER study, the technique that was done in human patients initially showed an increased risk for vitreous hemorrhages. The technique for implantation was modified to include laser cautery of the corneal bed]. After this, the incidence of vitreous hemorrhages dropped precipitously. Prior to the amendment, there were 6 out of 10 cases of vitreous hemorrhage. After the amendment, there were no cases of vitreous hemorrhage out of 48 patients within the first month, which is generally considered the postoperative period. At 2 months, there was 1 patient who did have a vitreous hemorrhage.

Although the procedure is generally well tolerated, since it is surgical procedure, there are some potential complications that surgeons and patients should be aware of. Initially, in the LADDER study, there was a higher rate of vitreous hemorrhages. A modification of the procedure has since reduced those rates tremendously. Any surgery has a risk of infection, and with respect to the implant itself, if the conjunctiva is not closed properly or not covering the implant adequately, there is a possibility of the implant being exposed. Also, if the conjunctiva is very thin, there is a possibility of erosion. Therefore, presurgical evaluation and meticulous care to close the conjunctiva are very important.

When evaluating a patient preoperatively, you want to take note of a few things. Particularly, you want to take note of the conjunctiva to see if it’s very thin, and if there’s good mobility of the conjunctiva, so that you can adequately access the subconjunctival and sub-Tenon space. In addition, you also want to note any areas of potential scleral thinning, so that when you’re making your wound you’re aware, and so you don’t start making your wound too deep. In addition, you may also want to avoid those areas, so that there isn’t a risk of dehiscence or any other potential issues with the wound.

Expert insight on the history of the port delivery system in neovascular AMD and how it has impacted patient experience and outcomes.

The Development and Safety of Port Delivery System in Retinal Diseases 

: Before we conclude, I would like to get some final thoughts from all of you. Let’s start with Dr Korobelnik. Can you say a few words on the future of dry AMD [age-related macular degeneration]?

 We have seen a lot of research activities for new long-duration treatments in wet AMD and in diabetic retinopathy. There is also a lot of research and developments for advanced dry AMD, for geographic atrophy, and there are currently 2 ongoing phase 3 trials from 2 companies that are looking at inhibition of the complement cascade. We should know later in 2021, or in 2022, [whether] those drugs are beneficial to slow down the progression of the disease. If it works, this will be interesting because it’s a completely unmet need [right now]. We’ll see.

 Thank you. So it’s all about inflammation at this time?

 Dr Moosajee, do you have some concluding remarks?

Mariya Moosajee, MBBS, BSc, PhD, FRCOphth:

 I am truly excited by my field. For the first time in our careers, we can now say that there is an approved gene therapy available for patients with inherited retinal disorders, with a wealth of trials to follow up. I would like to see more genes being covered, and that, at the moment, is still a very costly process, so maybe it’s targeting more common pathways. There are gene therapies that are being developed towards a factor called rod-derived cone viability factor, which essentially helps cones to uptake glucose and to convert that into energy and work better. Hopefully that kind of universal treatment will be able to be accessed by more patients with inherited retinal disorders rather than on a gene-based system. It is a promising field and we will learn a lot from the work that is being done in AMD and diabetic retinopathy, in terms of the devices that you’re using and trialing now, and how we can apply that to our field.

 Thank you. Dr Peto, some words from your side?

 I completely agree that we live in an exciting era of diagnostics and treatment. Something we’ve learned from the pandemic is that patients adapt very well to the new environment. We are now seeing patients over the age of 90 who will happily have a virtual consultation with us. We are seeing people who are using home monitoring devices, and we’re also seeing patients who happily come to virtual clinics where they spend very little time, get images quickly, and then only come back to a busy clinic if they need injections or treatment. We need to learn from these developments, we need to cherish them and go on with providing the best service because this helps us to strategize and restratify our clinics and get everyone to the right clinical pathway.

 Do you think this digital world will reduce the quality? Five years ago we all spoke about multimodal imaging, high-quality images, and combining images from different modalities, just to be more secure and do more sophisticated diagnostics. Now everything is digital. We do images with devices at home, which don’t have the quality as compared with devices in a big hospital, and you can’t combine different images. Do you think the quality will go down a little bit?

 What we need to do is to make sure that the quality of those images that we get supplied with go up. When they started the anti-VEGF [vascular endothelial growth factor] injections, we didn’t have SD OCTs [spectral domain optical coherence tomography], we had time domain OCTs. As soon as more people used them, more people needed to have an OCT, and more people needed more details—suddenly the price dropped, and a lot of new functions appeared. I’m hoping that the home monitoring devices will undergo the same type of development. We must remember that, in a lot of patients, we only need to decide if they need to come in or not, and if they need an injection or not. So we might not need every single time and every bit of imaging that we usually do at diagnosis. If we’re clever about it and we get good images, then we might be able to change the dynamic of a clinic to those who are higher risk.

 We must differentiate between initial visit baseline to make the diagnosis, then we need multimodality and follow-up. For follow-up, OCT probably does it all. So home monitoring with OCT can be promising. We don’t need multimodality on each visit.

 I think that’s why we call it monitoring, because, for diagnostics, you need to get the diagnosis right. They can have all sorts of other diseases that mimic AMD, and old patients with diabetes can have a lot of other diseases as well. We need to establish a secure diagnosis, especially if we don’t see them regularly in the clinic.

 Thanks to all of you and to our viewing audience. We hope you found this 

 discussion to be rich and informative. Thank you very much.

Key takeaways from a discussion on the management of age-related macular degeneration, diabetic macular edema, and inherited retinal disease and insight regarding what to look forward to as the field advances.