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Retinal Physician

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Real-World vs Clinical Trial Data for Retinal Drug Regimens

A Q&A with Charles C. Wykoff, MD

By: Jennifer Ford, senior managing editor
Retinal Physician April 1, 2020 Vol 17, Issue April 2020 Page(s): 34-37

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Since the introduction of anti-VEGF agents for wet age-related macular degeneration (AMD), a number of clinical trials have attempted to define the most effective treatment regimen, beginning with fixed dosing. When the FDA approved ranibizumab for wet AMD in 2006 (Lucentis; Genentech), fixed monthly dosing was demonstrated to improve visual acuity through 2 years in the MARINA and ANCHOR trials.1,2 Subsequently, the PIER, EXCITE, and SAILOR trials studied fixed quarterly dosing of ranibizumab.3-5 Those studies found that quarterly ranibizumab did not achieve equivalent outcomes to monthly dosing. The VIEW 1 and VIEW 2 trials of aflibercept (Eylea; Regeneron), which led to the 2011 FDA approval of aflibercept for wet AMD, studied both fixed monthly and fixed 2-month dosing after 3 monthly loading doses.6 In the ensuing years, ophthalmologists have tried in practice and in clinical trials to elucidate treatment regimens that would reduce the burden of injections while maintaining efficacy. Retinal Physician spoke with Charles C. Wykoff, MD, who has been an investigator in several related clinical trials, about the evolution of these treatment regimens and the trials that have attempted to improve treatment of AMD.

Charles C. Wykoff, MD, PhD, is director of research at Retina Consultants of Houston, Retina Consultants of America, and Blanton Eye Institute and a clinical assistant professor of ophthalmology at Weill Cornell Medical College at the Houston Methodist Hospital in Houston, Texas. Dr. Wykoff reports consultancy for and research with Adverum Biotechnologies, Iveric Bio, Kodiak Sciences, Genentech/Roche, Novartis, Opthea, Regenxbio, and Clearside Biomedical. Reach him at ccwmd@houstonretina.com. Editor’s note: This article is discussed in an episode of The Retina Podcast. Listen at www.retinapodcast.com .

Q: How have treatment trials evolved since those first fixed-dose trials?

A: Most clinical trials in wet AMD have studied fixed dosing, as-needed or pro re nata (PRN) dosing, or treat-and-extend dosing. The biggest PRN trial to date is HARBOR with ranibizumab.7 Treat-and-extend trials include TREX-AMD, LUCAS, and TREND,8-10 and more recently there were the CANTREAT, ALTAIR, FLUID, and RIVAL studies.11-14 The idea of PRN is that not every patient needs fixed dosing, and some patients can do well with many fewer doses. That was proven to be true through the PRN trials. The treat-and-extent trials aimed to take the best of both worlds by maintaining a more aggressive schedule for patients who need it and incorporating less-frequent dosing for patients who don’t need it. Those trials have validated what is done clinically outside of trials, and they have also helped retina specialists to understand what proportion of patients may continue to need more aggressive monthly dosing and what proportion of patients with ranibizumab, aflibercept, and bevacizumab (Avastin; Genentech) may be able to go longer between doses.

More recently, 2 types of trials have taken center stage: fixed quarterly dosing and adaptive designs. Earlier, there was an attempt at fixed quarterly dosing with ranibizumab in the PIER, EXCITE, and SAILOR trials, which demonstrated inferior results compared to monthly ranibizumab dosing.3-5 More recently, fixed quarterly dosing after loading doses was used for abicipar (Allergan/Molecular Partners) in the CEDAR and SEQUOIA phase 3 trials,15 results from which indicated that abicipar can do quite well at both every-8-week or every-12-week dosing. The adaptive trial design, which is perhaps the most interesting, was exemplified by the HAWK and HARRIER trials of brolucizumab (Beovu; Novartis).16 Those trials led to the FDA approval of brolucizumab for the treatment of wet AMD in 2019. This adaptive approach is also being applied to other drugs being studied, for example faricimab (Roche/Genentech) and KSI-301 (Kodiak Sciences); the concept is that you allow patients to be put into different fixed-interval dosing patterns depending on the disease activity. Continuous dosing is probably optimal overall, and within that we want to make sure the patients who need more aggressive dosing receive it. However, many patients can do very well with much less frequent dosing, especially, it appears, with next-generation therapeutics.

Q: How do these data translate into real-world practice?

A: According to the Preferences and Trends Survey administered by the American Society of Retina Specialists, the majority of retina specialists across the United States pursue a treat-and-extend management approach, or a variant of it.17 There are many ways to implement treat and extend. We often talk about it as if it were one treatment pattern, but there are variations. For the most part, there are 3 phases to treat and extend. First is a monthly phase during which patients are treated monthly until as dry of a retina as possible is achieved. Many retina specialists used to think that the retina had to be completely dry before treatment could be extended, and many still practice that way. But now there are some data, including from the prospective FLUID study, that indicate retina specialists may be able to tolerate some fluid, in particular subretinal fluid, while continuing continuous dosing, but slowly extending the interval between treatments using a treat-and-extend approach.18

The second phase is the extension phase. The key here is to continue to treat patients at every visit. We slowly extend the interval between injections until we reach a point at which we see recurrence of exudative disease activity as evidenced by recurrence of intraretinal or subretinal fluid.

The third phase is continued fixed dosing. Once we find the interval between injections at which exudative disease activity recurs, we continue to treat at a slightly shorter, or more frequent, interval. The key here is that we are not constantly rechallenging the maximum tolerated interval. We find a patient’s maximum interval without exudation and then we maintain it with fixed dosing.

Q: Is that maximum tolerated interval static?

A: Overall, data suggest that the maximum interval is static. In the small, prospective, randomized TREX-AMD study, we included a mechanism to challenge that longest interval and found that approximately 75% of patients had a stable longest interval.8 On the other hand, approximately 25% of patients, a clinically meaningful proportion, could go longer when their longest interval was rechallenged. So, in the real world, it depends on the clinical situation and it depends on what that interval is. But physicians often will rechallenge the longest interval, maybe every year or every couple of years. It depends on the patient and the physician circumstances.

There are also several manuscripts that Fauser and colleagues published19-23 that explore the intra-individual variability in VEGF suppression time during ranibizumab or aflibercept dosing. Fauser’s elegant work indicated that the duration of anti-VEGF activity in a given eye for a given drug at a given dose is remarkably consistent over time. Those data suggest that the interval between retreatments remains fairly consistent over many months to years of follow-up.

Q: Have there been variations in how retina specialists apply treat and extend?

A: Yes. One way that practice patterns vary is with loading doses. In my practice, I treat patients monthly until I achieve as dry a retina as possible. So, if an eye is completely dry after 1 injection and the visual outcome is good, I have no problem extending the interval at that early stage. In my clinic, almost every new wet AMD patient receives at least 1 monthly injection, and then if the retina is dry, the patient can begin to go longer between injections. Some retina specialists give a series of monthly loading doses before considering extending the interval between doses.

Another variation is tolerance of fluid. This is in flux as we continue to learn more about the effects of different fluid compartments on both short-term and long-term outcomes. We have evidence from multiple data sets including HARBOR, CATT, and IVAN that subretinal fluid and intraretinal fluid have different prognostic values.7,24,25 For example, we believe that the presence of subretinal fluid at baseline is a positive prognostic indicator: overall, eyes with subretinal fluid achieve better visual outcomes than eyes that don’t have subretinal fluid. Conversely, intraretinal fluid is a negative prognostic indicator. Those eyes tend to have worse visual outcomes compared to eyes without intraretinal fluid. Because of such retrospective analyses, some retina specialists think that maybe we can be more tolerant of subretinal fluid. It is important to realize, however, that all 3 of these data sets were PRN trials. Also, in the presence of subretinal and/or intraretinal fluid, those eyes continued to receive monthly dosing in all 3 of those prospective studies.

The FLUID study, which was a well-designed prospective study, examined tolerating subretinal fluid in a treat-and-extend pattern, increasing the interval between dosing even if there was a little bit of subretinal fluid.18 The outcomes overall were not as robust as anticipated based on other trials, but nonetheless they did not show meaningful differences in visual acuity outcomes between the patients who were more aggressively treated and those who were more leniently treated, allowing toleration of some subretinal fluid, in the presence of continued dosing. Some retina specialists treat monthly until there’s resolution of most of the fluid except a little bit of subretinal fluid in some eyes. Then they begin to extend the interval between doses with that small amount of fluid serving as a new baseline. If that subretinal fluid then worsens, or if the eye begins to develop intraretinal fluid, the interval between dosing can then be shortened again. While I think this is a reasonable approach, my approach, using our current agents, is to continue monthly dosing for patients with persistent fluid regardless of whether it is intraretinal or subretinal.

Monitoring is another important piece of the puzzle. There are at least 2 major companies, Notal Vision and Acucela, that are developing devices for home monitoring during active wet AMD management. If we had a reliable way to monitor these patients remotely, we might be able to skip the extension phase of treat and extend. We could treat patients monthly until the retina is dry, and then prvide patients with a home-monitoring device. When the device detects recurrent fluid, we would bring patients back in to define each patient’s maximum tolerated interval. I think that home OCT may help decrease the number of injections needed over time, and I look forward to more data related to home monitoring.

Another point to consider about treat-and-extend variations is the longest interval: is it 10, 12, or 16 weeks? The LUCAS study contributed valuable data toward answering this question. Berg et al found that patients who had recurrence of exudative disease activity while being treated quarterly on average did not regain the vision that they had before they experienced a recurrence.9 The authors concluded that either we should not extend out to 12 weeks with current therapeutics, because that was a trial with bevacizumab and ranibizumab, or we should more aggressively decrease the interval between dosing when a recurrences is identified at a 12-week interval.9 I’ve taken this to heart in my practice. If a patient has recurrence of fluid while on quarterly dosing, I will often treat more frequently until I have the disease under control before extending the interval longer again.

Cessation of therapy is also a consideration. The retrospective treat-extend-stop (TES) protocol study26 explored whether therapy can be stopped if patients are stable without fluid after multiple doses. I think that’s a reasonable approach. We studied that in the third year of the TREX-AMD trial and found that about one-fifth of patients who were transitioned to PRN retreatment after being stable without fluid on quarterly dosing experienced recurrence of exudative disease activity within 1 year of follow-up.27 We also recently published a retrospective analysis of this topic across my practice, in which we found that a substantial proportion of similar patients, approximately 20% to 50% over 2 to 5 years, have recurrence of exudative disease activity, demonstrating that many patients will continue to need long-term consistent dosing. Despite this long-term risk of recurrence, a minority of patients do appear to remain stable for multiple years without repeated treatments in that context.27

Q: When would a patient with wet AMD not receive treatment?

A: There are eyes with active wet AMD that we may not treat, and there are many reasons for this. One reason is if there is a disciform scar with very limited visual potential in the context of a well-sighted fellow eye. With very poor vision, many physicians would choose to observe such an eye or consider infrequent dosing to maintain the limited visual function. We also might stop dosing toward the end of life. It is important to deal with these challenging clinical scenarios in the context of each individual patient.

Q: How do you handle patients who miss an injection because they are hospitalized or for any other reason?

A: This is a real-world challenge and we do the best we can. Fortunately, sometimes when patients miss 1 or 2 doses, they come back and are remarkably stable. Sometimes, however, they return and the disease has progressed. We are not very good at predicting which eyes are going to reactivate aggressively and which are going to smolder and be relatively stable when a medical or life event prevents consistent treatment. When a patient is an inpatient in most facilities across the United States, there is currently no good mechanism to obtain routine outpatient ophthalmic care.

Q: What is next for the treatment of wet AMD?

A: Fortunately, the field is moving forward and there are many exciting advances in development. Overall, current programs are aimed at improving durability and/or efficacy. There are several approaches currently being explored to improve durability. One is the Port Delivery System with ranibizumab (Genentech), currently being studied in 3 large phase 3 programs. We are anticipating data in the second half of 2020 from the wet AMD program, which uses an approach that refills the device in clinic every 6 months.

Another approach under study is novel pharmaceutical agents that may last longer than our current medications, including faricimab, KSI-301, conbercept (Chengdu Kanghong), and GB-102 (Graybug Vision). Perhaps potentially most disruptive is gene therapy, which is currently being developed for wet AMD by Regenxbio and Adverum Biotechnologies. The early-phase data from both trial programs have shown remarkable durability in the large majority of patients.28,29 Both programs are moving into phase 2 studies from which we will continue to learn about the potential for creating a biofactory in the eye that produces an anti-VEGF agent over the long term. RP

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