Specialists look positively at complex, dynamic landscape of wet AMD
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With emerging treatment options and technological advances that make detection and monitoring more precise, timely and easier, wet age-related macular degeneration continues to be a vibrant area of research and innovation.
The path is not always smooth: The risk for severe inflammatory events cooled down the early enthusiasm for Beovu (brolucizumab, Novartis), and concerns about septum dislodgement and potential adverse events led Genentech to voluntarily recall Susvimo (ranibizumab injection).
Source: Courtesy of Christina Y. Weng, MD, MBA/Photographer: Agapito Sanchez Jr./Baylor College of Medicine
However, progress and innovation never come without challenges, and the landscape for wet AMD today is exciting, complex and dynamic, according to Christina Y. Weng, MD, MBA.
“I can’t remember another time where we had so many options being investigated concurrently. These include drugs that may offer longer durability and therefore decrease treatment burden, molecules with novel mechanisms of action that may raise the bar even higher in terms of efficacy, and increasingly sophisticated technologies, including Home OCT, that will allow us more and more to personalize treatment,” she said.
Undertreatment a worldwide problem
Data from the American Academy of Ophthalmology IRIS Registry, Medicare and other databases show that patients with AMD are undertreated in the real world.
“We all know from many studies that outcomes are strictly related to regular follow-up and treatment, and we make this very clear with our patients. We have also made positive efforts to identify the populations of patients who are less likely to get lost to follow-up so that we can target them better,” Jennifer I. Lim, MD, said.
Several studies have recently investigated the correlations among socioeconomic factors, anti-VEGF injection utilization and visual outcomes. Ethnic minorities and Medicaid insurance were associated with lower use of anti-VEGFs and lower visual acuity.
“Health care disparity factors hit very hard, and underrepresented groups are not treated as aggressively as more affluent groups, who in general enjoy better health in many ways. Access to care issues are greater with retinal diseases that are more prevalent in minority communities, such as diabetic retinopathy, but there are plenty of people with macular degeneration who live in underserved areas, such as Appalachia or Indian reservations, and in many geographically isolated and disadvantaged areas around the world where it is very difficult to get treated,” OSN Retina/Vitreous Board Member Julia A. Haller, MD, said. “The pandemic has also affected access and continuity of care. Schedule disruptions, delays and even short-term treatment interruptions have had a persistent negative impact on vision.”
In addition, although it is well known that timing is critical, studies have shown that patients who are diagnosed with AMD are rarely treated on the same day.
“A good quarter of them are deferred, and this is mostly because we cannot obtain prior authorization on the same day. Most insurances provide it within 10 to 14 days, but sometimes it is difficult for the patients to come back because they need to have a family member take further time off work. This also contributes to undertreatment,” Lim said.
New approved pharmacotherapies
New pharmacotherapies with longer duration of action will help improve access and compliance while reducing patient burden.
“In the TENAYA and LUCERNE studies, faricimab (Vabysmo, Genentech) administered every 16 weeks showed sustained efficacy. This could markedly decrease the number of injections as compared with other anti-VEGF agents,” Lim said.
“I have been switching to faricimab in a number of patients who required frequent injections and, in spite of having treatment every 6 or even 4 weeks, still had residual fluid and those patients who have been on therapy for a long time with barely acceptable outcomes. In these patients, there is likely upregulation of other factors besides VEGF, and faricimab, which targets and inhibits two disease pathways, might offer some novel benefits,” Haller said.
The jury is out, she said. Vabysmo was approved by the FDA in January 2022, insurance companies are still deciding on coverage policies, and the new drug is just beginning to break into the market. Further clinical experience is needed to provide more definite answers.
Another promising option is high-dose aflibercept (Regeneron). The results of the PULSAR trial, recently presented at the Retina Society meeting, demonstrated that aflibercept 8 mg every 12 or 16 weeks was noninferior in vision gains to Eylea (aflibercept, Regeneron) every 8 weeks.
“We only have 1-year data so far, while faricimab has reached 2 years, so it would be premature to draw conclusions, but aflibercept is a well-known agent that we have learned to trust over many years,” Lim said.
Alarming signs and recalls
Beovu has shown good outcomes in some patients, but retina specialists maintain a cautious attitude after reported cases of severe inflammatory reactions.
“When cases started being reported, obviously I was concerned, but I did not discontinue the treatment in patients who were doing well. However, those reports really threw a wrench into the rollout of adoption,” Haller said.
The main advantages shown by brolucizumab were better drying effect and longer duration, but they were not enough to overcome the reports of severe side effects.
“It is a great drug for drying, but when we were starting on the approval process to include it in our formulary at the University of Illinois, the inflammatory adverse events were reported, and we decided not to go down that road,” Lim said.
The voluntary recall by Genentech of the Susvimo port delivery system, due to some cases of septum dislodgement, was praised by ophthalmologists as a responsible gesture, showing commitment to prioritizing patient safety.
“I applaud the management for recognizing the problem, calling everybody’s attention to it and doing the responsible thing, which is just stopping any distribution of it right now,” Lim said.
Genentech is going to perform further testing to address the problem, and hopefully Susvimo will become available again.
“It is a good option that saves a few injections. I already had patients who were doing well, and they continue with it,” Haller said.
Biosimilars
Two biosimilars to Lucentis (ranibizumab, Genentech) are currently approved in the U.S. for wet AMD: Byooviz (ranibizumab-nuna, Biogen and Samsung Bioepis), and Cimerli (ranibizumab-eqrn, Coherus BioSciences). The Samsung Bioepis SB-15 biosimilar to Eylea is undergoing phase 3 study, and results at 32 weeks, recently presented at the AAO meeting, demonstrated comparability to the reference aflibercept.
“More ranibizumab biosimilars, as well as aflibercept biosimilars, are in the pipeline but not yet approved,” Maria H. Berrocal, MD, said.
The cost of anti-VEGFs is a burden on the system in many countries, and the cost saving of biosimilars might help to increase patient access to therapies.
“In the U.S. Medicare, the top-cost drug is aflibercept, which accounts for over $12 billion a year. If we can get similar effects with drugs that are significantly less costly, it will be a win-win for the health care systems and for the patients because many of them have to pay co-pays or out of pocket for the drug. I think biosimilars will have an important place in the market,” Berrocal said.
She believes that the many players in the biosimilar market will create healthy competition, which will lead to further reduction of drug costs.
Weng is watching the entry of biosimilars with curiosity but also with some trepidation.
“They might demonstrate similar efficacy to the reference products we have used very confidently over the past decades, but the trials are significantly smaller and shorter in duration. And they are not simply copycat molecules. There can be variability between batches because they are biologic agents,” she said.
In addition, to some extent, adoption might be dictated by market forces and insurance companies.
“It is very possible that retina specialists may not have total control in terms of what patients receive,” she said.
In October 2022, the FDA accepted the biologics license application for the bevacizumab biosimilar ONS-5010 (Outlook Therapeutics), and a decision may be rendered soon. This drug is not following the same biosimilar regulatory pathway because no approved bevacizumab agent is available for ophthalmic use.
“This is interesting and has the potential to make waves in the field because this could become the first on-label FDA-approved ophthalmic version of bevacizumab. How that might impact access to compounded bevacizumab, which the majority of the world uses right now, is going to be something that we are watching carefully as well,” Weng said.
Treatment regimens
Treat and extend (T&E) is the preferred regimen today among U.S. retina specialists.
“The advantage of T&E is that we don’t have the burden of monthly injections. Although we have results that say that monthly treatment gives the best results, the burden for the patient and the system is significant, and many patients do not need to be treated at such close intervals anyway,” Berrocal said.
As-needed dosing is more common outside the U.S., but the burden of monthly monitoring is equally difficult to sustain in real-life clinical practice and often leads to missed appointments and undertreatment.
T&E was an attempt to encompass the best aspects of both fixed and as-needed regimens, maximizing visual outcomes while minimizing treatment burden, Weng said. But even the T&E approach is evolving.
“There are technologies such as Home OCT on the horizon, which might allow us to treat more on a PRN basis in the future. This will be a better way to tailor the treatment intervals to each patient individually, which is essentially what we are currently trying to do in a more unrefined way with treat and extend,” Berrocal said.
In the real world, T&E regimens are highly individualized, with great variation in injection intervals and overall treatment patterns.
“We are still learning what might be the best T&E protocol, particularly with some of the longer-durability agents coming down the line. The pivotal trials for faricimab, TENAYA and LUCERNE, looked at extending and contracting intervals by 4 weeks rather than 2,” Weng said.
Subretinal fluid tolerance is another important issue in T&E. The FLUID study showed that tolerating small amounts of stable subretinal fluid does not affect visual outcomes and may allow more patients to have their treatment interval extended beyond 4 weeks.
“Interest in this issue has been piqued again by some of our latest neovascular AMD trials because their re-treatment criteria often allow some tolerance of fluid,” Weng said.
Home monitoring
One thing that is clear across all wet AMD trials is that early detection and timely treatment are crucial to preserve vision.
“Regardless of the agent, regardless of any of our technologies, nothing beats the impact of time. Along with our drug discovery pathways, we should be thinking about how we can do better with early detection,” Weng said.
Home-monitoring technologies can be a step forward, a true game changer in the management of patients with AMD.
“I have recommended the Notal Vision ForeseeHome to many of my patients. It is a small device that serves a similar purpose as an Amsler grid but is much more precise and refined. With a short and simple self-performed test, patients with intermediate dry AMD can be checked daily for signs of conversion to wet AMD. Thanks to this device, I have been able to start treatment early, sometimes before the patients even notice any subjective vision changes, and help them maintain excellent visual acuity,” Weng said.
Even more exciting is the Notal Home OCT, which is not yet on the market but has been designated as a breakthrough device by the FDA.
“There is a lot of potential there for optimizing treatment outcomes even further. Initial studies have shown excellent accuracy and usability amongst elderly patients. The DRCR Retina Network is now branching out into looking at conditions beyond diabetic eye disease, and one of their future trials will evaluate Home OCT-guided treatment vs. a more standard T&E approach for wet AMD patients. The two arms will be compared to investigate how this technology might affect outcomes as well as treatment and visit burden,” she said.
Currently, the ForeseeHome is only given to patients who are considered to be high risk, with a lot of large drusen or choroidal neovascularization in one eye. Access to this technology should be expanded, according to Berrocal, because it is helpful in detecting early disease.
“Some patients, about 20%, find it cumbersome to use, but this is likely to change with the upcoming generations that are more technology-savvy,” she said.
Another way to monitor vision at home is the My Vision Track app (Vital Art and Science), which detects small areas of metamorphopsia in the central 3° of the field of vision.
“It has been cleared by the FDA, but it is not yet widely used. It can detect any kind of maculopathy, not just wet AMD,” Berrocal said.
Dealing with poor responders
About 10% to 20% of patients, or even more in some studies, do not have an optimal response to anti-VEGF therapy. Fluid does not dry up, and visual acuity does not improve, Berrocal said.
She said specialists now have a better knowledge of the characteristics typical of nonresponders or poor responders. These may include pigment epithelium detachments, whether serous, fibrous or hemorrhagic, type 1 choroidal neovascularization, a fibrous component, polypoidal lesions, presence of vitreomacular traction, outer retinal tubulation and cystoid degeneration of the retina.
“But we also know that some poor responders may rather be short-term responders. If we see them 2 to 3 weeks after the injection, the response is there,” she said.
Poor responders are often patients who need frequent injections and do improve with these tight schedules. Therefore, whenever there is a suboptimal response, patients should be checked at 2 weeks after injection.
“I do inject some selected patients every 2 to 3 weeks. In other cases, I try switching to another anti-VEGF agent, and this may also lead to a better response,” Berrocal said.
Some nonresponders are just too far advanced in their disease state, Weng said.
“If the photoreceptors have already become nonfunctional, and the retinal pigment epithelium has already atrophied, we are limited in what we can do. It can look like nonresponse when it is actually just very advanced disease,” she said.
Finally, there are the true nonresponders.
“That only represents a small fraction, and for those patients there might be something that we just don’t completely understand about the pathophysiology. We have been hyper-focused on VEGF-A because we can address it so readily, but we know from basic research that more is involved,” Weng said.
In the pipeline
Some molecules under investigation can more broadly target potential pathophysiologic aspects. One of them is OPT-302 (Opthea), which targets VEGF-C and VEGF-D. Two pivotal phase 3 trials, ShORe and COAST, are evaluating the benefit of using OPT-302 in combination with ranibizumab and aflibercept, respectively.
Other potentially longer-acting therapies are EYP-1901 (EyePoint Pharmaceuticals), a tyrosine kinase inhibitor combined with an anti-VEGF in a biodegradable implant, and KSI-301 (Kodiak Sciences), a novel antibody biopolymer conjugate.
“KSI-301 failed to demonstrate noninferiority to aflibercept, but the company is committed to doing further investigation,” Lim said.
There is also gene therapy on the horizon. RGX-314 (Regenxbio) and ADVM-022 (Adverum) are in early-phase studies.
“They might potentially create an anti-VEGF factory in the eye. What remains to be determined is safety. Inflammatory reactions and also the effects of constantly suppressing VEGF production remain to be seen,” Lim said.
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- For more information:
- Maria H. Berrocal, MD, can be reached at Drs. Berrocal & Associates, 150 José de Diego Ave., Suite 404 San Juan, Puerto Rico; email: mariahberrocal@hotmail.com.
- Julia A. Haller, MD, can be reached at Wills Eye Hospital, Suite 1510, Philadelphia, PA 19107; email: jhaller@willseye.org.
- Jennifer I. Lim, MD, can be reached at University of Illinois at Chicago, 1855 W. Taylor St., Suite 250, Chicago IL 60612; email: jennylim@uic.edu.
- Christina Y. Weng, MD, MBA, can be reached at Baylor College of Medicine, Cullen Eye Institute, 1977 Butler Blvd., Houston, TX 77030; email: christina.weng@bcm.edu.
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