Neovascular AMD: Treatment Durability, Risk of Undertreatment, and Drying the Macula

Michael S. Ip, MD
Doheny Eye Institute, University of California Los Angeles
David Eichenbaum, MD
Retina Vitreous Associates of Florida, Tampa, Florida

Key Takeaways

  • Undertreatment of patients with neovascular age-related macular degeneration (nAMD) continues to be a challenge.
  • Data consistently point to a correlation between the number of injections and visual acuity.
  • Treatments with longer durability are still coveted.
  • Newer treatments still under investigation (including a bispecific molecule, the Port Delivery System [PDS; Genentech], and gene therapy) might help reduce treatment burden. 
  • Data support the contention that a small volume of subretinal fluid might be protective in nAMD and can be tolerated, but that intraretinal fluid is not protective and should not be tolerated.
  • An ideal treatment for nAMD would provide antiangiogenic and antifibrotic effects.
  • The amplitude of fluid fluctuation in the macula in patients with wet AMD might be more important than the dryness of the macula.

David Eichenbaum, MD, is an ophthalmologist who serves as director of research for Retina Vitreous Associates of Florida and has been principal investigator in more than 45 early- and late-stage clinical trials studying common retinal diseases, such as dry and wet macular degeneration, diabetic eye disease, and retinal vascular disease. Michael S. Ip, MD, is an ophthalmologist and chief of the Vitreoretinal Surgery Service at the Doheny Eye Center at UCLA. His practice focuses on the surgical management of complex retinal detachment, complications of diabetic retinopathy, macular holes, epiretinal membranes, and other vitreoretinal diseases amenable to surgical intervention.

Is there a risk of undertreating nAMD? If so, as physicians treating patients with nAMD in the COVID-19 era, how do you overcome this risk?

Dr Ip: Undertreatment has certainly been a risk, even before COVID-19. We’ve been evaluating that for years, and real-world and Medicare claims studies clearly show that, at least compared with randomized clinical trials that had strict monthly dosing, in the real world, we are likely undertreating our patients.1-7

Prospective studies — TREX-AMD and PrONTO ( Identifiers: NCT01748292 and NCT00344227, respectively) and others — show that less-than-fixed monthly dosing can provide a good outcome.8,9 But the problem is, in the real world, we’re just not able to replicate those results. The COVID-19 pandemic is likely to make this problem a lot worse.

We had problems getting our patients into the clinic in the first couple of months after the lockdown here in Los Angeles in mid-May 2020. Interestingly, findings from a soon-to-be-published paper by my colleague at UCLA, Irena Tsui, MD, show that, during lockdown at West Los Angeles VA Medical Center, patients and physicians were self-selecting and aware that wet AMD was a more urgent diagnosis that needed treatment. In my practice, there was an access issue during the lockdown for most of our patients.

Dr Eichenbaum: At our medium-sized private practice, we did push patients with wet AMD in particular to keep coming in, even at the peak of pandemic uncertainty. It would be interesting to see what mean visual acuity was 16 weeks after lockdown, because some of those patients didn’t come in for 6 or 8 or 10 weeks and, by then, their vision had decreased. Some of them are not going to get that vision back. We never really had a shutdown here in Florida, but our clinic did reduce elective care substantially.

We made the decision that wet AMD is not elective care, based on available data. Holz and colleagues10 looked at all the European countries correlating injection frequency with level of visual acuity and found that countries that had a greater mean number of injections had better visual acuity in their wet AMD population.
David Eichenbaum, MD

We do have a couple of cases in which patients just didn’t come in — either they were scared, they were in an assisted-living facility that had restrictive quarantine rules, or family members didn’t want to bring them in. That resulted in some cases of disease advancement and irreversible visual loss directly related to access restrictions during the pandemic. You’re on target, Dr Ip, when you note that the data point to a correlation between number of injections and visual acuity.

What I found myself wishing for during the pandemic was that the PDS was readily available. We have a number of patients enrolled in the PDS parent and extension studies for nAMD; in the clinical trial setting, those patients continued to do really well.  PDS technology, which is on the cusp of being commercially available, would have mitigated the effects of the pandemic on vision loss.

Q. Dr Ip, what are your thoughts? Were any of your patients in those studies?

Dr Ip: Dr Eichenbaum makes really good points. His clinic experience is very similar to what my colleagues have noticed at the West Los Angeles VA Medical Center.

It’s encouraging that clinicians from coast to coast recognize what is urgent and what is not, and that we all place high value on treating our patients with wet AMD. What’s becoming obvious is that we are on the cusp of getting some newer technologies and treatments with a longer duration of effect and better durability.
Michael S. Ip, MD

It would have been great to have those technologies and treatments during the lockdowns, but it might be a year or longer before some of them are approved. In addition to the PDS, other treatments such as faricimab (Genentech) and other longer-acting, more durable drugs are showing positive trial results.11,12

At this year’s Angiogenesis, Exudation, and Degeneration 2021 virtual conference, the wet AMD data presented for faricimab are encouraging. Approximately 70% of patients made it 12 to 16 weeks without retreatment.13 So, even if you can squeeze out 4 more weeks between treatments, that would’ve helped many patients who were unable to keep their appointments.

During the height of the pandemic, it became difficult for some of our patients to maintain access. But if what is being investigated in the phase 2 studies works, we should have more options than we currently have that are more durable, from a treatment burden perspective. 

Q. What are some of these newer compounds?

Dr Ip: Some of the earlier-phase approaches that might be promising include KSI-301 (Kodiak Sciences) and some gene therapy approaches.14-19 We cannot predict what the results might yield, however I suspect that in 1 to 3 years we are going to have something besides current anti-vascular endothelial growth factor (VEGF) drugs in our armamentarium. 

Dr Eichenbaum: We can translate some of what Dr Ip is talking about to the technology. I’m excited about the opportunity to translate some of the delivery technology for neovascular macular degeneration to something that shows clinical efficacy in the atrophic macular degeneration. In geographic atrophy, we don’t have a biomarker like an optical coherence tomography-B scan or central retinal thickness, with which you can titrate your patients’ treatment. However if we develop an agent that works well in geographic atrophy, you could load a port with it, train a vector with it, or perhaps put it in a polymer, like Antibody Biopolymer Conjugate technology (Kodiak Sciences). There are probably ways you can translate these products that deliver antiangiogenic proteins in a more durable fashion to deliver a protein that affects geographic atrophy in a similar fashion — perhaps, for example, an anti-C3 or anti-C5 protein. 

There’s a lot of translational science we’re going to see to help with the burden across disease states. Already we’re seeing new agents across disease states: positive phase 3 results of the faricimab molecule for patients with diabetes are, to me, even more impressive than the wet AMD results in regard to efficacy.13,20

If you look at the American Society of Retina Specialists (ASRS) Preferences and Trends Survey from 2019, our colleagues are asking for durability in nAMD treatment.21 That’s the Number 1 unmet need in wet AMD, and we will see new technologies try to deliver on that. 

Q. Let’s get deeper into the matter of durability. Some approved compounds have longer durability and had great data on drying the macula. Is getting and keeping the macula dry still the primary goal for wet AMD treatment? 

Dr Eichenbaum: That’s a tough question. Do you want to be bone dry, or do you want just the right amount of subretinal fluid? I still opt for drying the macula, but I am more tolerant of subretinal fluid, given how much the post-hoc data and some prospective data support its relative protective effect.22-26 There are caveats, of course. All the prospective data are relatively short term and the post-hoc data have limitations.  Tolerating subretinal fluid is, to me, more acceptable than it was in the past, but there should continue to be limited tolerability for intraretinal fluid.

Dr Ip: The jury, as Dr Eichenbaum said, is still out in terms of whether we want to treat to be completely dry. If I had my druthers, I would have an agent that dries the retina and keeps it dry. That being said, in some of these post-hoc analyses of large clinical trials, and even in some prospective clinical trials, such as the FLUID study ( Identifier: NCT01972789), we’ve found that some fluid can be tolerated.27-32 

Some of these post-hoc analyses indicate that it might be good to have some fluid; we’ve now distinguished between intraretinal fluid as being potentially more harmful than having a little bit of subretinal fluid, which might actually be somewhat more benign.33 

Q. Moving forward, should the goal of therapy go a little beyond preserving vision to trying to stop disease from being active in the first place?

Dr Eichenbaum: Ideally, we want to stop the disease process. I would like to see an effective antifibrotic agent. In advanced trials, we don’t have anything that shows a lot of efficacy that way or that has aspirations for fibrotic regression, like the promise of antiplatelet-derived growth factor a few years ago.34

Getting the macula dry and maintaining that anatomic dryness is still where virtually all clinicians aim their treatment. Suppression of disease activity, more so than disease modification, is the current practical approach for nAMD.

Dr Ip: I’d like to have something that works on fibrosis; that would be an excellent adjunct to the anti-VEGF agents. So, I think another Holy Grail, in regard to drying the retina completely or achieving even better visual acuity results than we’re able to, might be to combine an anti-VEGF agent with something that works on VEGF-independent pathways. 

There might be other cytokines responsible for exudation in AMD. There might be profibrotic or proinflammatory pathways that we want to bring from bench to bedside. So there’s a lot of promise that we’re going to be looking at during the next couple of years to really get that retina dry and to achieve a more durable result.

Dr Eichenbaum: There’s a post-hoc data set that I’m working with for ASRS, looking at fluid fluctuation in wet AMD and amplitude of fluctuation affecting visual acuity. We’re finding that amplitude of fluctuation might be more important than absolute dryness. Trying to get your patients to have less fluctuation is what some of these longer-acting agents, devices, and depots might do, which might result in better visual acuity over a longer period. 

We have a gap in long-term prospective studies. We don’t have multiple truly long-term, prospective, controlled studies with protocol treatment. Some of the longer-term studies switched over to investigator-determined injection intervals or they are evaluating small populations. It would be nice to see late-phase series over 3, 4, or 5 years from inception of treatment, with some of the newer delivery systems and compounds on a protocol-mandated dosing schedule, even if that schedule is individualized to subjects. I would like to see those data.

Q. Based on what Dr Eichenbaum just said about fluid fluctuation, should we be thinking about wet AMD as a chronic disease with fluid fluctuations being “spikes,” if you will? 

Dr Eichenbaum: Maybe. What do you think, Dr Ip? Are we going to be looking for “pops” in fluid?

Dr Ip: Again, maybe. The point of looking at fluctuation is that it is becoming something that’s recognized as a potential marker of how a patient might do in terms of their visual acuity response. The goal is to reduce the amount of fluctuation above and beyond just getting the retina dry. We now see these types of treatment response markers being evaluated in post-hoc analyses of clinical trial data.

Q. Some compounds had great drying data and longer durability but an increased risk of increased inflammation.22,35-37 Are there particular patients who might still benefit from brolucizumab-dbll?

Dr Eichenbaum: That’s a highly topical question. Our site was a good enroller in the HAWK trial ( Identifier: NCT02307682) that compared brolucizumab and aflibercept, and we’ve been in a series of brolucizumab-dbll trials for other disease states, as well. There was a lot of excitement in our practice when brolucizumab-dbll (Beovu®; Novartis) was approved for treating nAMD. We went through phases, you could say: First, we were “Beovu-curious”’ because of the data from HAWK.22 Then, we were “Beovu-avid” when the drug was approved; we had a good deal of real-world experience, which is now part of a recent publication.38 Then we became “Beovu-shy” because we had some episodes of inflammation. Fortunately, throughout our practice, we had no episodes of irrecoverable vision loss related to vasculitis, but we did have some significant vitritis and a reasonable amount of anterior-segment inflammation.

If we look at our overall practice data, 3% or 4% of our injections are, on a weekly basis, still of Beovu. We thought that percentage would be close to 100% Beovu for branded use when the drug was first commercially available. However, we pulled back once reports of inflammation started. But Beovu is still a highly effective drug; I probably inject it in about 5% or 6% of patients whom I treat.

Dr Ip: I’m more of a late adopter of some new therapies. I waited until the permanent J-code came out before using brolucizumab-dbll, early in 2020. By that time, we had already started to get reports of inflammation.

The ongoing issue with using brolucizumab-dbll for nAMD is that we have other really good, effective, and safe agents. They’re quiet drugs, so to speak, with an outbreak of inflammation on occasion and some patients who are recalcitrant to therapy even if you give it every month, which might be due to retinal angiomatous proliferation lesions or polypoidal choroidal vasculopathy. So there are a variety of reasons why you get resistant cases. In such cases, brolucizumab-dbll can be highly effective. I know that Novartis is doing a root-cause analysis of reported inflammation, and I trust that they will do their best to find out what the problem is, and eliminate it.

Dr Eichenbaum: The problem might be unsolvable. There’s no obvious answer yet. I wish there was a smoking gun that we could just douse. I don’t know if we’re going to find that.

Dr Ip: But I think we all wish that they would find what the problem is. It would be great to have such an efficacious drug available and be as safe as what we use now, more often, in the clinic.

Brolucizumab-dbll adverse effects
Adverse effects commonly reported are blurred vision (10%), cataract (7%), conjunctival hemorrhage (6%), eye pain (5%), and vitreous floaters (5%).

Q. Or at least know exactly which patients are likely to have a poor outcome or be at increased risk of inflammation?

Dr Eichenbaum: True. If we can identify risk factors, that would be useful.  There has been some recent work looking at patients who may be at higher risk.39

Q. With Lucentis® (ranibizumab; Genentech) coming off patent this year, what are your thoughts on potential biosimilars entering the market?

Dr Eichenbaum: First, it depends on the data; there have to be intraocular data for biosimilars. I’m waiting to see what the data show and, then, what the access issues are. That’s going to be really important. Introducing a biosimilar for Lucentis in a post-faricimab world might be like unveiling a new steam engine when you’ve got powerful V8 engines already on the ground.

Second, Outlook Therapeutics is testing an investigational injectable bevacizumab (bevacizumab-vikg [ONS-5010/LytenavaTM]) preparation. This option might have greater impact than biosimilars because it is likely that low-cost repackaged bevacizumab (widely used as Avastin®) would be difficult to distribute if ONS-5010/Lytenava is approved. The absence of low-cost Avastin would be a major change in how we deliver care for common retinal disease.

Dr Ip: As Dr Eichenbaum said, it will be interesting to see what happens, because this is the first time our field has had this kind of a situation, where we’ve got multiple drugs and now we’ve got potential biosimilars. If there’s a therapeutic that comes out soon, such as KSI-301 or faricimab, will we even want to use a biosimilar?

Biosimilars are going to come into play in regard to issues of cost and access. In the face of newer drugs becoming available — drugs that are safe and perhaps more efficacious and durable — why would we need biosimilars? Perhaps they could be considered when there’s an insurance or access issue, but many insurance companies have been doing a good job expanding their access programs.

Q. Any concluding thoughts on the state of the field in treating wet AMD?

Dr Eichenbaum: I’m excited about the potential for a second mechanism of action become commercially available shortly, as with faricimab. I’m equally excited to see if the retina space is ready to adopt something like the PDS with the veracity and out-of-the-box thinking with which we adopted frequent intravitreal injection in 2005. So, it’s certainly a more exciting time now. 

I’m hopeful that if we have this conversation in another 10 years, we’ll be practicing much differently than we have been from 2011 to 2021. I hope we continue to advance, and I hope patients benefit from our scientific efforts. Our aspirations are for patients to do the best that they can without getting as many injections.

Dr Ip: As retina specialists, we adapt relatively quickly using evidence-based approaches. We went from the laser straight to photodynamic therapy, and then to multiple anti-VEGF treatments. But it’s also been impressive to see the industry adapt to the retina space. If you look at the number of companies that are in this space now, it’s quite astounding. And industry involvement seems to be getting broader and bigger as every year passes. So, when I think about where we go from here, the prospects look limitless.

The Q&A was edited for clarity and length.


David Eichenbaum, MD, reported affiliations with Alimera Sciences, Inc., Allergan Plc., Clearside Biomedical, Inc., Roche Holding AG, Novartis International AG, and Regeneron Pharmaceuticals, Inc. 
Michael S. Ip, MD, reported affiliations with BioTime, Inc., Boehringer Ingelheim, Roche Holding AG, Novartis International AG, Quark Pharmaceuticals, Inc., and Oxurion NV.


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Reviewed May 2021