Carl Regillo, MD, Thomas Jefferson University School of Medicine  

Besides gene therapy, we hopped over some other potentially very useful, valuable, and promising intravitreal biologic injections, going back to anti-VEGF–like approach of injecting in the office. Can you tell me, Diana, a bit about what else is out there on the horizon?


Sure. There are some exciting new agents also in late stage development. One of them is KSI-301, which is an intravitreal anti-VEGF agent built on a novel ABC platform. ABC stands for antibody biopolymer conjugate, and this medicine is designed for enhanced durability with up to 6 months of VEGF suppression via a single injection. That is also in phase 3 clinical trials right now in wet macular degeneration, diabetic macular edema, and retinal vein occlusion, and the early data have been very promising, with robust visual acuity gains, long duration of VEGF suppression with the need for very few repeat injections, and fortunately no safety signals. I think that’s a very promising program in late stage development. Carl, you’ve had some experience with that. What are your thoughts on KSI-301?



I agree. KSI is looking very promising in that category of second-generation anti-VEGF therapy with greater durability. It seems to work as well; it seems to be as safe, although that experience is still quite limited, but nonetheless looking good. Durability, boy that looks to be at least as good as faricimab. We have about 60% of patients going 6 months in the maintenance phase. That’s quite good, after the load. This ABC platform effectively doubles or more the half-life of the drug. It’s a nice way to keep it in the vitreous longer, and that’s looking like its mechanism to get that greater degree of durability. I also put that in the next-generation or second-generation anti-VEGF category.

There is another drug that is interesting. It’s not a VEGF-A blocker, but it blocks VEGF-C and VEGF-D, and is called OPT-302. That’s a fusion protein that blocks C and D. This is an add-on; it’s not a standalone drug. In phase 2 it was added to VEGF-A blocker ranibizumab and did show enhanced vision benefit. It’s aiming at getting maybe better visual acuity outcomes, not necessarily greater durability, because it has to be injected pretty frequently, either every month or every other month, that’s been tested now in phase 3. That’s the only thing on the horizon that might actually get us better acuity. We mentioned limited durability and hoping to get more durable drugs as our big unmet need, and it is. But getting some better vision outcomes of course would be welcome, and that’s working by this combo approach, VEGF-A blockade like we’ve been doing and is still coming, and then adding in a VEGF-C and VEGF-D blocker. Again, an intravitreal injection, fusion protein, and it’s combination therapy, so it’s got to show superiority in vision to what we’re using now.

Then there is this class of tyrosine kinase inhibitor [TKI] molecules, small molecules that have to be packaged in a sustained-release platform, all of which are being injected intravitreally. It’s not a surgery, and there are 4 programs. Three are intravitreal injections, either suspension of microparticles with given TKI, or maybe a biodegradable implant injected intravitreally. There is even a suspension of TKI suprachoroidal injection. They are all aiming to get an anti-VEGF–like effect over about 6 or more months, but that has yet to be demonstrated adequately. What are your thoughts about what you’re hearing about these TKIs?



I think it’s terrific to see all of this innovation continue to push the field forward for patients. It’s wonderful to think out of the box. Certainly, there is room for improvement because not all patients have an optimal response to VEGF inhibitors, and angiogenesis is complicated. There are lots of different cytokines and molecules in play. I think exploring these different inhibitors is a terrific way to try to improve the outcome for all patients. I’ll be excited to see more data as they emerge.



 In the TKI category, there are few things they have to prove. They have to prove they work as well as our anti-VEGF biologics, have to be as safe, and truly give us the durability factor, give us 6 months or more, not just 3 or 4 months, because the other medicines we’ve been talking about like faricimab and KSI are probably going to achieve that 3 or 4 or more benchmark and durability. They’ve got a hurdle there to try to stack up to what’s on the near horizon with biologics, again KSI-301, faricimab, and then we’ve got the port [Port Delivery System], all in the very near future. A lot is going to be in our hands. There will be a lot of choice for our patients, and that’s all good in terms of decreasing treatment burden with greater durability and hopefully getting better vision outcomes in practice.

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Carl Regillo, MD and Diana Do, MD react to newer therapies being explored for wet AMD and discuss their place in future therapeutic algorithms. 

Innovative Therapies on the Horizon to Treat AMD 

 We can carry on with that theme of durability; the ultimate durable type of anti-VEGF treatment might be gene therapy. There is a lot of excitement. It’s only in phase 1, and while it’s moving along, the data we have are only from phase 1. Tell me, there are a couple of programs, can you tell me about gene therapy for wet AMD [age-related macular edema]?

 Gene therapy is a very exciting new field for retina. In wet AMD, the goal of gene therapy is not specifically to replace a defective gene, but the aim is to insert a viral vector that delivers a gene encoding for an antibody that could inhibit VEGF. The VEGF inhibitor is produced within the eye, and therefore would theoretically decrease the need for injections because the eye would be already producing an antibody to inhibit vascular endothelial growth factor. There are several programs underway in clinical trials. One of them is testing RGX-314 gene therapy. It’s being evaluated in phase 2 clinical trials, and it can be delivered either as a surgical subretinal injection, or it’s being evaluated as a clinic-based suprachoroidal injection. The clinical trials are evaluating the efficacy and safety of RGX-314.

Also recently, ADVM-022 is being evaluated as a gene therapy. This is unique because it’s an office-based intravitreal injection of this gene therapy. Although the early phase 1 clinical trials were quite promising, more recently there was a pause in their phase 2 clinical trial in patients with diabetic macular edema [DME] because in the highest dose of ADVM-022, a subject developed intraocular inflammation, low eye pressure, and decreased vision. That is being evaluated right now. I think gene therapy is exciting. It’s still in its infancy, and of course we will have to determine the long-term safety effects of gene therapy in wet AMD. Carl, what are your thoughts about gene therapy?

It’s super exciting. It’s potentially “one and done” treatment for many of our patients, but in reality, 1 administration of gene therapy is not likely to eliminate all anti-VEGF injections. But it could potentially significantly reduce; there could be some patients who never need another injection, which the prospect of that is wonderful for our patients. That will certainly not only decrease burden but maximize the vision gains over time. They are 2 very different programs, and like you said they are looking really good coming out of phase 1 in terms of accomplishing that. Big reductions, and these are patients who have been getting frequent treatment injections and then gene therapy administered. This is maintenance phase, like the Port Delivery System trials. We saw some patients not even getting or needing another intravitreal anti-VEGF injection for a year or two, and that’s in both programs. They’re looking like they’re performing as we hope in that sense, disease control with very few supplemental intravitreal injections. 

Safety issues: a surgical approach with RGX, for example, can have complications. The suprachoroidal approach is really new, very interesting; it’s not something we do in practice but it has been done to deliver steroids in that way. We know it works in that regard, but how well it’s going to work as gene therapy we just don’t know. That’s in phase 2 testing. And the subretinal approach, the original approach with RGX, is now moving into phase 3. From 1 to 3, we’re speeding along, and that’s looking very promising to be able to do that. 

You mentioned ADVM-022, the intravitreal injection, that too in the optic neovascular AMD phase 1 study performed beautifully. The inflammation was common but not a major issue because it was very well controlled, typically mild, and steroid eye drops seem to be all that was necessary to keep it in check, and patients were doing really well. That very recent adverse event you’re referring to in the DME study was more than what we had been seeing in the wet AMD study, so we don’t know if it is unique to that disease or that particular patient. Time will tell, we’ll have that sorted out, but I think both approaches are looking really good. ADVM-022 is also looking into going to phase 3 for wet AMD within the next year. Those are really moving along. We used to think that was on a 4- or 5-year horizon, but it actually could be sooner.

An overview of new gene therapy options for wet AMD that are currently being explored in clinical trials.  

Intravitreal Gene Therapy for Wet AMD 

There have been other exciting developments in our field in the past year, and going on that theme of more durable anti-VEGF effect, now we’re back to simple intravitreal injections, but there is a novel biologic called faricimab. Can you tell me a little about what faricimab is and about the phase 3 experience we just heard about?

Recently the phase 3 global studies of faricimab, which is a novel bispecific antibody that inhibits both VEGF and angiopoietin-2, were released. These trials met the primary end point in that people who received faricimab injections at fixed intervals of up to every 16 weeks had similar visual acuity outcomes that were noninferior to fixed dosing of aflibercept. More importantly, nearly half, about 45% of patients who were treated with faricimab, could go 16 weeks between treatments. This is very promising because this would be the first office-based intravitreal medicine that could provide up to 16 weeks of durability in nearly half of the patients. This is a very exciting development, and hopefully this will be available for retina specialists to use in the near future. In addition, thankfully there have been no significant safety signals with faricimab, so it appears to be both effective and safe. Carl, what do you think of this new bispecific antibody? Will you be using it for your patients?

 Yes, I agree, this is looking really promising. It’s a very successful phase 3 trial program. It works as well as the drugs we’re using now and definitely looks to be more durable. I think we’re on to the next generation of anti-VEGF therapy, something that can break us beyond 3 months in our patients. The median durability of what we’ve been using is about 2 months. This is looking like 3 months and maybe pushing the envelope to 4 months or so to get good anti-VEGF effect. We’re talking about burden, it’s not just coming to the office and getting the injection, it’s also about maintaining those gains because this is an unforgiving disease. You can miss visits, there are lapses in time required to get the drug on board, and we’ll start to lose vision and that can be permanent. That accounts for why in the real world our vision outcomes are not as good as the clinical trials where the patients are coming in on a fixed, frequent basis. Here, the patients miss visits. A drug that is more long-acting is more forgiving, and we’re less likely to lose vision over time. I think that is going to help with long-term outcomes.

I am very excited with the prospect in the next couple of years to have both PDS [Port Delivery System] and faricimab, and pick and choose. I can already think of at least 30% to 40% of my patients who are getting drug frequently who want to switch right over to faricimab to see how that works. If we’re not getting great durability in some patients, we can think about PDS. It will be wonderful to have them both. I think they complement each other very well. What about you with faricimab? I am glad you also mentioned the safety because it’s great to say it works as well and lasts longer, but it’s got to be as safe or else we’re back to the brolucizumab issue where we don’t want to use it because we’re afraid of vision problem, even if it’s only 1% or 2%. Fortunately, like you said, in the clinical trials we’re not seeing that. We’re getting even more durability, but the safety profile looks to be comparable to what we’ve been using. That’s best of both worlds. Your impressions?

 I agree. I think the combination of efficacy, durability, and safety is very promising for faricimab, and it’s advantageous because it can be delivered in the office as an intravitreal injection. I think that’s going to be great for treatment-naïve patients who have new onset wet AMD [age-related macular degeneration], and I’ll be eager to use that in that patient population. Certainly, I’ll also use it in my prior treated patients who as you mentioned we want to see if we can extend the durability of VEGF suppression over time. I think it’s unique because it’s a bispecific that inhibits both VEGF-A and angiopoietin-2, which has also been implicated in the angiogenic pathway. It might provide a little more benefit over time. That remains to be seen, but trying to get at the pathophysiology of angiogenesis can only help in this chronic disease.

That added mechanism of action of blocking, you mentioned it blocks all VEGF-A, which is what our current drugs do. It also blocks angiopoietin-2, and that’s at least getting us the durability part of the benefits. As you said, it may also enhance the drying, which could help some of our patients who don’t have a complete or ideal response to some of the drugs we have been using now. There is a hint of that in the DME [diabetic macular edema] studies, which are looking just as promising, where better drying definitely correlates to better vision. This is really a big step forward to have both the PDS and faricimab potentially in our hands in the near future. But there are other exciting things coming.

Results of recent phase III clinical trials with respect to efficacy and safety of faricimab, an investigational bispecific antibody which inhibits both VEGF-A and angiopoietin-2.   

Faricimab: A New Bispecific Antibody with Promising Durability in AMD 

We’ve just talked about this great safety profile.

 Exactly. That’s what I want to ask you. Are there any safety concerns with the Port Delivery System? This indwelling implant seems great, gives this drug, but are there any concerns?

 Yes. It would be unrealistic to think you’re going to get the exact same safety profile; it’s just unrealistic. You’ve got a foreign device in the eye. You’ve got a surgical procedure. The good news is most of the adverse events associated with the device, the surgery, the refill and so forth, most of that is within the first year. When we think of adverse events and safety profile, to compare apples to apples, we have to think about the safety profile of many intravitreal injections in a patient over the course of 5, 6, 7 years in the real world of getting injections. The rate of infection may be only 1 in 3000 per injection, but the cumulative rate of endophthalmitis for a patient undergoing 5 or more years of many injections could be up to 1%. In the trial, what were the adverse events associated with the device? It was vitreous hemorrhage, most of that was postoperative, most of that was mild, most of it went away on its own, about 5% or 6%. There was erosion or retraction of the conjunctiva over the device. That’s not good because it requires surgical repair. It puts the patient at risk for endophthalmitis, a serious intraocular infection. The rates of those were in the 4% or 4.5% range that necessitated usually a trip back to the OR [operating room] to repair. And there was an endophthalmitis rate, 4 patients in the clinical trial. All of it occurred early on for the most part within the first year, and the rate was about 1.5%. It doesn’t sound as good as 1 in 3000, but for over 18 months the intravitreal injection arm also had a case of endophthalmitis, so the rate effectively per patient was 0.6%. You can see over time it is becoming a little bit more equal. The device can still have issues or complications like dislocation later on. Fortunately those are rare.

So, the safety profile overall, I think most people would say it’s acceptable, looks pretty good considering what it is. For some patients, I think that’s a reasonable trade off when it comes to the potential benefits of having that sustained release in very few injections or manipulations and even potentially office visits over time. What do you think of the surgery? You’re a vitreoretinal surgeon, you’re going to potentially put this in. It’s through phase 3, it could be commercialized and FDA approved in our hands within the next year or two. You’re going to use it; what do you think?

 I love surgical innovation, and certainly this device, Port Delivery System [PDS], is an out of the box way to develop a sustained delivery system. So, it seems very exciting. The surgical implant, based on the videos and the early clinical trial experience, looks very straightforward as long as you follow the recommended steps to mitigate any potential postoperative vitreous hemorrhage, and of course to appropriately cover the implant at the end of the case. I think there is a role for this implant in select patients. The question many retina specialists will have is, after you implant the PDS system, how often do you need to see patients? Do you implant and then have them come back in 6 months, or would you follow them more closely, Carl?

At first, definitely follow more closely. Again, most of the issues, the adverse events, complications are occurring within the first few months. You want to get through the perioperative period, the first 6 to 8 weeks for sure, seeing the patient a few times. Thereafter, I think what’s going to happen is I’ll probably see the patient every 2 months and then maybe every 3 months. I’ll try to get a feel for when they need a refill because I may not necessarily refill the device on the clock every 6 months, and really put it to the test for a given patient. I do want to say that we learned a lot about the surgical approach and how to mitigate these complications, going from phase 2 and through phase 3. We’re still learning. We’re looking back at all the videos from all the surgeries in the clinical trials. I think we can do better and bring down some of these complicate rates, including infection, conjunctival issues, and so forth. There has already been good progress in that way, especially with regard to hemorrhage. Hemorrhaging was a big problem in phase 2 early on, and then surgical technique modification took place, and further modifications are being recommended now, which I do think is going to help make this a very acceptable approach from a safety standpoint for our patients. What type of patients do you think you’re going to use it in? If it’s in your hands, you’re comfortable with it, you’ve been trained on it. What’s the ideal patient?

 Certainly I don’t think it’s a first-line treatment, because many patients who come in with new onset wet macular degeneration, we want to treat them rapidly and that day, usually in the office. So, those patients will receive an intravitreal medicine. I think for the Port Delivery System, I’ll probably select patients who I know are responsive to anti-VEGF agents and who are doing well, and for whom I want to maintain the benefits, but stretch out the intervals. Of course, these patients have to have healthy conjunctiva, no other issues like glaucoma or things that might necessitate other surgeries that involve the conjunctiva in the future. But I still am trying to determine exactly what would be the best patient population for this. What are your recommendations, Carl?

 I agree. We throw around this term frequent fliers, those patients for whom we can’t extend the treatment interval with our drugs that we’re using now with intravitreal injections in the office, the ones who need to get it every 4, 6, or even 8 weeks. There may be a patient interested in getting injections less frequently, but you’re right. We’re going to start doing injections. We’re going to see what the patient’s individual needs are, and we probably are going to self-select. The patient will be much more inclined to want to do this if they can’t break out of a frequent, every 4-, 5-, 6-week routine. This could go on for years. That’s the type of patient to whom we’re most inclined to want to offer the device and the patient most inclined to accept it. I think it’s going to be a good tool to have in the tool chest, if you will, for patients who want something more durable.

Retina specialists provide insight into the patient selection and safety concerns with the innovative Port Delivery System (PDS) that offers a new means of sustained anti-VEGF therapy.

Carl Regillo, MD, Thomas Jefferson University School of Medicine

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