Article
`
`Ongoing Treatment for Patients With Neovascular AMD
`
`October 1, 2007
`
`0
`
`Ongoing Treatment for Patients With Neovascular AMD
`Dr. Rosenfeld: Once you decide to initiate anti-vascular endothelial growth factor (anti-VEGF) therapy for a
`patient with neovascular age-related macular degeneration (AMD), how do you proceed?
`
`Dr. Hariprasad: The randomized controlled clinical trials completed thus far support monthly injections for
`achieving the best visual outcomes with ranibizumab (Lucentis, Genentech). However, practically speaking,
`monthly treatment is a tremendous burden for our patients and our practices. Therefore, I treat with ranibizumab
`monthly until optical coherence tomography (OCT) shows the macula to be completely free of fluid. Some patients
`reach that point after 2 injections; others require as many as 8 injections. When the macula is dry, I withhold
`treatment and bring the patient back in 2 months. If OCT shows the macula is still dry at that visit, I have the
`patient return the following month to receive another injection.
`
`Alternatively, if fluid has reaccumulated 2 months after a dry OCT, my patients receive ranibizumab at that visit. In
`other words, all of my patients get a minimum of 4 ranibizumab doses per year.
`
`Is there solid science behind this approach? Probably not, but an aspect of the PrONTO trial that bothers me is
`1
`that a certain amount of fluid was allowed to accumulate before retreatment. (See "The PrONTO Study.") I like the
`idea of having a consistently dry macula. It is based on theory alone at this point, but perhaps the delicate
`photoreceptors sustain damage every time the macula thins and thickens. It might be possible to achieve a better
`outcome if we keep the macula dry over the course of treatment.
`
`Dr. Apte: We all want to reduce the number of injections for the sake of our patients and our practices. However, I
`do not hesitate to continue treatment when it appears the disease in a particular patient is aggressive. In those
`cases, following the MARINA and ANCHOR protocol of monthly dosing may be the most appropriate decision.
`
`Dr. Rosenfeld: So you sometimes use monthly dosing?
`
`Dr. Apte: Yes, in cases where I have not seen evidence of a dry macula or if a switch to off-label bevacizumab
`(Avastin, Genentech) has been unsuccessful, I would consider continued monthly dosing. I also might dose
`monthly in a situation where OCT and the fluorescein angiogram (FA) showed the disease had stabilized but then
`recurred. That tells me the lesion is more aggressive and makes me more inclined to continue treatment. I follow a
`patient like that more closely, and I am not hesitant to give additional injections as needed.
`
`The PrONTO Study
`
`Exhibit 2103
`Page 01 of 07
`
`

`

`PrONTO is a Phase 1/2, 2-year, single-center, uncontrolled, open-label study (n=40) evaluating variable dosing
`1
`with 0.5-mg of ranibizumab (Lucentis, Genentech) guided by optical coherence tomography (OCT). Patients
`receive a 0.5-mg intravitreal injection of ranibizumab at baseline and months 1 and 2. Thereafter, they receive
`additional injections if any of the following criteria are met since last visit:
`• Visual acuity loss of ≥5 letters with any fluid on OCT
`• Increase in central retinal thickness ≥100 μm
`• New hemorrhage
`• New classic choroidal neovascularization (CNV)
`• Persistent fluid detected by OCT 1 month after an injection.
`The visual acuity results achieved at 1 year in the PrONTO study were comparable to the results achieved with
`monthly dosing in the Phase 3 MARINA and ANCHOR trials ranibizumab.
`
`Reference:
`1. Fung AE, Lalwani GA, Rosenfeld PJ, et al. An optical coherence tomography-guided, variable dosing
`regimen with intravitreal ranibizumab (Lucentis) for neovascular age-related macular degeneration. Am J
`Ophthalmol. 2007;143:566-583.
`
`KEEPING THE MACULA FREE OF FLUID
`Dr. Rosenfeld: I think everyone agrees that we want to keep the macula dry. The PrONTO study was designed to
`demonstrate that if a small amount of fluid accumulates, more fluid follows, so our conclusion was that treatments
`should try to maintain a dry macula, but our data suggest that a small amount of fluid was not detrimental. This
`should be reassuring to both patients and doctors if a monthly return isn't possible because of scheduling conflicts,
`and the patient has to delay a return visit to the office. At least we know it's OK to have a small amount of fluid in
`the macula for a short time, and it's not an emergency even if the fluid returns.
`
`The conclusion of the PrONTO study wasn't that we should purposely allow fluid to accumulate. The goal was to
`1
`get the macula dry but minimize the number of injections. In fact, in the second year of the PrONTO study, we
`amended the protocol to allow retreatment when there was any qualitative change on OCT no matter how
`miniscule the fluid change. We did not inject even when the macula was dry as in the "treat and extend" strategy,
`because we wanted to know the length of the fluid-free interval so we could inject as infrequently as possible. Now
`we know the two extremes: Monthly injections vs. PrONTO-style injections known as "treat and observe."
`
`What is your strategy for keeping the macula dry? One strategy is monthly dosing, another is treat and observe,
`and the third intermediate strategy is known as treat and extend.
`
`Dr. Brown: For patients with good initial visual acuity or in whom we are dealing with the primary eye, I treat and
`extend from the start. I give 3 monthly injections and see them in 8 weeks. If fluid is absent at that visit, I give
`another injection and see them in 10 weeks.
`
`Dr. Rosenfeld: You always administer 3 initial monthly doses?
`
`Dr. Brown: Yes, I administer 3 doses in all cases except extrafoveal lesions.
`
`Dr. Rosenfeld: Who else on the panel always administers 3 doses?
`
`Dr. Apte: I do.
`
`Exhibit 2103
`Page 02 of 07
`
`

`

`Dr. Reichel: I do not. I am a big believer in prn dosing. I give patients 1 injection and see them 4 weeks later. If the
`macula is dry, I see them in another 4 weeks.
`
`Dr. Hariprasad: I do not necessarily give 3 initial doses. I give as many consecutive monthly doses as necessary
`to dry the macula.
`
`Dr. Brown: Even though I am giving every patient 3 initial monthly injections, I look at the macula at each of those
`visits. If the macula is dry at 1 month, I think we have a good chance of maintaining a dry macula after 3 injections.
`If the macula does not leak, hallelujah! Every time it does leak, I go to the treat-and-extend strategy.
`
`Dr. Rosenfeld: So, you do not waste a visit. If a patient comes in, you treat whether the macula is dry or wet?
`
`It may be that the fewer injections we give, the more likely we are to maximize vision. Even if a small
`amount of fluid appears, we may lose the battle but win the war by giving fewer treatments.
`— Elias Reichel, MD
`
`Dr. Brown: Yes, but if the macula is dry, I extend the visit interval. If the macula is wet, I bring the patient back
`much sooner. Treating and extending reduces the number of times the macula accumulates fluid. Any time fluid
`appears, we have the chance of degradation. Any time we have to dry the macula again, we have another chance
`for a retinal pigment epithelium (RPE) tear.
`
`Dr. Reichel: I see patients 4 weeks after the initial injection. If the macula is still wet at that time, I give another
`injection and see them in 4 weeks. If the macul is dry after 2 cycles, I may extend the visit interval to 6 weeks. In
`general, I am seeing each patient every 4 to 6 weeks. It is a lot of visits, but it ends up being a reduced number of
`injections overall.
`
`What makes me uncomfortable about treating and extending is that I cannot predict whether fluid will accumulate
`during that interval. I have seen some patients from the ANCHOR and MARINA trials do really well but then
`accumulate fluid at an unpredictable time. I do not want to miss that.
`
`Dr. Rosenfeld: As we stated previously, no one wants to see fluid in the macula. However, one point that the
`PrONTO study demonstrated is that the macula, once dry, can tolerate some reaccumulation of fluid; however, this
`happens gradually and does not come rushing back like we have seen following photodynamic therapy (PDT) with
`verteporfin (Visudyne, Novartis Ophthalmics).
`
`Dr. Reichel: We may learn in the future that monthly injections necessitate monthly injections because we are
`upregulating VEGF each time we treat. It may be that the fewer injections we give, the more likely we are to
`maximize vision. Even if a small amount of fluid appears, we may lose the battle but win the war by giving fewer
`treatments.
`
`Dr. Apte: After 3 initial monthly injections, I follow a treat-and-observe approach. Even when the macula is dry
`after 3 injections, I see the patient in 4 to 6 weeks. That way, I do not miss the patients who leak in the interim. But
`I do not treat again if the macula remains dry.
`
`Exhibit 2103
`Page 03 of 07
`
`

`

`Based on the clinical data, I believe we need an initial quenching of VEGF. Yes, there is a theoretical positive
`feedback loop with anti-VEGF treatment, but that is still experimental. I am not willing to treat only once and follow
`a prn regimen until I am convinced there is clearly a mechanism that supports that type of regimen. It is important
`to note that only the monthly dosing scheme has been proven for ranibizumab and all others are experimental and
`still need to be proven in a large-scale clinical trial.
`
`Dr. Rosenfeld: Whether we use a treat-and-observe or treat-and-extend paradigm, we will find that most patients
`fall into a pattern of retreatment every 6 to 12 weeks. However, there will be some patients who really fall outside
`this pattern and need very few retreatments.
`
`Throughout 2 years of treating and observing, this group of patients might receive 3 treatments while the treat-and-
`extend approach might result in 10 treatments if the patient gets 3 initial monthly injections followed by an injection
`every 3 months whether needed or not. That's OK as long as we realize that some patients might receive
`injections that aren't necessary, but they aren't harmful either, just costly with a very small risk of endophthalmitis.
`
`It is reassuring to know that even with monthly dosing over 2 years in the MARINA and ANCHOR trials, a
`downward trend in visual acuity was not observed. It is unlikely that chronic treatment is deleterious to the macula,
`and endophthalmitis was very rare in the studies. Perhaps we will find that is not the case after 3 or 4 years, but it
`is unlikely that treating more often than is absolutely necessary is deleterious.
`
`Dr. Reichel: It may not be harmful, but we may be increasing the risk of endophthalmitis and the economic burden
`by treating more often than is absolutely necessary.
`
`Dr. Rosenfeld: I let the patients decide whether I will use the treat-and-observe or the treat-and-extend strategy.
`Some do not want an injection unless they absolutely need it. Others say the last thing they want to do is come
`back again the next month and wait.
`
`Dr. Hariprasad: I have seen that divergence in my patients, too. That is why I let them decide.
`
`RELATIVE IMPORTANCE OF RPE TEAR RISK
`Dr. Rosenfeld: Would anyone on the panel not treat a neovascular AMD patient with an intravitreal anti-VEGF
`agent because of the risk of an RPE tear?
`
`Dr. Apte: Whether a patient is at risk for an RPE tear is not a consideration for me in terms of whether I would use
`an anti-VEGF agent.
`
`Dr. Rosenfeld: Other than a serous pigment epithelial detachment (PED), is there anything that makes you
`concerned that a patient might develop an RPE tear?
`
`Dr. Reichel: A retinal angiomatous proliferative (RAP) lesion. Also, an RPE tear is not necessarily the end of the
`world. If it rips through the fovea and vision declines, of course, that is a serious problem. But if vision remains
`good after the tear, often those eyes can maintain good vision for a long time. Often, the tear does not continue
`once it stabilizes after the initial insult.
`
`PERI-INJECTION ANTIBIOTICS
`
`Exhibit 2103
`Page 04 of 07
`
`

`

`Philip J. Rosenfeld, MD, PhD: How do you prep patients for an intravitreal injection of an anti-vascular
`endothelial growth factor agent?
`Rajendra S. Apte, MD, PhD: For the most part, I follow the consensus panel guidelines that were published in
`Retina in 2004. I use povidone iodine, gloves and an eyelid speculum. I use a topical, but not subconjunctival,
`1
`anesthetic.
`Prior to the injection, I use a broad-spectrum topical antibiotic. I also displace the conjunctiva because I would
`rather have the egressed vitreous under the conjunctiva than coming out of the eye in order to reduce the
`theoretical risk of an infection. I follow the injection with povidone iodine and a topical antibiotic. I do not check
`IOP after the injection. I use an indirect ophthalmoscope to make sure the optic nerve head is perfused.
`Dr. Rosenfeld: Does the rest of the panel also use antibiotics before the injection?
`David M. Brown, MD: In most cases, we prescribe topical antibiotics for 3 days prior to the injection.
`Elias Reichel, MD: I do not use preinjection antibiotics.
`Seenu M. Hariprasad, MD: I use a fourth-generation fluoroquinolone for 30 minutes (1 drop every 10 minutes)
`before the injection and also afterward for 3 days qid.
`Dr. Rosenfeld: I do not use antibiotics prior to injection.
`Whether it is necessary to use antibiotics after the injection is a controversial issue. Currently, at least one of the
`Diabetic Retinopathy Clinical Research Network's ongoing studies is leaving the use of antibiotics after
`intravitreal injections to the discretion of the treating physician. For me, it is difficult to imagine that anything we
`apply topically will matter if bacteria are introduced into the vitreal cavity, but we do not know for sure.
`Dr. Hariprasad: There is evidence in the literature that fluoroquinolones applied topically can decrease
`conjunctival bacterial load greater than betadine alone. Obviously, we don't know for certain that peri-injection
`antibiotics actually change the rate of endophthalmitis. However, given the severe consequences of
`endophthalmitis, it makes sense to me to decrease conjunctival bacterial load to the best of my ability before
`passing a needle through the conjunctiva into the vitreous cavity.
`
`REFERENCE
`1. Aiello LP, Brucker AJ, Chang S, et al. Evolving guidelines for intravitreous injections. Retina. 2004;24:S3–
`S19.
`
`Dr. Apte: Unfortunately, all of the RPE tears that have occurred in my patients have involved the fovea.
`
`Dr. Rosenfeld: Does everyone agree that even though anti-VEGF therapy may accelerate a small percentage of
`eyes toward an RPE tear, we do not have an option other than to treat these patients?
`
`Dr. Reichel: Certainly, the effect of the anti-VEGF agent shrinking the neovascular membrane causes more tears
`than leaving it alone. However, if we want to achieve better vision, we have to use the treatment.
`
`DEFINING AN ANTI-VEGF THERAPY FAILURE
`Dr. Rosenfeld: With anti-VEGF therapy, what do you consider a treatment failure?
`
`Dr. Brown: A treatment failure is when multiple anti-VEGF treatments have been applied, and fluid and perfusion
`persist on OCT and FA.
`
`Dr. Reichel: It is unclear what is happening in eyes where a thin layer of subretinal fluid persists while vision
`remains as good as 20/40 or 20/50. I am not sure whether that is a treatment success or a treatment failure. To
`me, a failure is when I am treating a patient and either subretinal fluid is increasing or vision is declining for no
`apparent reason. Vision has to be part of the equation. We cannot rely simply on the presence of subretinal fluid.
`
`Exhibit 2103
`Page 05 of 07
`
`

`

`Dr. Apte: The primary determinant of treatment failure is vision loss. Ancillary points for treatment failure are
`increased or unresponsive fluid on OCT, increase in lesion greatest linear dimension or total lesion size on the
`angiogram.
`
`Dr. Brown: We can have treatment failures but also treatment disappointments. One type of disappointment is
`when a patient requires monthly injections to keep the macula free of fluid. Another is when a patient responds to
`treatment anatomically but does not achieve better vision.
`
`Dr. Rosenfeld: What about the patients who do very well in terms of vision but need to be injected every month?
`Would you consider those cases treatment failures?
`
`Dr. Brown: When patients maintain good vision, we are keeping them functional, so I suppose that is not a
`treatment failure. It certainly is not ideal, however. The vision part of the equation is the primary concern for
`patients. They want to know if they can keep their driver's license, see the television, etc.
`
`Dr. Rosenfeld: Everyone on the panel agrees that an anti-VEGF treatment failure has to do with vision loss. Also,
`we agree with Dr. Brown's suggestion that we also have "treatment disappointments."
`
`Dr. Hariprasad: We should keep in mind that treatment disappointments and treatment failures can be from the
`point of view of either the physician or the patient.
`
`COMBINATION THERAPY
`Dr. Rosenfeld: When do you use combination therapy for neovascular AMD?
`
`Dr. Reichel: I have not used combination therapy yet for AMD. Instead, if a patient is not doing well with
`ranibizumab, I may switch to bevacizumab.
`
`Dr. Apte: For some patients, I offer the option of enrolling in the single-center or multicenter combination therapy
`study at our practice. Otherwise, when facing less than desirable results with ranibizumab, I try another anti-VEGF
`monotherapy, mainly bevacizumab. For patients who are still refractory, I consider adding PDT and/or a steroid.
`
`Dr. Brown: To patients who are not happy with their vision despite effective but disappointing anti-VEGF
`monotherapy (poor vision despite requiring multiple injections to maintain a fluid-free macula), we often offer lower
`fluence PDT with ranibizumab or bevacizumab. To that combination, we also add a steroid if we will not be seeing
`the patient for a long time (although we require IOP checks following any steroid injection). We feel this decreases
`the amount of anti-VEGF injections that will be required to keep a "spare-tire" eye.
`
`Dr. Rosenfeld: It is important to note that these combination therapies have not yet been proven, but studies are
`planned or under way to examine various PDT/anti-VEGF and triple therapy regimens.
`
`VISUAL OUTCOMES VS. TREATMENT BURDEN
`Dr. Rosenfeld: How much visual acuity would you be willing to sacrifice to decrease the frequency of retreatment?
`
`Dr. Brown: It depends on the patient. Most of my patients would be willing to take a 1-line loss for a permanent fix
`vs. multiple injections for the rest of their lives.
`
`Dr. Apte: I do not think many of my patients would choose fewer injections if I told them they might lose a line of
`vision. Maybe that is because they do not know exactly how that would translate in real life, but just the thought of
`losing any vision is not appealing to them.
`
`Exhibit 2103
`Page 06 of 07
`
`

`

`Dr. Rosenfeld: We can complete our discussion with these important points. First, when we use combination
`therapy to decrease the frequency of anti-VEGF therapy, we may have a trade-off. We may be sacrificing visual
`acuity to decrease the treatment burden. Second, while we as physicians might be willing to tolerate a line of
`vision loss to decrease the treatment burden, that approach may not be acceptable to our patients. RP
`
`Reference:
`1. Fung AE, Lalwani GA, Rosenfeld PJ, et al. An optical coherence tomographyguided, variable dosing
`regimen with intravitreal ranibizumab (Lucentis) for neovascular age-related macular degeneration. Am J
`Ophthalmol. 2007;143:566-583.
`
`Retinal Physician, Issue: October 2007
`Table of Contents
`Archives
`
`Copyright © 2021, PentaVision, Inc. All rights reserved. Privacy Policy
`
`Exhibit 2103
`Page 07 of 07
`
`