Activity Transcript

Carl D. Regillo, MD: Hello. I'm Dr Carl Regillo, Director of the Retina Service of Wills Eye Hospital and Professor of Ophthalmology at Thomas Jefferson University in Philadelphia, Pennsylvania. Welcome to this program titled "New Frontiers in Sustained Delivery: New Data and Surgical Advances in Age-related Macular Degeneration (AMD) and Diabetic Eye Disease."

Joining me today is Dr Dante Pieramici, who is a vitreoretinal surgeon at California Retina Consultants and Director of California Retina Research Foundation in Santa Barbara, California. Also joining me today is Dr Charles Wykoff, who is a retina specialist and Director of Research at Retina Consultants of Texas, Houston Methodist Hospital and the Blanton Eye Institute in Houston, Texas. Great to have you both.

I'm going to start off by setting the stage, a little background. When we talk about the current standard of care for neovascular age-related macular degeneration (nAMD) and diabetic retinopathy (DR) with diabetic macular edema (DME), it's all about the use of intravitreal anti-vascular endothelial growth factor (anti-VEGF)-A injections. We have a few medicines we've been using to treat 1 or both conditions: bevacizumab, ranibizumab, aflibercept, and brolucizumab. They all work well for both conditions. They all work well to reduce the signs of exudation in the macula for most of our patients. And that in turn leads to usually some degree of visual acuity (VA) improvement. But the problem with the drugs is that they all have very limited durability and that's for both conditions.

Here, as you can see in nAMD, the way these drugs were initially tested, they were administered on a very frequent and regular basis. In the clinical trials there were monthly or even every other month but in practice, we try to individualize therapy, not to overtreat. But that can sometimes lead to relative undertreatment. And in practice, as seen here the real world, we don't average the same numbers of injections per year, especially in year 1, that we do in the clinical trials and therefore don't get as much vision gains as we did in the clinical trials.

You can see that in nAMD, you have to be up over 8, 9, 10 treatments in year 1 to really get the vision gains we expect and hope to have in our patients. A lot of patients don't get that number and therefore don't get those initial visual gains. Then over time, virtually all the real-world data show loss of initial visual gains over time, especially beyond years 2 the average number of injections are typically below 6 for the drugs we've been using for nAMD and the other conditions. And that does lead on average to vision loss over time. The fact is, there's very few studies published in which the average number of treatments in nAMD beyond year 2 are less than 6 and still maintain the vision gains well over time.

Then there's literature that's unfortunately replete with problems related to treatment lapses in AMD. You go for periods of time without these drugs, again, limited durability, you lose the effect of the medicine. Disease will progress, vision loss ensues, and often we can't regain or get back to where we were in terms of our vision control and control of the disease. The same goes for DME, such as in the DRCR network Protocol T. For all the drugs used in that trial, aflibercept, bevacizumab and ranibizumab, the average number of injections per year is high. The story is the same with DME too.

This is just an example of a patient of mine getting ranibizumab injections monthly for DME. It's a very typical case. We get slow improvement to the edema, slow improvement to the VA. And these are monthly injections. You can see by month 7 in this case, we're getting a very good effect, very good VA improvement but we still need to continue these treatments and continue them on a frequent and regular basis to maintain the macular optimal state and those vision gains that we got upfront. And again, the literature with treatment lapses and lost to follow-up in DR with or without DME is also unfortunately showing us the same as what we saw on AMD, which is vision loss will occur from disease progression in patients not on treatment in many cases.

In the field, we've done a lot in the research sector in trying to extend anti-VEGF durability. And there's a whole host of promising approaches in the pipeline, such as new anti-VEGF agents that are injected intravitreally, that might last a little longer, maybe a few weeks on average, maybe a few months and those are looking good. But there's also a very exciting sector of sustained release of VEGF blockade in the form of devices, biodegradable micro implants, and gene therapy. For this program, we're going to focus on the surgical approaches with new and exciting ones, such as the sustained release implant Port Delivery System (PDS) and a surgically delivered gene therapy called RGX-314. Dante, can you tell us about the PDS?

Dante J. Pieramici, MD: Sure, Carl. This is something that I think most of us are pretty excited about because it's really going to offer our patients an alternative to these intravitreal injections (IVIs). The PDS is a sustained delivery device. It's actually a small implant that's placed in the eye. Measures about 8 mm into the vitreous cavity by 2.5 mm at its apex. It's a relatively simple device. It holds 20 μL of a concentrated formulation of the drug ranibizumab but actually it's a platform therapy, so one could use this for a variety of different drugs. The drug is released by a release element that's titanium at the end of it. It follows first-order kinetics: passive diffusion. And as I mentioned, it's a device that has to be placed in the operating room (OR). It's an outpatient procedure, local anesthesia, but then can be refilled as needed in the office multiple, multiple times.

It's certainly a little bit more difficult than doing an IVI but it's very manageable in a busy clinic to go ahead and refill this device. The device is refilled with a 34-gauge needle; it not only refills the device but it flushes out the old material. And as we'll talk about, phase 3 clinical trials have now demonstrated this device refilled every 6 months, results in similar anatomical and visual outcomes to injecting a patient every month. It really allows us a potential for sustained delivery over time and perhaps improving long-term visual outcomes that, as you mentioned, Carl, drop off over time because patients don't get the injections that they need.

The device was developed in phase 1 clinical trials overseas and some modifications were undertaken. In a phase 2 trial called the Ladder trial, the device was filled with a variety of different dosages of ranibizumab and compared to monthly IVIs. The primary purpose in this Ladder trial was to see how long the device could go before it needed to be refilled, which was based on refill criteria. Then, to see if by refilling the device just as needed, you could get similar visual outcomes and anatomical outcomes to monthly injections.

With the high dose in the device, patients could go on average about 16 months without needing a refill. And 80% of the patients could go 6 months or more without needing a refill. For a vast majority of patients, this is at least a 6-month drug delivery device. And for many of them, it may be more than a year. This is a big improvement over every month or 2 of an IVI.

What's interesting though, too, is that even though the patients didn't need refills very much, they ended up with the same visual and anatomical results with monthly IVIs. I should note here that these are patients with wet AMD. These are patients who had been previously treated with IVIs in both groups. We're not going to put this device in somebody's eye without at least first testing that they have a response either for diabetes or for wet AMD to an anti-VEGF agent. What we're hoping is to keep things stable.

Because of the positive results of the phase 2 trial, the phase 3 registration trial called the Archway trial was undertaken. In this trial, the high-dose PDS was compared to monthly ranibizumab injections. That's the standard of care right now, these monthly injections. The PDS had a mandated refill every 6 months. It wasn't allowed to go until it needed to refill. And the primary outcome of this study was comparing noninferior inequivalence on visual outcomes and anatomical outcomes. What the study demonstrated again, like the Ladder trial, is that the PDS refilled every 6 months, the high-dose group had very similar equivalent, as you will, visual and anatomical outcomes to the monthly IVIs. And we can look at this in a little more detail and now we have data that extends out past 77 months with multiple refills being done. Again, seems to deliver drug at a very consistent basis, very similar visual and anatomical outcomes.

I would note that pharmacokinetic data was obtained during this time period too and that demonstrate that the device is delivering the drug at very adequate levels, above trough levels of IVIs throughout the study. It's resulting in good visual and anatomical outcomes equal to IVIs every month. Far fewer manipulations, every 6 months, and the pharmacokinetics backs up this data as well.

Patients were allowed in these trials to get supplemental therapy if criteria were met. Very few needed this. It is a durable device in the vast, vast majority of patients. Less than 2% of the patients needed a supplemental injection. And they also ask patients what they preferred. Remember, all these patients had been previously treated with IVIs, so they knew what it was like to have an injection. And many of these patients were getting it in the fellow eye. Almost 95% of the patients preferred the PDS with ranibizumab. There's some bias to this type of reporting of preference, but it does show you the patients like it. And it's been my impression too, in the patients that I've had in this study that they really do like this device and are enthusiastic about getting a similar device in the other eye when it becomes available.

Dr Regillo: Dante, the results are really very impressive in terms of how it stacks up as a sustained release of anti-VEGF in terms of VA and anatomy as you described. But it is unique in that it is a surgery and it is a device in the eye wall. And so we all know that IVIs are well tolerated and very, very low risk. We have some unique device-related adverse events (AEs). Charlie, can you comment on the AE profile of the device in the Archway study?

Charles C. Wykoff, MD, PhD: Thanks, Carl. Happy to talk about the device-related AEs. Dante, I absolutely agree that the efficacy and patient preference data are very strong. We've seen this in our own practice. The patients really do tolerate this remarkably well. It is important, absolutely, to consider the safety signals here, right? This is a very different approach to drug delivery than we're accustomed to with repeated IVIs. The first point I would make is that we've learned a lot. We've been using this port now in humans for many years. We've learned a lot through the first in-human studies. We learned a lot through the phase 2 program. And even through the phase 3 program we continue to refine the surgical approach to minimize any AEs.

I really think there's 2, maybe 3 phases of safety signals that we're seeing. Any surgical procedure is going to have peri surgical AEs or safety signals we need to be aware of, and those we're seeing out to maybe the first week or even 1 month post-implant placement. And then you get this longer-term phase. The safety signals we're seeing in these different periods are different. Associated with surgery you have the risk of retinal detachment. You have a hemorrhage inside of the eye. And then longer term you have things like conjunctival retraction over the device, implant dislocation, and potentially infections related to conjunctival issues around the device.

But to get specific about the numbers, the risk of vitreous hemorrhage in the phase 3 program has been 6% with the device compared to 3.6% with the monthly injections. Hyphema has been 0.4% with the device vs 0% with the injections. Conjunctival issues, particularly erosion and retraction, are probably the most notable long-term side effects to be aware of, at 4.4% with the device vs 0% with the injections. Retinal detachment, rare at 0.8% with the device compared to 0% with injections. And endophthalmitis, which we believe in the vast majority of cases is related to overlying conjunctival erosions and retractions, has been 1.6% with the device and 0.6% with the monthly injections.

Critically, again, this is a long-term placement of the device, so long-term safety signals are paramount, and fortunately multiple ongoing programs will continue to better inform this risk-benefit ratio.

Dr Regillo: Thanks, Charlie. That was a nice summary of the AEs. And again, some of these are unique to the device itself, like conjunctival issues and for the most part the hemorrhage, especially perioperative in nature. But the good news is, we now have longer follow-up. Follow-up as you see here is through 20 months. But very few events, new events, were seen after the primary endpoint, which was 40 weeks. Week 40 was the primary endpoint, and thereafter there were actually very few, so the safety profile is actually looking better with time. As you said, most of the events occurred early on.

We're still following patients in the Archway study. And as they roll into their extension program, both Archway and the Ladder study, patients rolled over into an extension program where they're getting the device monitored and refilled every 6 months. And we're going to have results from that so called Portal extension study in the coming months. And PDS is being launched globally now in a very similar study to Archway and that's called the Velodrome study and that's international investigation with PDS in nAMD. Back in the United States here, we're also looking at the port for the treatment of DME and for the treatment of DR in the Pagoda and PAVILION studies respectively. In years to come, we're going to have a lot of data, a lot of patients with this device in their eye and a lot of long-term follow-up, not only efficacy, but as you mentioned, the importance of safety.

Now, let's take a look at the PDS inserted in the OR. This is the initial surgical insertion of the device itself.

As mentioned by Dante, it's placed in the OR. The conjunctiva is opened up in the supratemporal quadrant and a 3.5 mm full thickness scleral cutdown in the sclera is made. And then the exposed choroid is then photocoagulated, which is a modification from the original surgical procedure to minimize postoperative vitreous hemorrhage. The vitreous cavity is then entered with a 3.2 mm. No vitrectomy is performed in this operation. The device is filled in the OR and then it's inserted and sits securely in the sclera without sutures. The overlying conjunctiva and tenons layers are then closed over the device.

I think it's important to note that there are a number of steps in this surgical procedure, many of which are somewhat unique, not particularly difficult. We've got these 7 basic steps:

• Conjunctival opening
• Implant preparation
• Scleral dissection
• Laser photocoagulation of the pars plana with the external use of an endolaser probe
• Entering the vitreous cavity
• Implant insertion
• Closure

Charlie, you mentioned how much we've learned over the course of Ladder and Archway and the clinical trials in the importance of these steps. How about some comments in your experience with the surgery, Dante?

Dr Pieramici: Well, I think that vitreoretinal surgeons, we certainly do much more complicated types of surgery but the importance of this is that all the steps have to be done very meticulously here. Remember, we're going to put this device in the eye and it's going to be there for the rest of their life. If they're a younger diabetic patient, this could be 40 years, 50 years, or something like that. One of the steps I think that is important is just the first step, cutting down and exposing the sclera, taking down the conjunctiva meticulously, getting a nice exposure so that you can put the device in and cauterizing adequately. And then at the end of the procedure is the second critical step that goes with this is closing this conjunctiva, number 7. The opening and the closing of the conjunctiva we've learned is very important. And doing this very meticulously can reduce the rates of the implant eroding through or retraction that can lead to things like infections, which is our most dreaded complication.

Dr Regillo: We also learned, we didn't mention that there was another type of complication which came up later. We're starting to see some implant dislocations and that seems to be occurring mainly at the time of the refill exchange procedure. And it's been correlated to the scleral wound size being a little too generous or greater than perhaps we were hoping for. We now know that it's really important that the scleral incision be precisely 3.5 mm. If it's larger, the device could move and could dislocate into the vitreous cavity.

Charlie, your experience with these steps.

Dr Wykoff: I would echo what Dante said. And then that's interesting how we've evolved this procedure. At the beginning in the first in-human studies, there was quite a high rate of hemorrhages inside of the eye, bleeding inside of the eye, what we call vitreous hemorrhages. And then there was a quite innovative approach to actually use a laser probe to cauterize the choroid, to prevent that bleed, which has been quite effective. But of course, 1 of the side effects of laser, it can be a contraction and potential expansion of tissue so important to really apply that laser to the tissue, the needs of the choroid and avoid sort of exposure to the overlying sclera, which can sometimes lead to wound expansion. It's very important to really maintain precise size of that scleral woun/d. Very easy to make that wound a little bit too large.

And we've all seen cases that need to go back to the OR, not only for dislocation of the implant but even because the wound is enlarging and there begins to be tilt to the implant where you have to re-suture the wound. Want to keep that wound really as small as possible expecting there may be some expansion over time.

Dr Regillo: It's a balancing act. If the wound is not big enough, the tissues are unstretched especially the uveal tissue and then that could increase the risk of hemorrhage. And too large, like you said, implant movement, dislocation and that's also a trip to the OR and potentially serious complication. And speaking about that, Charlie, can you tell us a little about your experience with the refill of the device in the office?

Dr Wykoff: Absolutely.You can watch a video here of that refill procedure being animated and it's a very different procedure than implantation of the device itself. This is much more similar to the standard IVI procedures that many specialists are comfortable doing repeatedly in the office. But the difference here is that when you do a regular IVI, there's sort of a circumferential band around the eye called the pars plana, where you put the needle through the eye wall and inject the medicine into the vitreous reservoir, into the eyeball itself. But here you actually obviously have to place it just to a very small septum. And so the needle is a specifically engineered needle for the specific role, which has a double bore to it, where the needle is placed through the septum directly into this little reservoir that holds the original fluid that was placed in there, this high concentration of ranibizumab. Then, as you press down on the plunger of the needle -- it's a very elegant design -- it flushes the reservoir up 1 bore of the needle and then refills the reservoir with a fresh concentration of highly concentrated ranibizumab so that then it is durable again for many months going forward as Dante beautifully described.

Very possible to do in clinic but it has to be done meticulously. It takes a little bit of pressure, a little more pressure than a typical IVI because you are piercing a plastic essentially or rubber septum, if you will. And so it takes a little bit of extra push, but you don't want to push too hard because the devices are certainly able to be dislocated if there's too much pressure that's applied. You want to make sure you know exactly where you are, place a little bit of pressure, and then get the exchange. Then, make sure after the refill that you check the conjunctiva to make sure that it's still intact over the device.

Dr Regillo: It's definitely a little bit more difficult. It helps to have some magnification and good lighting to make sure, as you say, you target that needle and it's got to be precisely perpendicular and right in the center of that septum, otherwise the needle will bend. It just won't work and you've got to start all over again. It's definitely not very forgiving and more challenging than a standard IVI but it is really well tolerated. Patients actually, I think sometimes tell me that they prefer it or find it more comfortable than an IVI, which in general is not so bad.

The device has yet to be FDA approved. It's not in our hands yet but it could very well be in the near future. We're already starting to think about how we might want to use the device in practice, what types of patients. Dante, the device is being tested, of course, probably to market first for the wet AMD indication and then ultimately maybe DME. Let's concentrate on wet AMD because that's what we have for the Ladder and Archway studies. What's the ideal patient you're going to potentially offer this device to?

Dr Pieramici: As I mentioned, this is not something that a patient who just gets diagnosed right off the street with wet AMD you're going to just take right to the OR and do it. You're going to want to do a few IVIs and sort of get a sense, first of all, do they respond to the anti-VEGF agents? And if they don't then maybe this is the wrong disease or something else. But if they show a response, then I think we have to determine how often is this individual patient going to need an injection? There are a wide variety of needs in patients. Not every patient is the same and needs an injection every month. Some patients can go to 3 or even more sometimes months between injections. If you only needed an injection every 3 months, having this device and have to go through surgery may not be worth it to you.

You might just say, "I'll just get the 4 injections a year." But if a patient who needs frequent injections, every 4 or 6 weeks, I think probably in my mind would be the ideal sort of candidate for this. As long as they're responding but they're just needing more injections. If they're not responding to anti-VEGF, I don't know that there's evidence that they're going to do better with this but I think a patient who's responding but needing frequent injections to maintain that response would be the ideal patient for me, at least initially.

Dr Regillo: Previously treated and needing or having a high frequency of injections to control their disease and yet also being responsive. Charlie, any particular contraindications that you can think of for utilizing PDS?

Dr Wykoff: One of the unique considerations that I've seen a few patients have challenges with is at the steady state level of ranibizumab that's achieved in the eye is probably equivalent to the sort of third week following a bolus injection of 0.5 mg. And so you're sort of towards the back end of the monthly dosing frequency. If you have a patient that really needs monthly dosing and they really sort of slip if you go beyond monthly dosing, I worry that some of those patients may need a higher bolus concentration to maintain their exudative state under control with the steady state that we're achieving here with this port. I think it's going to be a fantastic option for patients and I love having an extra tool in our toolbox that's very unique and very different than our current therapeutics.

I do think for the really high need anti-VEGF eyes are ones that I'm a little bit concerned about and want a little more data on, that particular population of patients, for example, baseline levels of VEGF that were really high, for example. There are additional ways to make those analyses. That population I'd worry about a little bit. For the previously treated, I agree there are certainly patients there that really dislike injections, even though they're overall very well tolerated. I think those patients would be great. And the patients, I think that can go 6 or 8 weeks before they have recurrence of disease with ranibizumab would be sort of a sweet spot for me.

Dr Regillo: It sounds very good. And what about monitoring these patients? Obviously, you're able to monitor their disease and response to therapy, when they might need a refill or maybe a supplement or something like that. Also, device-related complications need to be monitored. Certainly our general ophthalmology colleagues also need to be aware that under the lid in the supratemporal quadrant is going to be a device. And if it looks exposed, that's a relatively urgent matter because it's a set up for infection. We have to look at that and watch for that. You're going to see these patients every few months and see how they're doing and check the device?

Dr Pieramici: I think initially at least we'll probably be seeing them in the office relatively frequently, probably at least monthly until we get a sense of how they're going to respond to the device. And we may refill them every 6 months and some of the patients, we may try to go longer if they can. I think we'll kind of get a flavor for it. And as it is right now, we have all the equipment in our office to monitor it with the optical coherence tomography (OCT) machine, looking at retinal thicknesses and being able to look at the device but perhaps in the future, there may be devices that one could use at home to supplement some of these visits to the office. Home monitoring type devices for the implant itself and for the anatomical response to the treatment. I look forward to that and I know things are being worked on for this already. That's probably the future. Not only to reduce the injections at the end of the day but the real goal would be to reduce the number of times a patient has to come into the office.

Dr Regillo: I think you're right, that it's not going to reduce necessarily office visits at first, but certainly reduce the treatment burden and probably keep those vision gains up very nicely because it's so forgiving. You know it's going to be a true sustained release delivery. I think you're right over time, as technology improves with more remote monitoring, we might be able to not have to have the patient necessarily come into the office so frequently to monitor their disease and potentially even the device itself.

Dr Wykoff: Unique patient education here will be important also because following an IVI, we give warning signs of red eye, pain and that especially the first week after injection, whereas here you have that unique sort of device-associated safety signal of conjunctival retraction and erosion with that device exposure over time. If patients begin to have any pain or foreign body sensation in the eye, really important that they go seek care so that if there are device related complications, they can be managed efficiently.

Dr Regillo: I'm glad you mentioned, that's a very important point. Patients need to know what the symptoms or signs are of device-related issues and the need for that to bring to our attention. Charlie, can you tell us a little bit about the exciting realm of surgical delivery of gene therapy?

Dr Wykoff: Thanks Carl. We'll keep this brief. Gene therapy has certainly been at the forefront of medicine for many, many years and there's fantastic science and fantastic biology. In retina in general, we have 1 FDA-approved gene therapy already for a very specific gene mutation causing a very specific form of retinitis pigmentosa. This is already a reality in the retina clinic, using gene therapy. Gene therapy in this context is very different though. Gene therapy in this context is actually creating a bio factory where you have a very specific virus and adeno-associated virus vectors specifically that has been engineered to be able to be injected subretinally. This is delivered with surgical approach and that virus is placed underneath the retina. It essentially then transfects or infects, if you will, the retinal pigment epithelium (RPE) cells, which then are transformed into a bio factory, producing now an anti-VEGF protein.

Everything we've talked about so far is an exogenous protein that we're injecting into the eye with these bolus IVIs or placing in a reservoir in the PDS and it slowly diffuses into the eye. But here we've really changed the paradigm where you're creating this anti-VEGF protein inside of the eye. The human bio factory is producing the anti-VEGF protein itself right in the back of the eye, right where it's needed. Very elegant, beautiful science.

As you can see on this slide, we now have good data in a phase 1/2a program with subretinal delivery of gene therapy that's producing ranibizumab inside of the eye. You can see maintenance of VA, actually increased VA in some population and really very high-quality stabilization of the retinal anatomy, sort of the exudative disease process is under quite good control with consistent anti-VEGF protein expression inside of the eye. Many of these eyes do not become re-treatment free. Some of them do continue to need bolus exogenous anti-VEGF injections to keep their disease under control. And the optimal dose here is still being understood as this platform and program move forward.

Last points I would make are just that this is a surgical procedure, just as we described the details of the surgical procedure for a PDS, there are many details to unpack here. At a high level, this is very consistent with what retinal specialists are used to doing. A standard 3 port pars plana vitrectomy is performed where we enter the eye with 3 different instruments. We remove the vitreous gel, which is essentially a collagen matrix that makes up the inside of the cavity of the eye. And then the gene therapy is directly injected under the retina. You take a very small needle and you pierce it through the retina making a little retinotomy that's actually self-sealing, it's so small. And then you inject between 200 and 250 μL depending on the program, into the subretinal space containing that gene therapy.

The gene therapy then will be uptaken by the RPE cells and then begin to produce the protein over the subsequent days to weeks. The instruments are then removed from the eye and these eyes typically heal quite rapidly over the first few days with the standard postoperative care that retina specialists are used to delivering.

The safety signals from a surgical procedure have been quite strong through the phase 1/2a program so far. All the eyes treated so far have been pseudophakic, which means they've had cataract surgery and the reason for that is we know that cataract surgery is 1 of the expected side effects of any pars plana vitrectomy in a patient that's phakic that's not had cataract surgery. And so the thought with this program was to take that AE off the table so that all the patients are uniform in their lens status. As with any surgical procedure, there are risks. And the main risk here that we've seen has been very small, but we have seen 1 case of retinal detachment, which is a known complication following pars plana vitrectomy. And then long-term safety analyses are ongoing.

Dr Regillo: Great. Thank you, Charlie. It is very exciting. I think most vitreoretinal specialists would be very comfortable with this approach and this way of delivering a gene therapy, which in turn would be a very promising way to control wet AMD. Potentially even one-and-done for some of our patients. But as you said, patients still occasionally needed some booster-like or rescue IVIs. Not all patients were injection-free after gene therapy but it's looking real promising. This is for the subretinal approach actually now in pivotal testing. Within the next couple years, we'll have some more definitive safety and efficacy results of this approach.

The future is certainly bright. We know we need a more durable anti-VEGF therapy and we are likely to have a very nice spectrum of different options, from intravitreal office-based injections of anti-VEGF agents that last longer, even VEGF blockers that have other mechanisms of action, dual acting such as blocking VEGF-A and Ang2 with faricimab.

In this program, we've talked now in detail about surgical approaches with both devices and gene therapy that they're looking really promising for true sustained delivery over many months, if not years. And Dante mentioned the notion of home monitoring because it dovetails perfectly with the notion of sustained delivery and helping to monitor the patients remotely with home-based OCT, for example, and knowing when the patients might need retreatment with something that's very long acting.

Charlie and Dante, thank you so much for this great discussion. And thank you for participating in this activity. Please continue on to answer the questions that follow and complete the evaluation.

This transcript has been edited for style and clarity.