Mitul Mehta, MD
Gavin Herbert Eye Institute; University of California, Irvine
SriniVas Sadda, MD
Doheny Eye Institute; University of California, Los Angeles

Key Takeaways

  • Determining which compound might be best for a treatment-naive case of neovascular age-related macular degeneration can, in part, be driven by the payor situation (depending on location), including the desire to initiate therapy with the least-expensive agent.
  • Treatment remains individualized: Some patients are dry after 1 injection, others never become fully dry. There is no “right” or “wrong” choice among PRN, PRN with monthly monitoring, monthly dosing, or treat-and-extend regimens.
  • The clinical trials CATT, IVAN, HAWK, and HARRIER all suggest that significant fluid fluctuations are associated with worse visual outcomes.
  • Although the risk of infection, inflammation, and endophthalmitis is low with anti-vascular endothelial growth factor (anti-VEGF) agents, the risk:benefit ratio has to make sense, and patients should be educated early on about risks.
  • Studies support that brolucizumab-dbll is more potent than aflibercept at achieving full resolution of fluid.
  • Building a differential diagnosis might be warranted if there is no response to an anti-VEGF drug, even after only 2 weeks. If there is no change by 2 weeks’ postinjection, it is unlikely that the disease is VEGF-mediated.
  • The VIEW study showed that subretinal fluid is better tolerated than intraretinal fluid; adding a steroid for patients with persistent intraretinal fluid might be beneficial.
  • There remains a role for photodynamic therapy in age-related macular degeneration; namely, treating polypoidal choroidal vasculopathy.

For the treatment-naive patient with confirmed wet age-related macular degeneration (AMD), how do you determine the most appropriate treatment regimen?

Dr Mehta: When a patient has wet AMD in one eye, assuming the other eye is dry, at the first visit we do the following:  perform fluorescein angiography or optical coherence tomography-angiography to look at the level of fluid, performa complete eye examination, get a family history, and ensure that we counsel them on smoking cessation and the use of sunglasses. I usually start the patient on bevacizumab because it is dramatically cheaper than all other options. Results from CATT (Comparison of Age-Related Macular Degeneration Treatments Trials; ClinicalTrials.gov Identifier: NCT00593450)1-4 show how effective bevacizumab is in wet AMD, so I’m not compromising on efficacy.
 
Dr Sadda: What Dr Mehta just described is the most common approach. My decision-making is, in part, driven by the payor situation. Many payors, at least in some regions, insist on starting with the cheapest possible drug; right now, that’s bevacizumab.

I tend to start with the brand-name drugs. In CATT,1-4 bevacizumab was prepared in a centralized process and distributed to all investigators; that’s not what we have access to in our clinics. If we did, I’d be very comfortable recommending that as starting therapy for all of my patients. There are rare cases of inflammation or infection5,6; however, some of those cases were linked to the compounding pharmacy.7,8 So, if there is no out-of-pocket cost for my patients, I prefer a brand-name agent.


Common symptoms of wet AMD
Flip
Most commonly reported symptoms include general haziness in overall vision, visual distortions, reduced central vision in one or both eyes, decreased intensity or brightness of colors, and abrupt onset and rapid worsening of symptoms.
Risk factors for wet AMD
Flip
Factors that can increase the risk of AMD include age, race, family history of AMD, smoking, obesity, and cardiovascular disease.

Do you treat to visual acuity or to findings on optical coherence tomography?

Dr Sadda: We are fortunate to have multiple agents that work, and there is no question that there are patients who after one injection are completely dry. For other patients, you may have to inject several times to get them dry.

I switch agents after even only 2 injections if I don’t think I’m getting a dramatic reduction, especially if I’ve started with bevacizumab. Patients who are dry earlier tend to do better. An argument can be made that, with switching, you might see what appears to be a beneficial effect that is, in fact, based on regression to the mean — an artifact of sorts and not a true change in therapeutic effect. My counterargument to this concern is: What is the harm in switching? Therefore, I prefer to switch to see if improvement can be obtained for an individual patient, because I believe in early drying.

Dr Mehta: I use a PRN treatment style, so knowing exactly how patients respond is highly variable, and every patient is different. I have had patients for whom a single injection dried them beautifully, and their next injection was 7 months later. One of my patients went 18 months before a second injection.

When I first inject someone, I bring them back 4 weeks later and ask if they noticed an improvement in vision after 1 or 2 weeks. The effect of the injection might have worn off after 4 weeks, so that’s a way to determine if they respond. You need to have enough drug in the eye to maintain a steady state, which is why the pivotal trials started with 3 loading-dose injections before they did either treat-and-extend (TAE) or moved to 8 or 12 weeks, depending on the trial.
For me, I usually wait until the third injection before making up my mind. But if there’s no response at all after the first injection, I might administer only 1 more injection before switching.

Dr Sadda, do you also treat PRN, or do you do monthly, TAE, or a combination?

Dr Sadda: I don’t do monthly, but I do a combination of PRN and TAE. The danger of PRN (even though that’s what I primarily use) is, obviously, if a patient doesn’t come for follow-up, then they might have problems, including vision loss. I do PRN with monthly monitoring, because I don’t want to run the risk of someone having uncontrolled activity. That works for patients who are pretty close to the office.

I’ll also use TAE in patients whom I call “big oscillators,” meaning that they’re dry, so I don’t treat, but the following month they have a large recurrence. Emerging data from CATT,2-4 the IVAN (Randomised Controlled Trial of Alternative Treatments to Inhibit VEGF in Patients with Age-Related Choroidal Neovascularisation; ISRCTN.com Identifier: ISRCTN92166560) trial,9 and now from the HAWK (Efficacy and Safety of RTH258 Versus Aflibercept – Study 1; ClinicalTrials.gov Identifier: NCT02307682) and HARRIER (Efficacy and Safety of RTH258 Versus Aflibercept – Study 2; ClinicalTrials.gov Identifier: NCT02434328) trials10 suggest that significant fluid fluctuations are associated with worse visual outcomes. A study yet to be published is also going to show that there can be increased subretinal hyper-reflective material that accumulates in people who have big oscillations. For patients with large fluctuations, I’ll switch to TAE, even if we initially opted for a PRN regimen. TAE does make it harder to find people who really need very little treatment because every time you see them, you’re treating them.

Dr Mehta: Dr Sadda makes a good point about subretinal hyper-reflective material accumulating. When you start seeing changes on optical coherence tomography, you know there’s activity there. At that point, you might give an injection to a dry eye just to keep disease under control.

Do you inject bilaterally at the same visit, presuming bilateral AMD?

Dr Sadda: I prefer not to treat both eyes on the same day. We bring the patient back, but there are patient factors that might make that challenging, including when people’s caregivers have to take time off from work.

I treat patients bilaterally on the same day if they travel a long distance or have transportation difficulties. The small risk of treating on the same day is outweighed by the benefit in that circumstance. In those cases, we use 2 different rooms and 2 lots of medications — 2 visits on the same day, essentially.

Dr Mehta: You actually have them get up and go to a different room?

Dr Sadda: Coronavirus disease 2019 (COVID-19) presented a different challenge because we perform an even deeper cleaning between patients and between rooms. Fortunately, I don’t treat bilaterally very often, but, yes, we actually move the patient to a different room and start to prep and set up again to do the other eye. We try to eliminate potential overlap features that could lead to bilateral infection.

Dr Mehta: A recent review11 found no cases of endophthalmitis in more than 100,000 bilateral, same-day anti-vascular endothelial growth factor (VEGF) therapy injections. Most of my patients also prefer to not have same-day bilateral injections because they say it’s almost intolerable for them to deal with the eye pain afterward, or their eyes are dry. In Southern California, dry eye is a big deal. I probably treat as much dry eye as I do retinal disease these days because povidone–iodine causes irritation of the eye. It doesn’t matter how much you rinse it out.

When I do perform same-day bilateral injections, I also use different lot numbers, different setups, different specula, different needles, etc. I instill subconjunctival lidocaine for most of my injections.

As you both touched on, endophthalmitis is a significant safety concern. Have you encountered safety issues with the current intravitreal anti-VEGF agents? When do you initiate a conversation about potential safety concerns with the patient?

Dr Mehta: I talk about the risk of infection from injections that they might not even need on their first visit, even if they only have dry AMD. The infection risk might be low, but when infection develops, it’s bad. So we want to make sure they understand the gravity of that, and I tell them about that at every injection that they get, whether it’s their first or their 100th injection.

I don’t initiate the risk profile discussion until I am at the point at which I am ready to recommend a particular treatment. And we mention not only the relatively uncommon risk of endophthalmitis but also the risk of retinal tear and detachment, vitreous hemorrhage, and sterile noninfectious endophthalmitis.
-SriniVas Sadda, MD

Dr Sadda: With brolucizumab-dbll (Beovu, Novartis Pharmaceuticals Corporation), there are reports of severe types of inflammation with occlusive vasculitis. Although these complications are uncommon, their severity makes them an important consideration when selecting patients.10,12 The risk:benefit ratio has to make sense.
 
We have a different discussion with patients for whom we are considering using brolucizumab-dbll, to reinforce that, although the risk of inflammation is less than 1%, patients need to be hypervigilant, beyond the first few days after injection, for such symptoms as redness, blurred vision, and eye pain.

You both touched on getting the patient dry as soon as possible. Is there ever a point at which the presence of fluid is acceptable, as long as you’re still monitoring it?

Dr Sadda: I try to treat to dry, but the key words are “as dry as possible.” Early on, some of us treated more frequently than monthly. We were alternating between bevacizumab and, 2 weeks later, aflibercept, thinking that we could get control and then maybe be able to back off later on. That didn’t work out well for me. I could get the patient dry but could never back off; treatment at that frequency became impractical because almost no one could tolerate it.

In our experience, brolucizumab-dbll is more potent than aflibercept at achieving full resolution of fluid; the studies also support that.10 I’ve had patients with polypoidal choroidal vasculopathy (PCV) who didn’t want photodynamic therapy (PDT) and who were difficult to control, but brolucizumab-dbll seems to be beneficial in that setting, so far, in my experience.
 
If I’ve done everything I can, and maybe the patient either isn’t a candidate for brolucizumab-dbll or brolucizumab-dbll couldn’t get them dry, I begin to wonder whether an alternative diagnosis is a possibility and maybe we’re dealing with a pachychoroid spectrum disorder, such as central serous chorioretinopathy. Then, I do the so-called 2-week test: I inject them and bring them back in 2 weeks. If there’s no change, it’s unlikely the patient has VEGF-mediated disease, and I need to think about alternate diagnoses.
 
But if the patient does respond, and it’s just that the effect doesn’t last and I’ve ruled out PCV and other confounders, then I tolerate some fluid. The data seem to support that and suggest that good vision can be achieved despite persistent fluid,13-15 although, in most of those studies, the fluid was still being treated. I keep those patients under treatment so the exudation doesn’t get out of hand, but I don’t lose sleep that I couldn’t get them dry despite doing my best.
 
Dr Mehta: We have to differentiate between subretinal fluid and intraretinal fluid. Subretinal fluid is better tolerated by patients for longer periods of time; the VIEW 1 (Vascular Endothelial Growth Factor Trap-Eye: Investigation of Efficacy and Safety in Wet Age-Related Macular Degeneration; ClinicalTrials.gov Identifier: NCT00509795) and VIEW 2  (Vascular Endothelial Growth Factor Trap-Eye: Investigation of Efficacy and Safety in Wet Age-Related Macular Degeneration; ClinicalTrials.gov Identifier: NCT00637377) studies showed that for aflibercept.13,16-18 In reality, we have to do what is practical for the patient, and dosing every 4 weeks is not practical for most people.

When patients have persistent intraretinal fluid, I break with convention and add a steroid. With a steroid on board, I’m more likely to feel comfortable putting in a brolucizumab-dbll injection because I’m already treating a theoretical inflammatory response. I haven’t seen a negative reaction to brolucizumab-dbll, but I have with aflibercept.
-Mitul Mehta, MD

Dr Mehta: If the patient has persistent fluid but they’re not losing vision, we’re not losing ground, and the practicality of increasing treatment frequency needs to be considered.

Based on your experience, is there still a role for laser and PDT in AMD?

Dr Mehta: There is still a role for PDT in some cases; PCV is a variant of AMD that responds well to PDT. Sometimes, increasing the dose of the medication works, too, and  I’ve injected 0.1 mL of ranibizumab or aflibercept. If the source of leakage is not actually in the macula, a thermal laser can be an option.
 
Dr Sadda:It is difficult to find patients who are amenable to laser. My practice is heavy in AMD, and I haven’t used a thermal laser in a couple of years. Most lesions are either subfoveal or close to the fovea. If a lesion is quite a distance away from the fovea, laser can be a great solution, because you have at least a 50% chance that the patient isn’t going to get another problem — at least not in the next 5 years.19

What are your thoughts on some of the newer compounds designed to reduce treatment burden by having a longer duration of action?

Dr Sadda: These are exciting developments. First, the Port Delivery System with ranibizumab (PDS, Genentech) is definitely exciting, but because the implant involves a surgical procedure, there is some risk.

Second, the bispecific treatment era and the potential value of faricimab (Genentech) will be interesting to watch.

My hope for brolucizumab-dbll is that we’ll get further information on predicting who might have severe inflammation. Frankly, that’s the agent I’d likely be using in the first line if it had the same adverse effect profile as some of the other agents.

Other potential exciting developments include gene therapy, although I would like to be able to “turn it off.” There is some concern, if you continue to suppress VEGF in the absence of needing to suppress it, whether you can promote further atrophy and other unintended off-target effects.

Dr Mehta: If we can determine what causes these adverse effects and who is more likely to be at risk, a lot of specialists would be more comfortable using brolucizumab-dbll or abicipar pegol.

An implantable system like PDS is attractive to a lot of patients, especially those who travel far for injections. But we’ll need to ensure that there is local support in case there are problems with PDS. That will be a concern with any of these longer duration-of-action treatments. What we found when the COVID-19 pandemic was in an earlier phase was that some patients were afraid to come to the office; missing appointments and injections meant that they lost vision.

The trillion-dollar question remains: Can science figure out what causes these issues and prevent the problem from occurring altogether? That’s what we’re hoping gene therapy might do.

This program was edited for clarity and length.

Disclosures

SriniVas Sadda, MD, reported affiliations with Amgen, Inc., Allergan Plc., Novartis International AG, Roche Holding AG, Bayer AG, Regeneron Pharmaceuticals, Inc., Apellis Pharmaceuticals, Inc., 4d Molecular Therapeutics, LLC., Merck & Co., Inc., and Oxurion, Inc. Mitul Mehta, MD, reported affiliations with Allergan Plc., Novartis International AG, DORC Holding B.V., and Carl Zeiss AG.

References

1. CATT Research Group, Martin DF, Maguire MG, Ying G-S, et al. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med. 2011;364(20):1897-1908. doi:10.1056/NEJMoa1102673

2. Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group; Martin DF, Maguire MG, Fine SL, et al. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results. Ophthalmology. 2012;119(7):1388-1398. doi:10.1016/j.ophtha.2012.03.053

3. Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group; Maguire MG, Martin DF, Ying G-S, et al. Five-year outcomes with anti-vascular endothelial growth factor treatment of neovascular age-related macular degeneration: the comparison of AMD treatments trials. Ophthalmology. 2016;123(8):1751-1761. doi:10.1016/j.ophtha.2016.03.045

4. Ying G-S, Maguire MG, Pan W, et al; CATT Research Group. Baseline predictors for five-year visual acuity outcomes in the comparison of AMD treatment trials. Ophthalmol Retina. 2018;2(6):525-530. doi:10.1016/j.oret.2017.10.003

5. Kiss S, Dugel PU, Khanani AM, et al. Endophthalmitis rates among patients receiving intravitreal anti-VEGF injections: a USA claims analysisClin Ophthalmol. 2018;12:1625-1635. doi:10.2147/OPTH.S169143

6. VanderBeek BL, Bonaffini SG, Ma L. Association of compounded bevacizumab with postinjection endophthalmitis. JAMA Ophthalmol. 2015;133(10):1159-1164. doi:10.1001/jamaophthalmol.2015.2556

7. Goldberg RA, Flynn HW Jr, Miller D, Gonzalez S, Isom RF. Streptococcus endophthalmitis outbreak after intravitreal injection of bevacizumab: one-year outcomes and investigative results. Ophthalmology. 2013;120(7):1448-1453. doi:10.1016/j.ophtha.2012.12.009

8. Goldberg RA, Flynn HW Jr, Isom RF, Miller D, Gonzalez S. An outbreak of Streptococcus endophthalmitis after intravitreal injection of bevacizumab. Am J Ophthalmol. 2012;153(2):204-208.e1. doi:10.1016/j.ajo.2011.11.035

9. IVAN Study Investigators; Chakravarthy U, Harding SP, Rogers CA, et al. Ranibizumab versus bevacizumab to treat neovascular age-related macular degeneration: one-year findings from the IVAN randomized trial. Ophthalmology. 2012;119(7):1399-1411. doi:10.1016/j.ophtha.2012.04.015

10. Dugel PU, Koh A, Ogura Y, et al; HAWK and HARRIER Study Investigators. HAWK and HARRIER: Phase 3, multicenter, randomized, double-masked trials of brolucizumab for neovascular age-related macular degeneration. Ophthalmology. 2020;127(1):72-84. doi:10.1016/j.ophtha.2019.04.017

11. Borkar DS, Obeid A, Su DC, et al; Wills Post Injection Endophthalmitis (PIE) Study Group. Endophthalmitis rates after bilateral same-day intravitreal anti-vascular endothelial growth factor injections. Am J Ophthalmol. 2018;194:1-6. doi:10.1016/j.ajo.2018.06.022

12. American Society of Retina Specialists. Clinical update: Beovu update for ASRS members. February 23, 2020.

13. Cho H, Shah CP, Weber M, Heier JS. Aflibercept for exudative AMD with persistent fluid on ranibizumab and/or bevacizumab. Br J Ophthalmol. 2013;97(8):1032-1035. doi:10.1136/bjophthalmol-2013-303344

14. Kaya C, Zandi S, Pfister IB, Gerhardt C, Garweg JG. Adding a corticosteroid or switching to another anti-VEGF in insufficiently responsive wet age-related macular degenerationClin Ophthalmol. 2019;13:2403-2409. doi:10.2147/OPTH.S224456

15. Unsal E, Cubuk MO. The outcomes of aflibercept therapy in patients with age-related macular degeneration resistant to bevacizumab or ranibizumab. J Curr Ophthalmol. 2018;30(4):337-342. doi:10.1016/j.joco.2018.07.002

16. Moshfeghi DM, Hariprasad SM, Marx JL, et al. Effect of fluid status at week 12 on visual and anatomic outcomes at week 52 in the VIEW 1 and 2 trials. Ophthalmic Surg Lasers Imaging Retina. 2016;47(3):238-244. doi:10.3928/23258160-20160229-06

17. Heier JS, Brown DM, Chong V, et al. Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology. 2012;119(12):2537-2548. doi:10.1016/j.ophtha.2012.09.006

18. Schmidt-Erfurth U, Kaiser PK, Korobelnik JF, et al. Intravitreal aflibercept injection for neovascular age-related macular degeneration: ninety-six-week results of the VIEW studies. Ophthalmology. 2014;121(1):193-201. doi:10.1016/j.ophtha.2013.08.011

19. Laser photocoagulation of subfoveal neovascular lesions in age-related macular degeneration. Results of a randomized clinical trial. Macular Photocoagulation Study Group. Arch Ophthalmol. 1991;109(9):1220-1231. doi:10.1001/archopht.1991.01080090044025.

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Reviewed November 2020