Experts weigh current, future options for AMD management
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The past 2 years have brought a decisive leap forward in the management of age-related macular degeneration.
Pharmacotherapies with increased efficacy and extended durability are allowing for more relaxed treatment schedules, and for the first time, treatment options for the atrophic stages of the disease have become available. At the same time, advances in AI and home monitoring are paving the way to more precise diagnosing and monitoring for truly personalized care, lessening the burden for both patients and health care providers.
Source: Armando Monroig, Bascom Palmer Eye Institute
“We have had more innovation in the past 2 years than in the past 15 years in the retina space,” Jaclyn L. Kovach, MD, said. “This is an important time to focus on individualized care and also a time to manage patients’ expectations.”
Retina specialists now have several new validated products to choose from and an exciting universe of future options to hope for, according to Baruch D. Kuppermann, MD, PhD. However, this sudden spur of innovation is disrupting consolidated protocols and routine practices, while new directions are not yet clear.
“It’s a challenging time now, in our wealth of choices, and there’s not yet a coherent strategy,” he said.
A first decision
When a patient presents with neovascular AMD, Kovach makes a first decision between Eylea (aflibercept 2 mg, Regeneron) and Vabysmo (faricimab, Genentech).
“Sometimes patients will request a certain drug — for instance, patients who have seen the Vabysmo commercial and want to try it,” she said.
Eylea HD (aflibercept 8 mg, Regeneron) was approved in August 2023. Kovach’s experience with it is limited, but she has been using it as a second-line drug for patients who are not able to achieve fluid-free status or a long treatment interval with Eylea 2 mg or Vabysmo.
“I am really impressed with the efficacy and the durability of that drug, so it may soon become my first-line agent,” she said.
“I have been using Eylea for a long time, and I have been gradually converting to more Vabysmo. The dual mechanism of VEGF-A and Ang-2 inhibition is really interesting science. But now I am beginning to add Eylea HD to the mix, given our long-standing satisfaction with Eylea regular dose. We’re very lucky to have so many great choices,” Kuppermann said.
Some insurance companies may request step therapy starting with Avastin (bevacizumab, Genentech) first, followed by a ranibizumab biosimilar, Healio | OSN Retina/Vitreous Board Member Peter K. Kaiser, MD, said.
“We follow the rules, but even in those situations, we quickly attempt to switch to one of the other medications, which have better drying results and allow us to have a more durable treatment response,” he said. “Things might change when aflibercept biosimilars are approved, but we don’t like to lose vision, and a problem with insurance companies requiring step therapy is that any loss of vision that occurs can often not be regained.”
A switch for better outcomes, longer intervals
Currently, the switch Kaiser makes is to either aflibercept 2 mg or faricimab, as his experience with aflibercept 8 mg is limited. In his mind, there are two use scenarios for aflibercept 8 mg. The first is patients who are doing well on aflibercept 2 mg and are on 12-week or even 16-week intervals.
“I switch them to Eylea HD to see if we can go even longer because in the trial the interval was extended up to 24 weeks. If I am successful, I get the same efficacy but only have to give injections twice a year, which is a huge benefit for my patients,” Kaiser said.
The second scenario is at the opposite end of the spectrum: patients who are not doing well on aflibercept 2 mg and require injections at 4- to 6-week intervals with either persistent fluid or loss of vision.
“In the recent past, I would switch those patients to faricimab, and quite a few of them did well, but just as many did not. Now, I switch them to aflibercept 8 mg. It is early, but I have seen a few of those back now, and I have been very impressed with the drying capability of aflibercept 8 mg. In many patients who I was not able to extend the interval beyond 6 weeks with either aflibercept 2 mg or faricimab, I am seeing them come back dry and can extend the interval,” he said.
Kuppermann has also been switching from Eylea 2 mg to Vabysmo in patients who still had some leakage. He estimated that about 40% or more did better after the switch and could have their interval extended by a week or more, approximately 30% to 40% did neither better nor worse and were kept on Vabysmo, and 20% did worse and were switched back to Eylea.
In this scenario, Vabysmo was gaining the largest share of his patients, but the approval of Eylea HD is offering a further opportunity.
“Those that I couldn’t extend out any further with Vabysmo, who were on Eylea 2 mg every 8 weeks and remained at 8 weeks after the switch to Vabysmo, I now view as candidates to be converted to Eylea HD to attempt to extend their treatment intervals further,” Kuppermann said.
One problem with Eylea HD is that the label does not allow an interval shorter than 7 weeks after the loading phase. Therefore, insurances might theoretically refuse to reimburse the drug if reinjection is required sooner.
“Other drugs, including Vabysmo, can be reinjected after 4 weeks,” he said.
“If a patient is not responding well to Eylea 2 mg, I’ll switch to Vabysmo, and if the patient is on Vabysmo, I’ll switch to Eylea HD. If they are on Avastin, we’ll go to Eylea 2 mg or Vabysmo,” Kovach said. “Patients may respond better to one drug than another, and sometimes it’s hard to determine why.”
However, poor responders are less often seen with Vabysmo or Eylea HD, she said.
Making decisions for GA treatment
Now that pharmacotherapies for geographic atrophy (GA) are available, the volume of patients requiring treatment is going to increase significantly. Wet AMD and GA may also be present at the same time, requiring further decision-making on how to combine anti-VEGF and complement inhibitor injections.
“We have a lot of decisions to make with our patients. Which drug do we use? Which patients do we treat? How often do we treat patients? And how do we best educate our patients on the risks and benefits of GA treatment? Should we start therapy? Should we wait? And we’re trying to figure out how to incorporate these drugs into our practices in terms of clinical logistics, especially when patients also have wet AMD,” Kovach said.
While Kovach does not inject both drugs on the same day, this would be desirable to avoid the burden of multiple visits.
“I don’t know how we are going to handle this because historically we have only been paid for one injection per eye per day,” Kuppermann said. “We have typically followed our GA patients every 6 months, but with the new complement inhibition treatments, they now come in every 2 months for an injection and might need two injections, on the same day or at different times, with different schedules depending on whether they also have neovascular AMD.”
The complement inhibition portfolio is also complicated because of the risk-benefit analysis.
“More risk than we anticipated and less benefit than desired, but still, in my mind, enough to justify injection,” he said.
Shifting the paradigm of treatment schedules
With all these drugs, the treatment schedules adopted in real-life clinical practice differ from those of clinical trials, and clinicians are currently exploring options.
“The clinical studies are designed to get the drugs approved, and a very well-defined re-treatment interval or disease activity assessment is required in the studies to make sure that everybody is treated the same way. In clinical practice, most of us use treat and extend, which allows us to tailor the treatment to each individual patient. In the studies it is just not possible to do such individualization of the treatment regimen,” Kaiser said.
Treat and extend is the most widely adopted regimen in the U.S. It allows treating physicians to rapidly see the difference between drugs and to organize schedules with increasingly longer intervals. The drawback is that patients are typically treated when the retina is dry, and doubt remains whether they really need that number of injections absent any sign of recurring exudation, Kuppermann said.
The next pivotal change will be home OCT monitoring, which will allow a treat-and-extend/as-needed regimen, he said.
“We can schedule the next injection, let’s say at 3 months, but if the Home OCT shows they have to be brought back sooner, we’ll have them back sooner,” he said.
“I think the use of home monitoring is right around the corner. We already use home monitoring to detect when dry AMD turns to wet with the Notal Foresee device. But newer devices that are hopefully going to be approved shortly use OCT, which is much more precise than preferential hyperacuity perimetry. I am very excited to see some of those receive agency approval,” Kaiser said.
Home OCT for true personalized care
Home OCT could be transformative and bring retina physicians one step closer to truly personalized care, especially in the setting of longer durability agents, Christina Y. Weng, MD, MBA, said.
“Imagine a time when you can tailor treatment so that patients only receive an injection when fluid recurs. That’s the appeal of Home OCT,” she said.
DRCR Retina Network Protocol AK was a prospective observational study in which 14 treatment-naive patients with wet AMD were instructed to use the AI-assisted Notal Vision Home OCT device to scan both eyes daily over a 6-month period.
“Patients scanned on average 6.3 times per week, and the scans took approximately 47 seconds per eye. Nearly 87% of the 2,304 scans were eligible for fluid quantification, and the agreement between in-office and Home OCT was 89% for presence of fluid and 71% for absence of fluid with all discrepancies involving very small fluid volumes,” Weng said.
These learnings were critical for setting up Protocol AO, the largest randomized controlled trial to date evaluating the role of Home OCT in managing treatment-naive wet AMD patients.
“I am honored to serve as the protocol chair of this trial because I think its results could transform the way we manage wet AMD,” Weng said.
The study is underway and aims to randomly assign 600 eyes 1:1 to either treat and extend or Home OCT-guided treatment. All eyes will receive faricimab, and the co-primary outcomes are going to be the mean change in visual acuity and the number of injections from baseline to week 104.
“While I don’t have any results to share at this point, we imagine that some patients in the Home OCT arm will be able to go very long stretches of time without any injections while others might never get dry in between their injections. We have never been able to properly evaluate intervisit fluid dynamics, and now we can thanks to this technology,” Weng said.
Home monitoring is new in ophthalmology but has already fueled a leap in health care with continuous glucose monitors (CGM) for diabetes.
“So many of my diabetic patients are finally gaining control of their glucose levels as a result of these devices, and I see a lot of parallels between Home OCT and CGMs in their ability to individualize treatment,” Weng said.
New organizational challenges
Home OCT can reduce the burden of multiple visits but will require a new and more flexible reorganization of clinic schedules.
“Right now, we have a very organized life with treat and extend. We are injecting nearly every established patient with neovascular AMD at every visit at well-established intervals. With Home OCT and as-needed treatment, suddenly, we’ll have an alert saying that fluid has been detected and treatment is needed, and we’ll have to figure out how to fit in this patient, or potentially a number of patients, in the next 3 days or so. We will need to adjust our schedule to accommodate all those people who are going to be calling in, but I am sure we will all figure out how to organize this,” Kuppermann said.
Weng said that Protocol AO will also be a good test of how to incorporate Home OCT in routine practice from a patient and retina specialist standpoint.
“The feasibility aspect and the operational logistics are going to be important learnings from the study,” she said. “Notal Vision provides compliance support services, reaching out to patients if they are not scanning regularly and to retina specialists if they have not responded to a fluid alert within 3 days. These safeguards are critical to the success of home monitoring.”
Whenever a new technology is ready for adoption, there are concerns to dispel, and sharing good experiences and best practices becomes important.
“I have been pleasantly surprised so far at how little of an added burden incorporating Home OCT has been from a retina specialist and practice standpoint,” Weng said. “Whenever I receive a patient alert, I simply review their most recent scans and decide whether the patient needs to present for an in-office examination. AI does a lot of the heavy lifting.”
In-office AI-based tools
In-office AI-based tools are finding their way in clinical practice and will allow the delivery of more personalized care with less burden. They are designed to assist and substantially empower physicians in three critical tasks: screening, monitoring in routine practice and evaluating new therapies in clinical trials, according to Ursula Schmidt-Erfurth, MD, PhD.
“We can do community-based screening with the help of AI so that disease detection and referral are done in a timely manner. We can do monitoring, which is a lifelong tedious burden for retina specialists because we have to see hundreds of thousands of images, and there is little standard in knowing where the changes are,” she said.
The Fluid Monitor, which was developed by RetInSight, a spin-off of the Medical University of Vienna, can identify, localize and quantify fluid on OCT.
“The Fluid Monitor is approved in Europe and has shown to reduce the workflow significantly by making monitoring standardized and fast,” Schmidt-Erfurth said. “In the trials, the clinical sites and sponsors have the evaluation according to protocol in real time, and this substantially shortens the paths to find new effective therapies.”
In GA, the support of AI is even more vital because of the ability to detect subclinical biomarkers of disease activity.
“AI can quantify photoreceptor degeneration directly by ellipsoid zone layer changes that are consistent with disease activity. We can identify patients with progressive disease who will benefit from treatment and predict the therapeutic response, and we can identify early-stage GA, which remained undetected until now,” Schmidt-Erfurth said.
The RetInSight GA Monitor is available in the U.S. for exploratory use, and clinical studies and real-world data have proved its efficacy in assessing disease activity, bringing GA into OCT-based clinical care by a mouse click.
“Artificial intelligence is fast, reliable and ubiquitous. That means that the patient can expect the same quality care at the same speed anywhere,” Schmidt-Erfurth said.
It will also lead to more personalized care based on fast, precise, automated analysis of patients’ condition in wet and dry AMD.
“Colleagues in Europe who are using the Fluid Monitor and the GA Monitor report that their productivity has increased significantly, around 40%,” she said.
In the pipeline
Exciting options are in the pipeline. “They include gene therapy where we use our own cells as a biofactory to produce anti-VEGF proteins for life,” Kaiser said.
ABBV-RGX-314 (Regenxbio, AbbVie) is currently in phase 3 trials in AMD with subretinal delivery of the viral capsid that transfects cells to produce a ranibizumab-like protein, and other companies are also working in this field with different capsids, payloads, protein products and delivery methods.
“The other area of intense excitement is the use of polymer implants impregnated with a tyrosine kinase inhibitor (TKI). TKIs work inside the cell to prevent the downstream activation of all VEGF receptors. Placed in polymers, they can last anywhere from 6 to 12 months, reducing the treatment burden. Phase 3 studies have started,” Kaiser said.
Drugs targeting alternative pathways to the VEGF pathway are in phase 1 and 2 studies.
“Anti-VEGFs reduce the leakage, but it would be nice to have a treatment that makes the choroidal neovascularization disappear,” Kaiser said.
In the area of GA, Stealth BioTherapeutics is working on the development of a mitochondrial membrane stabilizer, elamipretide, that has shown favorable effects on ellipsoid zone integrity, which has been recently accepted by the FDA as an approvable endpoint in dry AMD. A phase 3 study is starting.
“The drug is administered via a subcutaneous injection daily. That’s an interesting and challenging new drug delivery strategy,” Kuppermann said.
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- For more information:
- Peter K. Kaiser, MD, of Cole Eye Institute, Cleveland Clinic in Cleveland, can be reached at pkkaiser@gmail.com.
- Jaclyn L. Kovach, MD, of Bascom Palmer Eye Institute in Naples, Florida, can be reached at jkovach@med.miami.edu.
- Baruch D. Kuppermann, MD, PhD, of Gavin Herbert Eye Institute, University of California, Irvine, in Irvine, California, can be reached at bdkupper@hs.uci.edu.
- Ursula Schmidt-Erfurth, MD, PhD, of the Medical University Vienna, Department of Ophthalmology, Vienna, Austria, can be reached at ursula.schmidt-erfurth@meduniwien.ac.at.
- Christina Y. Weng, MD, MBA, of Cullen Eye Institute, Baylor College of Medicine in Houston, can be reached at christina.weng@bcm.edu.
Click here to read the Point/Counter to this Cover Story.
Related news
In a chart audit coordinated by Spherix Global Insights, a provider of life sciences market research, the data of 758 patients with age-related macular degeneration provided by 156 physicians were analyzed, providing interesting insights on current practices.
Of note, the study was fielded in late 2023, a few months after Eylea HD (aflibercept 8 mg, Regeneron) had entered the market.
These were the main findings:
- Due to payer requirements, many patients with wet AMD receive off-label Avastin (bevacizumab, Genentech) as first therapy. However, as soon as the step therapy requirements are met, most physicians switch patients to more effective and longer-lasting drugs.
- Eylea (aflibercept 2 mg, Regeneron) is the most frequently used second-line drug, but Vabysmo (faricimab, Genentech) is catching on. Many ophthalmologists trust the bispecific mechanism of action of Vabysmo, targeting both VEGF and Ang-2, to provide increased drying ability and durability. On the other hand, the majority still feel more comfortable using Eylea as a reliable drug they have used for many years.
- The most common reason for switching between agents is desire for more efficacy, specifically in terms of fluid resolution. The second reason is the desire to improve the previous dosing schedule.
- After only a few months on the market, Eylea HD showed to be gaining ground as a second- and third-line agent.
- Reference:
- Spherix Global Insights. AMD patient journey.
- For more information:
- Spherix Global Insights is a provider of life science market research with whom Healio has a partnership. Spherix can be reached at spherixglobalinsights.com.
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