Transcription:
Highlights from AAO 2022

Melanie Cole: Welcome to Better Edge, a Northwestern Medicine podcast for physicians. I'm Melanie Cole. And we have a panel round table for you today to share conference highlights from the Annual Meeting of the American Academy of Ophthalmology.

Joining me is Dr. Angelo Tanna, he's the Vice Chair in the Department of Ophthalmology, the Director of the Glaucoma Program, and a professor of Ophthalmology at Northwestern Medicine; Dr. Surendra Basti, he's the Director of Cataract Service and a Professor of Ophthalmology at Northwestern Medicine; and Dr. Manjot Gill, she's is a professor of Ophthalmology and Medical Education at Northwestern Medicine. Doctors, thank you so much for joining us today. Dr. Tanna, I turn it over to you.

Dr. Angelo Tanna: Thank you. Well, we just wrapped up a really great academy meeting, and I thought it would be great for us to get together and discuss some of the highlights within our fields. So let's start with Manjot. In retina, Manjot, what did you think was exciting? What do we need to know about as non-retina specialists? And fill us in.

Dr. Manjot Gill: Thanks, Angelo. So it truly was an exciting meeting. We had some really interesting clinical trial phase III results that were presented for the first time. So I'll go through the first one. Regeneron announced the first presentation of their positive results from two pivotal clinical trials that were investigating novel aflibercept or Eylea at 8 milligram doses. And to remind everyone, standard Eylea that is in current use is 2 milligrams dosed every eight weeks. So this is looking at a higher concentration of 8 milligrams to see if we would be able to extend out the dosing intervals to 12 to 16 weeks.

So the PHOTON trial was investigating DME and the PULSAR trial in wet AMD. And they were able to both meet the primary endpoint with 8-milligram arm demonstrating noninferiority in vision gains at both 12 and 16 week dosing regimens. In fact, they found that nearly 90% of patients with DME and almost 80% of patients with wet AMD were able to maintain 12 to 16-week dosing intervals through 48 weeks. And the safety profile was similar to the 2 milligrams and there were no cases of retinal vasculitis or endophthalmitis. So this is pretty exciting news allowing similar efficacy but with extended durability at least through 48 weeks. And the study is ongoing.

Dr. Angelo Tanna: So we'll be down to just a little over three injections a year?

Dr. Manjot Gill: Well, that certainly is the goal and the hope. You know, we certainly don't want to compromise our visual acuity outcomes. But at least at the 48-week data, that certainly is indication that up to 80% of patients with wet AMD could be extended out to 12 to 16-week intervals.

Dr. Angelo Tanna: Does that mean that the patients would not have to come in as frequently or would they still need to be monitored as frequently as they previously had been?

Dr. Manjot Gill: At this point, it looks like they would be able to be extended out safely to that three to four-month interval without having to come in between for followup visits and just would be dosed at those intervals.

Dr. Angelo Tanna: That's interesting.

Dr. Manjot Gill: So a similar study for geographic AMD reported out on phase III results. And this was the GATHER2 study and this looked at avacincaptad pegol, which is a pegylated RNA aptamer that inhibits complement. And what they found in this GATHER2 study, which is a prospective randomized sham controlled study looked at patients with geographic atrophy. And the primary endpoint here was achieved at one year with about a 14% reduction in growth of geographic atrophy versus sham. What they found is that this is the first investigational therapy for geographic atrophy to achieve the 12-month pre-specified endpoints with a consistent safety profile in two phase III studies, both the GATHER1 and the GATHER2. So this was also one of the first phase III studies that was reported out at Academy for geographic atrophy.

I should mention that currently we don't have any FDA approved therapies for geographic atrophy. There have been other agents that have been looked at which have shown conflicting results in their two clinical trials. And this is the first one that showed consistent results in both of their phase III studies.

Dr. Angelo Tanna: So a whole new way to manage geographic atrophy.

Dr. Manjot Gill: Yes. I mean it certainly is very exciting. You know, at this point, we don't have any therapies to offer these patients. And so, it is exciting that there is at least some treatment that is on the horizon for these patients and showing nearly a 15% reduction in the growth of geographic atrophy. This is, I think, a good start and certainly very encouraging.

Dr. Angelo Tanna: So put that in perspective for us from a clinical standpoint, from a clinical benefit standpoint. Is that a big effect size? How does that affect quality of life? How impressive are the results?

Dr. Manjot Gill: Well, I think, at the present time, we have no known treatment for geographic atrophy, so the fact that we have anything at all to offer patients, which can show a delay in growth of the geographic atrophy. Where I think that this would have significance would certainly be if a patient had already lost one eye to geographic atrophy. And if we could go to a patient and say, "We have something that could reduce the rate of growth by 15% over one year," I think certainly that it is something to consider. Now, this may not be for everyone, particularly if they have good vision in both eyes, but at least this is the start.

Dr. Angelo Tanna: Do you think it will help with the geographic atrophy that's observed in some patients with anti-VEGF therapy, or is this just for primary geographic atrophy?

Dr. Manjot Gill: Yeah, that's a good question. So this is really for patients with non-exudative geographic atrophy, not the "atrophy" that is induced by anti- VEGF treatment.

What I've also found interesting, there was a phase I study of gene therapy in geographic atrophy. And I mentioned this because this was the first in-human study that met its primary endpoint in all three doses and was found to be safe and well-tolerated after 24 months of followup and it was able to show a growth rate reduction at 24 months. Keep in mind, this is a phase I study, but it is the first of its kind for gene therapy. So there certainly are more things on the horizon.

And I will also mention on a similar note, there was a gene therapy trial for neovascular AMD, which was the OPTIC phase I trial. And this investigated one-time administration of ADVM-022, which is a recombinant adeno-associated virus gene therapy vector that carries a coding sequence for aflibercept. And what the investigators reported was that a single intravitreal administration was able to deliver stable levels of aflibercept through two years and led to an 80% reduction in annualized anti-VEGF. So this is very exciting because it will allow for extended durability of anti-VEGF and allow for similar visual and anatomic outcomes, but at the same time, reducing treatment burden significantly for both patients and for the physicians that treat these patients. And phase II LUNA study is currently underway. So both of these trials are really exciting because they demonstrate the promise that the gene therapy holds for us for the future.

Dr. Angelo Tanna: Surendra, what did you find to be some of the most exciting material presented at Academy?

Dr. Surendra Basti: I'm going to break this up into three broad areas, which are primarily my areas of interest: cataract surgery; corneal surgery, the corneal subspecialty as a whole; and then, refractive surgery. So in the field of cataract surgery, I think the most important advance that I think is beginning to gain center stage is light-adjustable lenses and their availability for routine cataract surgery. And just to provide a background here, all the intraocular lenses that we currently have are lenses that have a fixed power to them, which means once you implant it inside the patient's eye, the outcome they get is what they will have for the rest of their lives. There's no room to fine tune the outcome after the surgery if a patient finds that he or she's more nearsighted or more farsighted. There's no way to adjust that.

But this new lens called the light-adjustable lens is a lens made of silicon and lends itself to adjustment of outcome after surgery. So in that sense, this is a huge paradigm shift in the whole field of intraocular lens that we use in cataract surgery. Having said that, this lens is relatively new. All the reports on the lens that we saw at the Academy were very positive and encouraging. The lens is capable of adjusting the outcome up to about three diopters, which is very significant. And the group of patients that really would benefit from this are folks who have cataract surgery after previous LASIK or radial keratotomy-type surgical procedures because this is a subgroup of patients in whom some of the calculations we use to calculate the power of the lens are somewhat inaccurate. And so, the facility of being able to adjust the outcome after surgery is going to be very meaningful in this particular subgroup of patients. It'll also be useful in other subsets of patients, folks who are very particular about the reading distance that they want to be able to read or folks who want particular requirement with the outcome still have the option of refining that outcome after surgery based on their initial experience with how the lens focuses light.

So light-adjustable lens, I think, was among the important advances that was reported and its efficacy at least in the initial reports looks very promising. I'm happy to report that we'll have it here at Northwestern Medicine within the next month or two.

Dr. Manjot Gill: Wow. That's really exciting. Surendra, can I just ask, do these patients need to have healthy maculas similar to the multifocal IOLs? So does, you know, any macular pathology exclude them from being candidates for this type of lens?

Dr. Surendra Basti: So that's a very important question. These lenses are primarily monofocal with multifocal lenses, because light is split. We find that the overall vision has a lower level of contrast sensitivity, whereas monofocal lenses don't do that, which is why in people who have early macular degeneration, early diabetic retinopathy, this lens will remain an option.

Dr. Angelo Tanna: I'm going to play devil's advocate on this.

Dr. Surendra Basti: Please.

Dr. Angelo Tanna: I would argue first that we do have a way of adjusting things. We could still do corneal refractive surgery after cataract surgery to make up for any surprises. True?

Dr. Surendra Basti: True. That is an option available. It just brings in cost and financial considerations, logistical considerations. And the other consideration is that corneal refractive surgery is second best in terms of outcomes. I think if there's a way to get the lens itself to do the focusing, I would say that, optically and visually, that is the best outcome. However, we have had the option of fine tuning with corneal refractive surgery, Angelo, that's accurate.

Dr. Angelo Tanna: And how long is the window of opportunity for making adjustments after implantation of light-adjustable IOLs?

Dr. Surendra Basti: It's up to four months. The option very much remains up to about four months after the cataract surgical procedure. However, folks who have this lens understand how the process is after surgery. And typically, the process involves a first visit approximately 17 days after implantation to really determine the outcome and the patient's satisfaction with it, and any needs they may have in terms of getting the focal point to be further out or further in. So some of those specifications, they provide the surgeon on day 17 and a couple of visits thereafter, there's opportunity to adjust the lens optically using light and determine if the outcome is to the patient's satisfaction.

So between day 17 and week six, there are a minimum of three visits for the patient, Angelo. So, it's surely something that involves more patient visits and the adjustment is usually done in that period. However, your question's relevant, because surgeons are beginning to see the value of this lens, even in triple procedures like we call them, when we do corneal transplants for Fuchs dystrophy, for instance. These days, we are doing the DMEK corneal transplants where the vision outcomes are exceptional from a corneal standpoint. So when cataract surgeries combined with DMEK a study from Dr. Price's group in Indianapolis reported outcomes of using the light-adjustable lens. And in a DMEK situation, you can't adjust the lens in the first month because the cornea is still settling in. And typically, in those instances, you want to adjust a couple of months out. And that's where the report was, that the adjustment can be done up to four months after the implantation.

Dr. Angelo Tanna: And what do we know about the duration of time after cataract surgery that there continue to be changes in the capsular complex that could shift the position of the IOL, particularly a silicon IOL?

Dr. Surendra Basti: Yes. Again, very relevant and important question. When this lens is implanted, a couple of things I think are useful. They're not mandatory, they were useful. The first surgical nuance that's going to complement what the light-adjustable lens does, is to have a very predictable and circular capsulotomy to use either the femtosecond laser or the Zepto device to create the capsulotomy so that it's very symmetrical and has a uniform overlap over the intraocular lens.

The second recommendation is to carefully polish the lens epithelial cells on the posterior surface of the anterior capsule. So any capsular cells to the extent possible, polishing them is recommended with this lens, again to minimize the fibrotic change that silicon lenses can trigger. So, Angela, your question's relevant.

In terms of the big picture here, can the capsular bag continue to show fibrotic changes over several years? Indeed, it can. But the likelihood of major changes is not going to be huge, I don't think, especially if you polish the capsule, then movement of the lens at least in an XY direction is what we are contending with in terms of the long-terms. If there's any dense fibrotic reaction stemming from some of the lens epithelial cells, that will always be in the fornix of the capsular bag. And from our previous experience with these lenses, we know that those kinds of extreme fibrotic reactions are rare. So, I do think that if you don't polish the capsule or you have an asymmetric capsulotomy, you can have refractive shifts over the first couple of months. But if you're careful to ensure that you have a perfectly circular axis and polish the capsule, I think your outcomes are going to be superior.

Dr. Angelo Tanna: So no doubt, it's an exciting area of our field.

Dr. Surendra Basti: Right. In terms of other exciting things that we saw at the Academy, I think a common thread that emerged is that many of the devices and investigational tools that we use to determine the power of the intraocular lens. I'm seeing a steady movement of technology in a direction where various technological devices are integrated so that the surgeon has all of them coming together in one software, so that he or she can make decisions that are optimal for the patient.

For instance, what is emerging is a new phacoemulsification device called Quatera from Zeiss. The interesting thing about this phacoemulsification device is that it promises to provide even improved anterior chamber stability, that's an area of focus for all new phaco machines, and you routinely hear that with every new phaco machine. But the Quatera promises improved anterior chamber stability, but also great connectivity, meaning even in the operating room on the Quatera device, you can access, for instance, the steep meridian or any planning you may have made for a toric lens that your Callisto device gave you previously. All of that will be available on the same screen that the phaco machine itself has. And this is a much improved screen for the phaco machine. The assistant that is helping you with the case will see the image coming from the operating microscope on the phacoemulsification machine screen, and the surgeon will have access to, you know, any information he or she might need, for instance, the lens power, the axis to align the astigmatic correcting lens and so forth.

So much greater connectivity with Zeiss devices as well as non-Zeiss devices. For instance, the Pentacam is something that's emerging here with this device. And that's not just true for this device. Even with the Catalys, the Femtosecond laser that we have, their next version of software, it's not a hardware upgrade, but a software upgrade, version 7.0, will be available in the first quarter of next year and that will provide us IOLMaster-related information. And the IOLMaster is made by a completely different company. But this whole thrust towards integrating technology for cataract surgeons is, I think, a truly positive development for all cataract surgeons. Because, for instance, with the Catalys, one of the challenges we have is we're putting a toric lens, the Femtosecond laser doesn't really know where the steep meridian is unless the surgeon physically marks it. And that's an approach that's clearly not accurate. The surest way to accurately mark the steep meridian is if a device provides you that information or provides the laser that information. And the IOLMaster, like we know, takes a photograph of the front of the eye very clearly showing anatomic landmarks. And the Femtosecond laser is able to use those landmarks to actually determine where's the steep meridian. So I think we'll have much better accuracy with this kind of integration that we are seeing with various devices.

Another great example is what we've been using at Northwestern Medicine now for several months, which is called the Veracity Software, again from Zeiss. So, a broad change that I'm seeing in the field of cataract surgery is integration of various pieces of critical information that we use. And I think all of this collectively will mean better outcomes for our patients.

Dr. Angelo Tanna: Yeah, that's great. And I hope that happens in every aspect of EMR and all of the equipment that we use right now. There are some outliers that don't follow the DICOM standard and then we run into connectivity issues that's outside the area of cataract surgery. But yes, this would be important for everybody to do.

Dr. Surendra Basti: Yes. I'll quickly end, Angelo, by at least mentioning major advances that seem to be emerging in the field of corneal surgery. One of the major limitations, especially elsewhere in the world, is the availability of corneal tissue for transplantation. And one of the important studies that was reported at the American Academy of Ophthalmology meeting that we just attended was the option of doing cell injections into the anterior chamber, so endothelial cell injections into the anterior chamber to then cause those cells to resurface the back of the cornea and provide improved corneal clarity.

So, cell therapy as an option for patients with failing corneal endothelium is clearly emerging as a viable option for corneal transplantation probably five years from now. Broadly speaking, corneal endothelial cells are cells that, you know, don't proliferate. They can only expand or enlarge and cover any defects on the posterior surface of the cornea. Whereas in the lab, you can actually cause these cells to both expand and proliferate.

And so, the approach that I'm talking about with cell therapy really was pioneered in Japan approximately five years ago, but it's slowly getting to be technology that now is reproducible in clinical studies, where in an eye bank, cornea is harvested, but the cells are then sampled, expanded in the lab provided as a suspension for surgeons to inject. And in a patient with Fuchs corneal dystrophy, for instance, the surgeon has to remove the diseased endothelium, but then inject a suspension of cells, which progressively then settle on the back of the cornea and have been shown to slowly resurface the posterior surface of the cornea.

So the advantage with this approach is that a small sample of cells can be made to provide cell suspensions for multiple corneal transplants, decreasing the actual need for corneal tissue. So that's the promise here. I think it's a little too early to see how much this will be our predominant technology, but even the option of expanding these cells in the lab and then injecting into the eye and showing their efficacy is a major step forward, which is why it's clearly something that's worthy of mention in terms of major advances that emerged at this meeting from the corneal subspecialty.

Dr. Angelo Tanna: Are these inducible pluripotent stem cell-derived or are they derived from some other source?

Dr. Surendra Basti: So these are not pluripotent cells. These are cells taken from the peripheral cornea. So in the human cornea, it's believed that stem cells of the endothelium really lie very close to the anterior chamber angle. And these are cells that have refined from pluripotent stem cells into the lineage that leads to endothelial cells. So these are clearly downstream from a pluripotent cell, but cells that are already thought to be stem cells of the corneal endothelium. So those are the ones that are used in the lab to expand and then be provided for a cell therapy.

Dr. Angelo Tanna: I see. That's why you would need to get tissue from one source for multiple recipients.

Dr. Surendra Basti: Correct.

Dr. Angelo Tanna: It's really interesting and exciting, the holy grail.

Dr. Surendra Basti: It is the holy grail. You're right.

Dr. Angelo Tanna: Well, I want to highlight one really important glaucoma paper that really should trigger a paradigm shift in how we manage patients with ocular hypertension and open angle glaucoma. So I think most people are familiar with the LIGHT clinical trial that was conducted in the UK. The three-year results were published in Lancet in 2019. And at Academy, we just heard the six year outcomes. So this was a prospective randomized controlled clinical trial, and over 700 patients were randomized to receive as initial treatment for newly diagnosed open angle glaucoma or ocular hypertension either SLT or medical therapy first. And the trial was really very well-designed. Every patient, every eye had an individualized target pressure, which was a fairly aggressive target pressure.

And it turns out that patients treated with SLT first had much better outcomes than patients treated with medication first. There wasn't really much of a difference in the three-year outcome data. But with six years, we now know that among the people who underwent laser first, about 70% of them remained well-controlled at six years, not requiring any medication, so eyedrop-free. But what's even more exciting and important, I think, is fewer eyes with ocular hypertension, who underwent SLT first progressed to developing open angle glaucoma. The absolute difference wasn't very large, 20% versus 27%, but was highly statistically significant. And even more importantly, fewer patients who underwent SLT first had progression of their glaucoma and fewer patients who had laser first required a trabeculectomy, both statistically significant results.

So for the first time, I can clearly say to my patients with newly diagnosed open-angle glaucoma ocular hypertension, that we have very strong evidence from a prospective clinical trial that SLT first is the superior method of treatment. And I think now we're really obligated to offer this first, and I think this is a paradigm shift for us.

Dr. Surendra Basti: Wow. Clearly represents a huge change in thinking. We always thought that starting an eye drop first was a relatively easy way to ease someone into the treatment of glaucoma. But the results of the study, Angelo, are truly indicating that's not the direction to take.

Dr. Angelo Tanna: Yeah, that's right. And the six-year results are published ahead of print. It will appear ultimately in ophthalmology and print, but the whole paper is available to look at right now. And what's really interesting also is the difference in the outcomes for newly diagnosed patients who are initially treated with laser. The incidence of IOP spikes was very small. Only I think two patients perhaps had an IOP spike in the course of the study. Also, some patients required repeat laser treatment and it was effective. So we have even stronger evidence now, although I think it was very clear before that repeat SLT is efficacious. So again, a real game changer for our field.

Dr. Surendra Basti: Definitely agree.

Melanie Cole: Before we wrap up, is there anything else, any other important information or learnings from this year's AAO Annual Meeting that you would like your colleagues who may not have been able to attend to know about?

Dr. Surendra Basti: I could chime in here. It seems to me again from the American Academy of Ophthalmology and some of the presentations in there, that the major change that we will see in the next year or two literally is in trying to minimize the amount of operating room waste that emerges from some of our procedures.

So over the past 20 years now, especially in the United States, we've been using a lot of disposables and it's becoming increasingly clear to all of us that we have to be responsible in how we use disposable supplies, at least from an environmental standpoint. And it's been shown now that cataract surgery, unfortunately, is a major contributor to operating room waste. And the American Academy of Ophthalmology, the American Glaucoma Society, the American Retina Society, Cataract Refractive Surgery, every society now has made that an important priority to try to come up with protocols that will minimize operating room waste. And we are proud to say from Northwestern Medicine, our own colleague, Dr. David Palmer, is an important leader in the field helping bring in some of these changes. And I do expect that within the next year or two, we will see very significant changes in how and how much of disposable supplies and drapes we use in the operating room. I think there are many examples to tone that down significantly and help the environment. It's an important priority for our profession and I'm pretty sure that this change is going to happen very soon.

Dr. Angelo Tanna: Yeah. That's a very good point, Surendra. It's absolutely amazing to see the quantity of waste generated in the course of a day of cataract surgery in the operating room. And we're very proud of David Palmer for his leadership in this area.

Dr. Surendra Basti: Right.

Melanie Cole: I want to thank you all so much for joining us today. Absolutely fascinating physician round table today. Thank you for sharing those highlights from the Annual Meeting of the American Academy of Ophthalmology. To refer your patient and for more information, please visit our website at breakthroughsforphysicians.nm.org/ophthalmology.

That concludes this episode of Better Edge, a Northwestern Medicine Podcast for physicians. Please always remember to subscribe, rate, and review this podcast and all the other Northwestern Medicine podcasts. I'm Melanie Cole.