Novel Technologies for Treating Neovascular Age-Related Macular Degeneration

Activity Transcript

Dante J. Pieramici, MD: Hi, I'm Dante Pieramici, a retina specialist based in Santa Barbara, California. Welcome to this program, Novel Technologies in Treating Neovascular Age-Related Macular Degeneration (nAMD): Who Might Benefit? Joining me today in the studio is Veeral Sheth, a retina specialist based here in Chicago. Welcome, Veeral.

Veeral Sheth, MD, MBA: Thank you.

Dr Pieramici: And we have a special guest from Germany, today. Armin Wolf, a retina specialist based at the University of Ulm. Armin, welcome, and thanks to the audience for being here today.

In nAMD, anti-vascular endothelial growth factor (VEGF) treatments have been transformative, but still, because of the burden of therapy, patients go undertreated, and this undertreatment can lead to inferior visual results. Surgical solutions are being developed to improve durability and lessen treatment burden. The aim today is to update you on the latest data on novel technologies in nAMD. And we'll discuss what this means for patients and physicians. We'll discuss criteria for selecting appropriate patients. We'll share our experience to ensure the best outcomes and safety when using surgical solutions.

The technological approaches we're going to discuss are aimed at increasing durability in nAMD treatment. We're going to discuss anti-VEGF implants: the port delivery system (PDS) with ranibizumab. We're going to also discuss in some detail, anti-VEGF-A suppression using gene therapy as a biofactory. We're not going to discuss small molecules and biopolymers, but there's a lot of other technology that's being advanced in our field.

Let's start with a discussion about gene therapy and the treatment of nAMD. There's a lot of excitement for this in our field. We're going to update you on the 2 most advanced gene therapies, RGX-314 and ADVM-022. Let's start with RGX-314.

RGX-314 is a gene therapy that uses an adeno-associated virus (AAV) 8 viral vector to insert DNA material that codes for a protein that looks a lot like ranibizumab. This is being investigated as a subretinal delivery in a number of phase 3 clinical trials: the ATMOSPHERE and the ASCENT trial. And it's also being looked at in the treatment of nAMD via a suprachoroidal delivery approach in the AAVIATE, which is a phase 2 clinical trial at this point.

Phase 1/2 data on RGX-314 was very encouraging, and this was delivered via a vitrectomy and then subretinal delivery of the RGX-314 gene therapy. In these trials, we found, first of all, that high levels of ranibizumab were measured in the eyes following this gene therapy approach. No prophylactic steroids were needed, and this is one of the advantages to a subretinal delivery. They found, particularly in cohorts 3-5, that there was a substantial reduction in the need for VEGF suppression in these patients. Remember that all patients included in this trial had been previously treated with anti-VEGF over a number of years and were high needers of anti-VEGF suppression. But this was significantly reduced following the gene therapy approach. So proof of concept, producing the protein and reducing the treatment burden in these patients.

AAVIATE is a phase 2 approach using suprachoroidal delivery of the RGX-314. This again will produce the same ranibizumab protein, but instead of requiring a vitrectomy procedure in the operating room, this could be done in the office. It's too early to tell, but patients have been recruited, and they seem to be tolerating this approach well at this point.

Let's look now at ADVM-022, which is another gene therapy approach. This approach uses a modified AAV2 vector, which codes for a protein that looks a lot like aflibercept. So, instead of ranibizumab, this gene therapy approach is producing something that looks more like aflibercept. The OPTIC trial was a phase 1 clinical trial looking at ADVM-022 in the treatment of patients with nAMD. Once again, these are patients that have been previously treated, shown to be responsive to anti-VEGF therapy and needing a fairly frequent burden of treatment. This drug was delivered intravitreally, not subretinal, but in the office in an intravitreal approach. And 30 patients were recruited in this trial and followed up to 2 years and now being evaluated in an extension trial. They could receive supplemental therapy if it was necessary based on re-treatment criteria.

The most important thing about this phase 1 trial was that the ADVM-022 was well tolerated. There were some dose-dependent, mild to moderate intraocular inflammation, but most of it resolved with corticosteroids that were used topically. There were no cases of vasculitis, retinitis, choroiditis, or vascular occlusion, and there was no significant hypotony events in these patients. The visual acuity and optical coherence tomography (OCT) findings were very stable over time in both dosing cohorts in this trial. And again, remember we don't expect a lot of improvement because these are previously treated patients. The hopes are to maintain the vision, maintain the anatomy with a much lower treatment burden.

Also, proof of concept: sustained expression over a long period of time of this protein was seen in both dosages, following intravitreal administration of the gene therapy. So proof that we're making the protein that we are planning to make. And the second proof of concept was there's a significant reduction in the treatment burden, 98% reduction in the need for intravitreal injections in the high dose group and about an 80% reduction in the lower or 2E11 dose group. So again, doing what it's supposed to do, reduce the treatment burden.

This is a case here, and these are the OCT findings prior to the administration. You can see at some time points the patient was dry following intravitreal injections, and at some time points there was fluid. Following the administration, there was no need for further treatments, there was complete drying of the retina, intraretinal and subretinal fluid, and the patients maintained good visual acuity.

Well, Armin, we've seen now these 2 different approaches to gene therapy as using a gene therapy as a biofactory to produce an anti-VEGF agent. Do you have any comments about this? What are your thoughts on these approaches in our patients with nAMD?

Armin Wolf, MD: Well, I think it's a very interesting time that we have all the patients that we still need to treat with a high treatment burden and at the same time becoming options available for longer treatment periods in between the injections. And gene therapy seems to be one of the options that we have, or by all of us are aware that we are looking at early studies at this point.

Now, I would be interested in your opinion about one safety aspect that has occurred in voretigene. Some groups have described retinal pigment epithelium (RPE) atrophy after subretinal injection. Do you feel that this could be due to the injection procedure itself, or do you think it's rather transported by the vector?

Dr Pieramici: Yeah, I think certainly safety is going to be a big issue with this gene therapy. As I show in the data, it's pretty good proof of concept that we can make the protein, we can deliver the protein, it can reduce the treatment burden. So, I think the safety's the big issue. And as you mentioned in the recent report, there was shown signs of atrophy following the administration of the gene therapy in those patients.

And in the studies, we've seen RPE pigmentary changes in the RGX-314 patients. And in all these gene therapy approaches, particularly when it's intravitreal administration, we worry about inflammation, and it can be mild to moderate as we saw in the OPTIC trial, or it can be more severe as we saw in the INFINITY trial with ADVM-022. That this perhaps inflammation or toxicity could lead to significant hypotony, which is really a scary thing.

So yeah, I agree with you Armin. I think we really need to have better safety, long-term safety data, but we're at the infancy of gene therapy at this time, so we're just learning things. We're learning how to prophylax, we're learning patient selection. But the bar's going to be a bit higher, I think, for using it as a biofactory than for treating an inherited retinal disease. Veeral what do you think? What's your-

Dr Sheth: Yeah, I think you hit it on the head. We're still early on. I think we're in that period where we're observing. Because these things like pigmentary change, we see it, but we don't know what it means clinically yet. And so, I think we're going to find these things out, it may take years. But, I think the important part is that we are making these notes, and potentially changing how we do these things moving forward.

Dr Pieramici : Yeah, we'll figure out how to make this work with proper prophylaxis, patient selection, proper dosing, maybe different vectors that'll come along down the road. So I'm optimistic but cautious like you Armin, that we need to be very careful in these patients.

Another new and exciting technology in nAMD that really may help with the burden of therapy is delivery of an anti-VEGF agent via an implant. Veeral, can you tell us a little bit more about this approach?

Dr Sheth : Yeah, absolutely. We're specifically talking about the PDS, and there's some similarities to what you've just described with gene therapy. In that, we're looking at more durable therapies, things that are going to last longer for our patients and reduce the treatment burden. But the key differences here are this is a now FDA approved therapy. And so, thankfully, we're able to get these to our patients today

So, the PDS, just in a nutshell, is a surgically delivered device that carries ranibizumab. And once that is implanted, we're able to refill that device every 6 months in the office. And so, we're able to treat our patients every 6 months, meaning we're decreasing that treatment burden for these patients. We have good data. The ARCHWAY study for example, looked at the PDS in nAMD. And what we see is a continuous delivery of this medication of the ranibizumab which is different than how we were currently doing the treatments which was monthly or every week treatments of injections, which were going in as bolus injections and then kind of clearing over time. So this is a much more sustained approach to these diseases.

What we saw in the ARCHWAY data, and we'll talk a little bit more about the subsequent extension data, is that we saw results on par with the PDS, dosed every 24 week refill. On par with every-4-week injections of ranibizumab which is the first time we're seeing that type of durability in an FDA approved product. The other nice thing that we saw in this study was that 93% of the PDS patients preferred the PDS implant over injections. And I can understand why, I would much rather have fewer treatments in the office, if possible, with equal outcomes.

We did see adverse events, and we can certainly talk more about that as well. I think with any surgical procedure you're going to have to be much more aware of those things. Endophthalmitis being one in particular, and we can certainly talk about ways of potentially mitigating that risk.

One of the things, I think, is worth highlighting is looking at the anatomic outcomes in these patients. What do we see in the OCTs and the central subfield thickness (CST) of these patients? And especially, when we're comparing the 2 groups, and what we see is exactly what we want to see, which is with this PDS, we're seeing real nice drying effect and a sustained drying effect, again, on par with every-4-week injections of ranibizumab. When you look at those charts plotted out, you see the vast majority, 70% or so, of patients really is demonstrating no fluctuations, really nice anatomic findings. But even in the patients that you do see fluctuations, they get very good outcomes visually speaking. And so, I think what you're seeing overall is a stabilization of the disease that translates to better vision outcomes for our patients.

When we talk about fluid, I think, we always like talking about types of fluid and intraretinal fluid, subretinal fluid. And what we see is again, really reassuring data that both intraretinal fluid is being improved in these patients as well as subretinal fluid. And in the PDS, we actually saw some improvements in subretinal fluid, above and beyond what we saw in the injection group.

We now have data on extension at 144 weeks after the implantation of a port delivery device. We're seeing really good stable vision outcomes as well as, what we really want to see is, an anatomical stability. We don't see sawtooth patterns or worsening in CST or fluctuations in those OCT findings. So, good disease stability over a long period of time. We see that with these patients that receive the PDS, we don't have to do too many supplemental therapies and in fact, 95% of patients that have this surgical device don't need subsequent injections or rescue therapy, so to speak, once that's been implanted. And so, again, that's reassuring. That's a number that I talk to my patients about.

When we talk about these surgical treatments and these new therapies. We talked about it with gene therapy, but safety is really, really critical. And so, understanding what we have to look out for, and potentially, being proactive about these things is really important. And so, we did see increased endophthalmitis rates with these patients, and I think with any surgery we do worry about those things. We worry about vitreous hemorrhage as well. And again, there are ways to mitigate that which we can certainly discuss as well. We did see that patients really, even in the extension, really did enjoy this type of treatment and much more so than intravitreal injections with 88% in the long run preferring the PDS.

Dr Wolf: That's very interesting data. And in Europe, none of this technology are available yet on the market for medical use. But however, we are starting to think about how they might affect our practices in treating patients. We are treating them now and inside the study with clear inclusion and exclusion criteria. Now, can I ask you, with PDS available on the market for medical treatment, how is your patient selection, is it similar to the inclusion criteria? Do you have tips for those countries that do not have the PDS available on the market yet?

Dr Sheth : Yeah, I think patient selection is critical. I mean, I think we're used to getting a new therapy and intravitreal injection and being able to use it on everyone. And I think that's a little bit different here, especially when we're talking about surgical approaches to these disease states. And so, I think picking the right patient, especially when you're first starting out with this new surgical technique is very important because you want success right off the bat. And again, not a therapy that's for everyone. I think that's important to discuss as well. And so, we can certainly talk about certain patient-specific characteristics that might be beneficial, especially when you're early on in the process.

Dr Pieramici : Why don't we talk about that a little bit? I mean, what characteristics of a patient might make them a poor candidate for the PDS?

Dr Sheth : Yeah, so, poor candidate, that's a great question. So patients that don't tolerate the injection procedure at all. That are squeamish or that are difficult to get that injection in, you would think, "Well, I want a more durable agent." But you still have to refill these patients in the office. And so, you don't want that hurdle to be there. And so, those are patients we would want to think twice on. And anyone with ocular surface issues, conjunctival issues, I mean, those are things you want to be careful of as well because if we're trying to minimize complications for example, we want to make sure we're setting ourselves up for success, and that starts with good anatomy to start with.

Dr Pieramici : And what about a patient who had say trabeculectomy surgery or retinal detachment repair? I mean, we're going to be putting these in the superotemporal quadrant, and we want to have pretty good covering of this at the end. It seems to be key to reducing some of the complications.

Dr Sheth : Yeah, I would be hesitant. I think anyone with prior surgery, I mean, for us as vitreoretinal surgeons, people that have had scleral buckles for example, you want to stay away potentially from those patients, especially early on until we know more because they have potentially issues already with their conjunctiva and tenon's surface.

Dr Pieramici : What about Veeral, I mean, the FDA indications are you have to have at least had 2 prior intravitreal injections. I mean, is there a limit to how long the patient could have, or do they need a certain burden before you select them as a patient to undergo the surgical procedure?

Dr Sheth : It's a good practical question. I mean, I think in the studies we didn't necessarily look at patients that were treated for long, long periods of time, but I think if patients respond well to anti-VEGF, I think they would be a good candidate all other things considered. And so, I think really the bar for me is do they respond well to anti-VEGF? Do they need anti-VEGF? I mean, those are 2 important questions and if the answer is yes to both of those, then I think you can take those next steps and figure out if anatomically, it's something we can do.

Dr Pieramici : Yeah, I mean, probably, if a patient was getting an injection every 4 months, maybe they'd say, "I'll just stick with the injections." So it's probably going to be the more frequent needers of intravitreal injections that would be more of a candidate, I think, for this. Armin, do you have any thoughts on patient selection as you contemplate the use of this outside of the clinical trials?

Dr Wolf: Well, I think, I do have patients within the studies that keep on asking me about the fellow eye because the logistic structures, they would need to come to intravitreal injections in the fellow eye even though they have the PDS in the study eye. Now, how's your experience with bilateral implantation? Do they play a role?

Dr Pieramici : Well, it's interesting you ask. It seems like the patients who have it in 1 eye want to have it in the other. That's been my experience.

Dr Sheth : I agree with that.

Dr Pieramici : And as we're getting more knowledge about this device and collecting more data over time, I'm being becoming less reluctant to not do the fellow eye. Because again, if you want to reduce the burden, and really the biggest thing about the burden in my opinion is coming to the doctor's office, having to go through the evaluation and have the injection. The injection itself isn't so bad, but it's the aftereffects in getting to the office, it's the real burden, I think, that reduces the compliance in the long run. Bilateral implants would be the way to go to really reduce this. So I agree, and I think patients are asking for it. But for some patients, just having to deal with 1 eye with injections is enough of a benefit, that they're happy that the implants in 1 eye. The other eye, they get an injection maybe every couple of months and that's okay for them.

Dr Wolf: Now, what about a refill procedure? When we first introduced it in the studies, it looked quite easy, but now, I do see that it's quite different from an intravitreal injection. How is your experience with the repeated refill procedures? Do you have any tips for that?

Dr Sheth: I mean, I think you're absolutely right. It's different than an intravitreal injection. I think that needs to be clear to patients and providers. The tips are the same whether you're doing your first refill or your sixth refill. I think positioning the patient, approaching them at the right angle, all of these things matter, lighting, magnification potentially. And so, I think once you get that rhythm, it becomes easier. But there's a learning curve just as there is with the surgery, with the refills as well.

Dr Pieramici : Yeah, I think in the beginning it's probably better not to put them in the middle of your busy clinic, but to set them towards the end because it's going to take more time for you and your staff. You have to properly visualize the septum, so using illumination and magnification. These are things I don't typically do in an intravitreal injection. I can pop in the room, do an intravitreal injection and pop out. This is going to take more time. You draw up the drug, you properly position the patient, you get good visualization and then you take your time positioning yourself. Because if you can see the septum, and you can come in perpendicular to the septum, you're going to be successful most of the time. I think that as we look at the PDS, and we think about, if we had a device or a treatment that lasted 6 months and maybe even longer in the LADDER trial, patients could go 15 months on average without a refill. It's a no brainer, but the downside of the trade off in this is of course the surgical complications that we mentioned a minute ago. And some of these are relatively significant, like increased rates of endophthalmitis, chances of erosion or retraction that might require some additional surgery. There's low risks of things like retinal detachment and most of the vitreous hemorrhages resolve on their own. But Veeral, what sort of things do you think about, or what kind of tips can you give a new doctor to try to reduce these complications so that this is less of a negative when we're deciding for the PDS?

Dr Sheth : Yeah, it's a great question. These are not surgeries that are difficult. They're certainly within our skillset, but they do take a little bit of thoughtfulness in the approach. There's a learning curve as we've mentioned. And so, I think understanding the steps, even the steps have evolved over time over the course of the clinical trials. And of particular interest for us in reducing the likelihood of conjunctival erosions and ophthalmitis is making sure that the beginning and the end of the case are done well. In other words, making that peritomy, taking down conjunctiva and tenons and then at the end, closing all that tissue up thoughtfully because that's what's going to give us the best long-term outcome.

Dr Pieramici : Yes, vitreoretinal surgeons nowadays, we just go right through the conjunctiva with our trocar cannulas and then we don't think much about it. I think we have to think more like a glaucoma specialist for these steps. And I agree. I think that carrying the steps out in a meticulous fashion is extremely important. Taking our time with the opening and closing of the scleral dissection, needs to be very accurate. 3.5 millimeters and then cauterizing the pars plana choroid is very important as well. But I think training is... You can't just watch a video or go to a lecture and then go out and do this procedure. I think training is important. And what sort of things to this end have you done?

Dr Sheth: Yeah, and we've had, while we're doing our cases, surgical liaisons in the room with us, who provide a wealth of information and experience. They've seen many, many of these cases, many more than we've done. And so, when questions come up, or when a reminder is needed of what steps next. They're a nice copilot to have in the room.

Dr Pieramici: Yeah, I agree. And Armin, in the clinical trials, you probably have had a lot of training as well up front.

Dr Wolf: Yeah, that's a very new perspective that we get as vitreoretinal surgeon, that we have someone sitting next to us, explaining us how to close the conjunctiva which we are used to just getting through. But I think it's very important that we deliver a vitreoretinal procedure and that we have a learning curve. And the learning curve, I think, is quite good with having the supervision in the trials.

Dr Pieramici: Yeah, I think we can mitigate a lot of these complications with proper surgical technique. Not 100%, I mean, there's always going to be those cases that occur, but I think any new procedure, sometimes the complications are the worst when you introduce it. Even intravitreal injections, if you look at some of the original trials, it was a 1% endophthalmitis rate in those trials because our intravitreal techniques have gotten better. And I think the same thing can happen here if we train well, if we mitigate, and we take our time, we can reduce these complications and really end up with better outcomes at the end. So Veeral, you have a lot of experience with the PDS. Maybe you could give us some tips, some fine tips and some videos that can help us a little bit.

Dr Sheth: Yeah, I mean, I think surgical videos are the best way to walk through some pearls and pitfalls, potentially. So we'll show a video here of a really good example. You've seen a good opening. The port delivery has been placed already, so now we're really wrapping the case up and closing the conjunctiva and tenons in one step here. So what we're seeing here is a nice suture being anchored into the sclera with at least a 2-millimeter bite of tenons and conjunctiva on both sides. And so we're anchoring it down on both ends.

Dr Pieramici : What kind of suture are you using here?

Dr Sheth: So yeah, I use a 7/0 Vicryl® suture on a spatulated needle. And what we're trying to do here is really get good closure for a couple of weeks until that scars down. And what you see in the video, I think of another important aspect of it is we get a little bit of overhang over the limbus because I think there's always a natural retraction that happens, a mm or two, postoperatively. And so, if we have a little bit of overhang once that conjunctiva and Tenon's sits in its permanent location it's right where we want it to be.

Dr Pieramici: Yeah, I see that the implant seems nicely away from the relaxing incision there, and you've got nice exposure in this quadrant too.

Dr Sheth: Yeah, there's a traction suture there to that point, and that suture really helps us get good exposure to that area, that quadrant we're working on. There's an example of a video here that may not be what you want in the end and I'll show you here. What we're doing is we're throwing these sutures in, but right off the bat you can see as we close this tissue here, there's already about a 1- or a 2-millimeter gap between the closure and the limbus. So right there, we discussed, there's always a natural amount of retraction that happens, and in this case, if that happens, we may start to retract over the implant. And here you can see some postoperative images of this patient where you do indeed see exposure of the implant, potentially erosion of that tissue which is a setup for things like endophthalmitis.

Dr Pieramici : And most of the cases of endophthalmitis, the vast majority of them were associated with conjunctival retraction and erosion.

Dr Sheth: Absolutely. And that's why that goes back to the really, the critical steps are opening properly, really having a healthy respect for the conjunctiva and tenons and then close closing that tissue as we described.

Dr Pieramici : And then monitoring, I think, too. Yeah, I mean, if you start to see retraction or erosion, you can fix that situation. Take them back to the operating room, do some additional undermining of the tissue, or use a split-thickness corneal graft before they develop endophthalmitis. So you might-avert a disaster

Dr Sheth : That's exactly what I do. You have to be on top of it. And just proper examination postoperatively.

Dr Pieramici : Armin, any comments?

Dr Wolf: How often do you control the conjunctiva or the follow-up? I guess, we don't need to control them every 4 weeks that thereafter, but what's your recommendation for the control of the conjunctiva side?

Dr Sheth: Yeah, I think from what I do personally is I see these patients, like many of my postoperative patients, I see them next day, a week later, and a month later. And usually, if you're going to see any conjunctival issues, you'll see a lot of those issues right away and then after that, depending on what's happening from a disease standpoint, how well they're being maintained as far as their nAMD. I'll start to space their visits out. And we have some patients now that are being followed quarterly, and maybe they will get to every 6 months just for their refills.

Dr Pieramici: Yeah, I agree that most of these complications, particularly retractions, are going to happen probably in the first month or 2. And maybe erosions, we can't forget about these patients, even if we're going to see them and then refill them every 6 months. Personally, I'd probably either want them monitoring it with some home monitoring picture or something or coming in just for a quick check. Because again, if I can see a problem and fix it before a big problem happens like endophthalmitis, that'll go a long way.

Well, this has all been very interesting, this discussion today, and I appreciate your guys' insights. And to conclude here, a few take home points is that there are new technological advances, things like the PDS and gene therapy, that really, I think, are going to offer our patients excellent anti-VEGF treatment but reducing the treatment burden and maintaining visual acuity and anatomy for extended periods of time. I think that it's very important that you select the proper patients for these. These new technologies aren't for everybody and for every patient. And it's important that we think about this upfront because your outcomes are going to be based on proper patient selection as well. There are a number of pearls and pitfalls. We've talked about some of these today, and how to mitigate against this with proper training, careful surgical technique that's meticulous. And I think we can end up with far less complications which is really the trade off with this technology.

Well, I want to thank our co-faculty today, Veeral and Armin. You guys have been great, and I appreciate the discussion. And I'd like to thank all of you for your attention, and please continue on to answer the questions that follow and complete the evaluation. Thank you very much.

This transcript has been edited for style and clarity.