Anti-VEGF Treatment Strategies for Wet AMD

Michael A. Singer, MD, is clinical professor of ophthalmology at the University of Texas Health Science Center at San Antonio. He is also the director of clinical research at Medical Center Ophthalmology Associates, also in San Antonio. Dr Singer has participated in more than 150 clinical trials and has published extensively on the treatment of retinal diseases and conditions.

How do you determine who begins treatment for wet AMD?

That process begins when patients come in because of a change in their vision; either their actual visual acuity is changing or their perception of their vision is changing. Their pupils are dilated for examination and if macular degeneration is suspected, the diagnosis is confirmed by performing an angiogram and ocular coherence tomography (OCT). Then we discuss the potential treatments available.

The therapies I offer are dictated by the patient’s insurance. If insurance is not an issue, I will initiate branded therapy with ranibizumab or aflibercept. If insurance is an issue, I will start with bevacizumab, which was not developed specifically for AMD.

How is treatment delivered?

I always start patients off with one intravitreal injection per month for the first 3 months and monitor their response to treatment with OCT. Depending on how they respond, I will decide whether to switch to a branded agent. If treatment with ranibizumab or aflibercept is working, then I change the paradigm. I am no longer trying to get to a stronger agent; I am trying to get to a longer-acting agent.

If the patient is stable and has good results after 3 injections, the treatment interval will be extended by 2 weeks. I will continue the 2-week extension unless there is reduced stability as evidenced by a decrease in vision, an increase in fluid, or the presence of blood. If there is a small decrease in visual acuity or an increase in fluid, the patient’s schedule will be set back 2 weeks. If blood is present, the patient’s schedule will be set back to 4-week intervals between treatments, and the injection regimen will be restarted.

Are ranibizumab and aflibercept your preferred treatments?

Yes. Both ranibizumab and aflibercept are stronger therapeutic options that do a better job of controlling fluid. The alternative agent, bevacizumab, is preferred by insurance companies because it is less expensive. Bevacizumab works well for treating certain lesions but less well for other types. The goal of treatment is to get patients as dry as possible as quickly as possible.

For what percentage of patients are you able to extend treatment beyond 4 weeks, and what are the treatment goals at this point?

It is probably around 70% to 75% of patients. The goal of therapy would be to increase the extension period for up to 3 months at 2-week intervals in the hope that I can increase patient adherence to treatment while maintaining the benefits of the injections. That is the basis for what we call “treat-and-extend therapy.”

How do you prepare patients for treatment? Undergoing eye injections must be challenging for patients.

I used to always treat patients on the same day that I diagnosed their wet AMD. These days, I work at a lot of satellite clinics and may not always have the medication on hand. Beyond the need for insurance authorization and treatment supply issues, this actually gives patients a little time to “get their heads around” what their treatment will entail. They have to come to terms with the idea of getting shots in their eyes, as well as the reality that their condition may not improve, and the primary goal is to prevent the situation from getting worse. That is a lot to understand, so it is good for patients to have that bit of extra time to digest all of this information.

Do you use any medications to decrease patients’ anxiety during the procedure?

We rarely do that. We are very good at numbing the patient. Often, the worst part of the process is putting in the eyelid speculum, and there are physicians across the country who do not even use this. We use local anesthetics, such as tetracaine or topical lidocaine, or we give patients a subconjunctival lidocaine injection to get them set up for the injection. Usually, after the first injection, patients are significantly relieved that it was not as bad as they had anticipated.

What is the usual level of treatment adherence?

For the first 3 injections, I typically get high adherence. As time goes on, however, adherence often decreases. Essentially, we get high adherence early on because patients experience an immediate improvement and notice a “return on their investment” when the drug is making a difference. As the improvement in vision quality and symptoms starts to wane, patients often get injection fatigue and start to push back — either passively or actively — by not making their appointments and/or stretching out the amount of time between appointments.

When patients push back their appointments, does macular damage increase and become permanent? Is it irreversible?

Absolutely. We have learned that when patients have both fewer in-office examinations and treatment sessions, their vision quality decreases. In the HORIZON (ClinicalTrials.gov Identifier: NCT04566445) and CATT trials (ClinicalTrials.gov Identifier: NCT00593450), results found that after 5 years, not only did some patients lose the vision they had gained through treatment, but their vision quality also fell below their baseline level.^1,2

There are a certain number of injections — which I call the “pivot point” — needed per year to achieve and maintain improvement. It seems to be a minimum of 7 injections needed in the first year. In 2019, the Intelligent Research in Sight Registry reported benefits from a minimum of 4 to 10 shots.³ Patients who had more shots ended up with better vision than those who had fewer shots. Then in years 2 through 5, having at least 5 shots per year seems to be the minimum requirement to maintain the improvement.⁴  

What are the unmet needs in wet AMD?

It is not just a patient issue, it is also a physician issue. If you look at data from the last couple of years of the Patterns and Trends survey of the American Society of Retina Specialists (ASRS),⁵ there is an unmet need in that physicians want treatment options for wet AMD that are stronger, act longer, and require less frequent administration. We want to maintain the great visual acuity that patients get from the loading dose, whether this is achieved through use of a different medicine, a different drug class, or a different mode of delivery.

What new therapies are in development to meet these needs in wet AMD?

If we look at the relevant drug pipeline, a variety of medicines are already in development. One very recent approval for administration using a port delivery system is Susvimo (Genentech, Inc.). This is a new ranibizumab injection therapy for adults with wet AMD who have responded to at least 2 intravitreal injections of a VEGF inhibitor. The drug is administered through a pump that is surgically implanted in the eye.⁶ It works on an infusion gradient to deliver drugs gradually over time, similar to an insulin pump. We fill the pumps up at the time of surgery and every 6 months thereafter; we refill them in the office.

I participated in early studies of this device in patients with macular degeneration and it has worked very well. In the Archway phase 3 study (ClinicalTrials.gov Identifier: NCT03677934), 98% of patients did not need rescue treatment within the first 6 months.^6,7 Use of the refillable pump was equivalent to receiving monthly injections with the benefit spread over 6 months. The downside is the increased risks associated with the initial procedure; however, for certain patients, this new option will be revolutionary.

In terms of newer potential approaches for wet AMD that would not require surgery, the bispecific antibody faricimab has been evaluated in phase 3 trials and is being considered for approval by the US Food and Drug Administration.⁸ Faricimab is both an anti-VEGF and anti-angiopoietin agent in a single molecule; one arm is anti-VEGF, and the other arm is anti-angiotensin II. The thought is that by combining them, we can achieve better improvement in vision over a longer period of time.

One study of faricimab looked at how long patients could go without reinjection. The investigators found that 50% of patients required rescue therapy after 16 weeks and an additional 20% of patients required rescue therapy after 12 weeks, indicating that 70% of patients may only need 4 shots per year to maintain visual acuity after the loading dose.⁹
 
There are 2 other molecules on the horizon now being evaluated in phase 3 trials that have different mechanisms of action. One is a big molecule connected to an anti-VEGF antibody (KSI-301; ClinicalTrials.gov Identifier: NCT04049266) that is built on an antibody biopolymer conjugate platform. Phase 3 trials of KSI-301 have shown that 66% of patients with wet AMD could go 6 months or longer between injections.¹⁰
 
Another molecule is an anti-VEGF agent with a sidekick that is able to block other forms of VEGF that ranibizumab and aflibercept cannot inhibit. Head-to-head trials are now comparing this first-in-class VEGF-C/D “trap” inhibitor, OPT-302, in combination with either ranibizumab or aflibercept vs ranibizumab or aflibercept alone.¹¹

The last potential treatment category in wet AMD is gene therapy. Two novel agents, RGX-14 and ADVM-022, both reported positive phase 1/2 data showing the ability of gene therapy to decrease the treatment burden in the vast majority of patients.¹² A phase 1/2 dose-escalation study with RGX-14 (ClinicalTrials.gov Identifier: NCT03066258), administered by subretinal injection in the operating room, showed that 73% of patients receiving the highest dose of RGX-14 did not require anti-VEGF injections for 6 months.¹² In the OPTIC trial (ClinicalTrials.gov Identifier: NCT03748784), more than  80% of patients treated with ADVM-022 did not require supplemental anti-VEGF injections.¹³
 
Overall, in the 15 years since anti-VEGF therapy was developed, this treatment and its outcomes in patients with wet AMD have stayed the same until very recently. I truly believe that the newer agents on the horizon for wet AMD are going to bring about revolutionary changes, such that we will be able to get good visual improvement with a meaningfully lower treatment burden.

How much of their vision can patients recapture with these therapies?

Approximately 90% of patients are able to maintain stable vision with these therapies, and approximately one-quarter to one-third of patients may actually get better vision. We cannot identify who those patients are yet, and that is still an unmet need.

Disclosure

Michael A. Singer, MD, reported affiliations with Aerie Pharmaceuticals Inc.; Allegro Ophthalmics, LLC; Allergan plc; Genentech, Inc.; Kodiak Sciences Inc.; Novartis International AG; Regeneron Pharmaceuticals, Inc.; Santen Pharmaceutical Co. Ltd.; EyePoint Pharmaceuticals, Inc.; Mallinckrodt Pharmaceuticals; Spark Therapeutics, Inc.; ICON plc; Ionis Pharmaceuticals; KalVista Pharmaceuticals, Inc.; Opthea Ltd.; Optos plc; Senju Pharmaceutical Co. Ltd.; and Sydnexis Inc.

References

1. Singer MA, Awh CC, Sadda S, et al. HORIZON: an an open-label extension trial of ranibizumab for choroidal neovascularization secondary to age-related macular degeneration. Ophthalmology. 2012;119(6):1175-1183. doi:10.1016/j.ophtha.2011.12.016
 
2. Maguire MG, Martin DF, Ying GS, et al; Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group. Five-year outcomes with anti-vascular endothelial growth factor treatment of neovascular age-related macular degeneration: The comparison of age-related macular degeneration treatments trials. Ophthalmology. 2016;123(8):1751-1761. doi:10.1016/j.ophtha.2016.03.045
 
3. Ciulla TA, Hussain RM, Pollack JS, Williams DF. Visual acuity outcomes and anti–vascular endothelial growth factor therapy intensity in neovascular age-related macular degeneration patients. A real-world analysis of 49 485 eyes. Ophthalmol Retina. 2020;127(2):142-147. doi:10.1016/j.oret.2019.05.017
 
4.  Khanani AM, Gahn GM, Koci MM, Dang JM, Brown SM, Hill LF. Five-year outcomes of intravitreal drug therapy for neovascular age-related macular degeneration in eyes with baseline vision 20/60 or better. Clin Ophthalmol. 2019;13:347-351. doi:10.2147/OPTH.S191170
 
5. American Society of Retina Specialists. Preferences and Trends (PAT) Survey. 2021. Accessed December 6, 2021. https://www.asrs.org/asrs-community/pat-survey
 
6.  FDA approves Genentech’s Susvimo, a first-of-its-kind therapeutic approach for wet age-related macular degeneration (AMD). News release. Genentech. October 22, 2021. https://www.gene.com/media/press-releases/14935/2021-10-22/fda-approves-genentechs-susvimo-a-first-
 
7. Holekamp NM, Campochiaro PA, Chang MA, et al. Archway randomized phase 3 trial of the port delivery system with ranibizumab for neovascular age-related macular degeneration. Ophthalmology. Published online September 28, 2021. doi:10.1016/j.ophtha.2021.09.016
 
8. Roche/Genentech initiate two large phase 3 studies in wet AMD for bispecific molecule, faricimab. Eyewire. March 7, 2019. Accessed December 8, 2021. https://eyewire.news/news/roche-genentech-initiate-two-large-phase-3-studies-in-wet-amd-for-bispecific-molecule-faricimab
 
9. Charters L. Faricimab satisfies primary study endpoint in TENAYA and LUCERNE trials. Modern Retina. Published online May 3, 2021. Accessed December 6, 2021. https://www.modernretina.com/view/faricimab-primary-study-endpoint-tenaya-lucerne-trials
 
10. Kodiak Sciences announces 1-year durability, efficacy and safety data from ongoing phase 1b study of KSI-301 in patients with wet age-related macular degeneration, diabetic macular edema and retinal vein occlusion at the Angiogenesis, Exudation and Degeneration 2021 annual meeting. News release. Kodiak Sciences Inc.  Published online February 13, 2021. Accessed December 6, 2021. http://ir.kodiak.com/news-releases/news-release-details/kodiak-sciences-announces-1-year-durability-efficacy-and-safety
 
11. Opthea treats first patient in phase 3 pivotal trials of OPT-302 in wet AMD. News release. BioSpace. Published on March 15, 2021. Accessed November 29, 2021. https://www.biospace.com/article/releases/opthea-treats-first-patient-in-phase-3-pivotal-trials-of-opt-302-in-wet-amd/
 
12. Cabral de Guimaraes TA, Georgiou M, Bainbridge JWB, Michaelides M. Gene therapy for neovascular age-related macular degeneration: rationale, clinical trials and future directions. Br J Ophthalmol. 2021;105(2):151-157. doi:10.1136/bjophthalmol-2020-316195
 
13. Charters L. Single injection maintenance. Ophthalmology Times. Published online June 1, 2021. Accessed December 6, 2021. https://www.ophthalmologytimes.com/view/single-injection-maintenance