- Email: [email protected]
Neovascular Age-Related Macular Degeneration
Neovascular Age-Related Macular Degeneration Individualizing Therapy in the Era of Anti-Angiogenic Treatments Jeffrey S. Heier, MD The treatment of neovascular age-related macular degeneration (AMD) had been revolutionized by the use of anti-vascular endothelial growth factor (VEGF) drugs: bevacizumab and ranibizumab. With the introduction of a third anti-VEGF drug, aflibercept, ophthalmologists have several options to choose from, as well as various treatment regimens they can follow. In this Interview, Jeffrey S. Heier, MD, of Ophthalmic Consultants of Boston, Massachusetts, discusses his approaches to managing the treatment of patients with AMD and providing them with individualized care. Ophthalmology 2013;120:S23–S25 © 2013 by the American Academy of Ophthalmology.
Q: Although anti-VEGF provides the cornerstone of treatment today for patients with neovascular AMD, challenges remain, such as which anti-VEGF agent to choose, how often to treat the patient, how long to treat the patient, and how to manage nonoptimal or suboptimal responders. How do you address these issues? Dr. Heier: There are a number of factors. In general, the trend over the last several years has gone from treating less frequently to treating more frequently. When the antiVEGFs first came out, most of us thought we did not need to use them that often. But what we have learned, at least in many patients, is that as we try to treat less frequently, recurrences develop and, over time, the patients lose vision.1–3 As a result, many of us have moved toward more frequent therapy. What that means is that I will treat a patient and follow up him or her carefully, and if the patient is doing great, I might stretch out the treatment a little bit and go from, say, monthly therapy to every 5 to 6 weeks. And if the patient’s progress is really outstanding, I might try to stretch out the treatments a little bit more from that. This is along the lines of the treat-and-extend paradigm. Q: How do you decide which patients to do that with? Dr. Heier: There are several factors that help guide that decision. One is whether it is the patient’s first or second eye. Although vision in either eye is valuable, if vision in the first eye has been lost, typically to wet macular degeneration, vision in the second eye is even more critical. Because fellow eyes often mirror the path in the first eye, such loss also suggests that more intensive therapy may be necessary. So there I am more hesitant to stretch out therapy. If the patient’s eyes continue to demonstrate recur-
Statement of Potential Conflict of Interest and Funding/Support: See page S25. © 2013 by the American Academy of Ophthalmology Published by Elsevier Inc.
rence, eyes that are somewhat resistant to therapy—those are eyes that I tend to treat more frequently. We have also clearly learned that even when we want to spread out therapy, the closer we monitor those patients, the better they do. Studies have shown us that if you really want to come close to obtaining the results that are seen with monthly therapy, then at the very least you have got to follow them up carefully.4 And although there are some studies that say we can go to treat-and-extend or we can do this less frequently, in general, the best results are achieved with frequent injections and, at the very least, frequent monitoring.4,5 Q: Are you saying that we are not really going to see much of an improvement in terms of the burden frequent treatment puts on patients to come in and see you at least every month, even if you are able to go to 5 or 6 weeks between injections? Dr. Heier: Not exactly. There are patients who do well with extension of treatment intervals, but the more careful this extension is exercised (i.e., the more cautious the treatment interval is extended), the better patients typically do. Now, with aflibercept, what is encouraging is that the VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD program showed us that patients who were treated every other month with aflibercept after a 3-injection loading phase did just as well as patients treated monthly with either aflibercept or ranibizumab.6 So although those patients were followed up monthly in the first year, there were no treatment decisions based on those intervening visits; they were really done for the sake of masking. The VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD results suggest that many, if not most, patients treated with 2 mg aflibercept may do well with every-othermonth dosing (after a 3-injection loading phase). I have no doubt that there are patients who will require more frequent dosing, but these patients likely will declare themISSN 0161-6420/13/$–see front matter http://dx.doi.org/10.1016/j.ophtha.2013.01.059
S23
Ophthalmology Volume 120, Number 5, Supplement, May 2013 selves over the initial 3-injection loading phase or within the first few attempts at every-other-month dosing. Q: What drives the decision of which VEGF treatment to use? Dr. Heier: The major factors are cost, efficacy, safety, and treatment burden. Patients in whom cost is an issue— either they do not have insurance or they have a significant copay—are typically started on bevacizumab therapy. If they do well—and many, if not most, do—I continue this therapy with the knowledge that we are probably going to have more of a treatment burden but at a far reduced cost. Whenever I initiate therapy in patients for whom cost is not an issue, I always discuss the available agents and many patients elect to go straight to the United States Food and Drug Administration-approved agents. Until recently, that was only ranibizumab. With the approval of aflibercept, we now have a third option. The potential of reduced treatment while following a proven regimen is appealing and it is likely its use will increase. Others prefer ranibizumab because of its track record of safety and efficacy. In patients who have suboptimal responses to (other) VEGF therapy, I am switching those patients to aflibercept to see if they achieve a greater response to that agent, which may have benefits over the current agents. The initial responses have been promising, but more time and patients are necessary to truly gauge the benefits. Q: Right. There hasn’t been a head-to-head trial yet. Dr. Heier: There has been a head-to-head trial comparing aflibercept with ranibizumab, as we discussed above. There have also been several trials comparing ranibizumab with bevacizumab. However, these trials have all been for treatment-naïve patients, not previously treated patients. Q: Is aflibercept on the Medicare formulary? Dr. Heier: Medicare in our region (region A) is covering it now. Q: Do you ever find yourself treating patients more frequently than every 4 weeks? Dr. Heier: Yes. I have a regimen for patients who are what I call suboptimal responders. Those are patients who either have increasing fluid and worsening vision (with treatment) or persistent fluid that does not really seem to be responding to anti-VEGF therapy. These patients typically are receiving ranibizumab, because I have a low threshold for switching from bevacizumab. Before aflibercept, I would switch them to ranibizumab. If the response was still suboptimal, I would try double-dose ranibizumab and bring them in at 2 weeks, rather than 4 weeks. By doubling the dose and shortening the interval, I should see an anatomic response. If I do not, then I assume that this is a patient who, for some reason, is not responsive to anti-VEGF agents. I look for other treatment alternatives, typically by first obtaining an indocyanine green angiography and then looking for choroidal neovascularization variants such as retinal angiomatous proliferation or polypoidal choroidal vasculopathy. If I do see a response (with the anti-VEGF agent), I bring the patient back 2 weeks later. Often, then, I will see that the fluid is back, and so that tells me that this is a patient who
S24
is anti-VEGF responsive but requires frequent therapy. In that patient, I may alternate ranibizumab and bevacizumab every 2 weeks, or I may treat them with double-dose ranibizumab every 4 weeks, or we try to find some other regimen that works for the patient. More recently, I have treated numerous suboptimal responders with aflibercept and have seen a significant anatomic response in many of them. To be fair, this is a relatively small subset, and over time it is very possible that we will see the reverse, with suboptimal aflibercept responders demonstrating a response to ranibizumab. However, my early impression of aflibercept in these hard-to-treat patients is a good one. Q: So it is very individualized treatment? Dr. Heier: Correct. Q: Have you noticed any characteristics of patients who tend to be unresponsive? Dr. Heier: I do look for characteristics, such as retinal angiomatous proliferation or polypoidal choroidal vasculopathy, that would explain poor responses. Some of the suboptimal responders are classified as sick retinal pigment epithelium syndrome, a disease with characteristics somewhat between exudative AMD and chronic central serous retinopathy. These patients in fact may have atypical central serous retinopathy, which is another disease that can be mistaken for exudative AMD but responds poorly to anti-VEGF agents. Q: That answers the question of when you would move to combination therapy, correct? Dr. Heier: Right. So, I have a suboptimal responder, we have done an indocyanine green angiography, and we found one of these variants that we think is amenable to combination therapy, which can be retinal angiomatous proliferation or polypoidal choroidal vasculopathy. Or we have seen what appears to be a typical occult or classic lesion that for some reason is not responding well or is requiring frequent therapy. For those patients, we consider combination therapy. My standard combination protocol is to isolate the area on an indocyanine green angiogram and to treat with reduced-fluence photodynamic therapy and intravitreal bevacizumab on the same visit. Then I bring the patient back 2 weeks later and gauge the response. Usually, we see a nice response, anatomically and, we hope, visually. In some patients, we see an improvement in the intraretinal fluid and an increase in the subretinal fluid. In those patients, we treat with an intravitreal steroid injection. So some patients require what has often been described as triple therapy. Q: When do you get to the point of putting patients into clinical trials? Dr. Heier: I may do that sooner than these other steps; it depends on the patient’s disease characteristics and what clinical trials are available. For instance, we have a trial right now that has a very strong anti-VEGF agent that is different from these (current) agents, so I would have a very low threshold for offering that trial to patients who are not responding to current agents. Q: Now you have 3 anti-VEGF options and there is so much coming down the pipeline. What does all this say to the community ophthalmologist? What is the ultimate message?
Heier 䡠 Individualizing Neovascular AMD Therapy Dr. Heier: It is outstanding that we have different agents to offer our patients. We are likely to have more in the future, not just anti-VEGF agents, but other agents as well. Although most patients respond to these agents—and most respond to all 3—there is still a small, but not in significant subset of patients who do not respond. So you need to treat patients as individuals. You need to recognize differences in patients, to know how to evaluate them, and to develop approaches to those patients who do not respond to best help them to achieve an adequate response. Acknowledgment. The author thanks Debra Gordon, MS, for writing and editing assistance, whose services were provided by Johns Hopkins in cooperation with ASiM. Responsibility for the content rests with the author.
2.
3.
4.
5.
References 6. 1. Regillo CD, Brown DM, Abraham P, et al. Randomized, double-masked, sham-controlled trial of ranibizumab for neo-
vascular age-related macular degeneration: PIER Study year 1. Am J Ophthalmol 2008;145:239 – 48. Abraham P, Yue H, Wilson L. Randomized, double-masked, sham-controlled trial of ranibizumab for neovascular agerelated macular degeneration: PIER study year 2. Am J Ophthalmol 2010;150:315–24, e311. Schmidt-Erfurth U, Eldem B, Guymer R, et al. Efficacy and safety of monthly versus quarterly ranibizumab treatment in neovascular age-related macular degeneration: the EXCITE study. Ophthalmology 2011;118:831–9. Lalwani GA, Rosenfeld PJ, Fung AE, et al. A variable-dosing regimen with intravitreal ranibizumab for neovascular agerelated macular degeneration: year 2 of the PrONTO Study. Am J Ophthalmol 2009;148:43–58, e41. Boyer DS, Heier JS, Brown DM, et al. A phase IIIb study to evaluate the safety of ranibizumab in subjects with neovascular age-related macular degeneration. Ophthalmology 2009; 116:1731–9. Heier JS, Brown DM, Chong V, et al. Intravitreal aflibercept (VEGF Trap-Eye) in wet age-related macular degeneration. Ophthalmology 2012;119:2537– 48.
Footnotes and Financial Disclosures Originally received: May 10, 2012. Final revision: January 8, 2013. Accepted: January 25, 2013.
Financial Disclosure(s): The author(s) have made the following disclosure(s):
tics, Paloma Pharmaceuticals, Pfizer, Inc., Regeneron Pharmaceuticals, Inc., and Sequenom, Inc.; Financial support - Alimera Sciences, Alcon Laboratories, Allergan, Inc., Genentech, Inc., Genzyme Corporation, GlaxoSmithKline, NeoVista, Inc., Notal Vision, Novartis Pharmaceuticals Corporation, Ophthotech Corporation, Paloma Pharmaceuticals, Pfizer, Inc., and Regeneron Pharmaceuticals, Inc. Supported by an educational grant from Regeneron Pharmaceuticals, Inc, Tarrytown, NY.
Jeffrey S. Heier - Consultant - Acucela, Alcon Laboratories, Allergan, Inc., ForSight Labs, Fovea Pharmaceuticals, Genentech, Inc., Genzyme Corporation, GlaxoSmithKline, NeoVista, Inc., Notal Vision, Oraya Therapeu-
Correspondence: Jeffrey S. Heier, MD, Ophthalmic Consultants of Boston, 50 Stanford Street, Suite 600, Boston, MA 02114. E-mail: [email protected].
Manuscript no. 2012-681.
Vitreoretinal Service, Ophthalmic Consultants of Boston, Boston, Massachusetts.
S25
Q: Although anti-VEGF provides the cornerstone of treatment today for patients with neovascular AMD, challenges remain, such as which anti-VEGF agent to choose, how often to treat the patient, how long to treat the patient, and how to manage nonoptimal or suboptimal responders. How do you address these issues? Dr. Heier: There are a number of factors. In general, the trend over the last several years has gone from treating less frequently to treating more frequently. When the antiVEGFs first came out, most of us thought we did not need to use them that often. But what we have learned, at least in many patients, is that as we try to treat less frequently, recurrences develop and, over time, the patients lose vision.1–3 As a result, many of us have moved toward more frequent therapy. What that means is that I will treat a patient and follow up him or her carefully, and if the patient is doing great, I might stretch out the treatment a little bit and go from, say, monthly therapy to every 5 to 6 weeks. And if the patient’s progress is really outstanding, I might try to stretch out the treatments a little bit more from that. This is along the lines of the treat-and-extend paradigm. Q: How do you decide which patients to do that with? Dr. Heier: There are several factors that help guide that decision. One is whether it is the patient’s first or second eye. Although vision in either eye is valuable, if vision in the first eye has been lost, typically to wet macular degeneration, vision in the second eye is even more critical. Because fellow eyes often mirror the path in the first eye, such loss also suggests that more intensive therapy may be necessary. So there I am more hesitant to stretch out therapy. If the patient’s eyes continue to demonstrate recur-
Statement of Potential Conflict of Interest and Funding/Support: See page S25. © 2013 by the American Academy of Ophthalmology Published by Elsevier Inc.
rence, eyes that are somewhat resistant to therapy—those are eyes that I tend to treat more frequently. We have also clearly learned that even when we want to spread out therapy, the closer we monitor those patients, the better they do. Studies have shown us that if you really want to come close to obtaining the results that are seen with monthly therapy, then at the very least you have got to follow them up carefully.4 And although there are some studies that say we can go to treat-and-extend or we can do this less frequently, in general, the best results are achieved with frequent injections and, at the very least, frequent monitoring.4,5 Q: Are you saying that we are not really going to see much of an improvement in terms of the burden frequent treatment puts on patients to come in and see you at least every month, even if you are able to go to 5 or 6 weeks between injections? Dr. Heier: Not exactly. There are patients who do well with extension of treatment intervals, but the more careful this extension is exercised (i.e., the more cautious the treatment interval is extended), the better patients typically do. Now, with aflibercept, what is encouraging is that the VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD program showed us that patients who were treated every other month with aflibercept after a 3-injection loading phase did just as well as patients treated monthly with either aflibercept or ranibizumab.6 So although those patients were followed up monthly in the first year, there were no treatment decisions based on those intervening visits; they were really done for the sake of masking. The VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD results suggest that many, if not most, patients treated with 2 mg aflibercept may do well with every-othermonth dosing (after a 3-injection loading phase). I have no doubt that there are patients who will require more frequent dosing, but these patients likely will declare themISSN 0161-6420/13/$–see front matter http://dx.doi.org/10.1016/j.ophtha.2013.01.059
S23
Ophthalmology Volume 120, Number 5, Supplement, May 2013 selves over the initial 3-injection loading phase or within the first few attempts at every-other-month dosing. Q: What drives the decision of which VEGF treatment to use? Dr. Heier: The major factors are cost, efficacy, safety, and treatment burden. Patients in whom cost is an issue— either they do not have insurance or they have a significant copay—are typically started on bevacizumab therapy. If they do well—and many, if not most, do—I continue this therapy with the knowledge that we are probably going to have more of a treatment burden but at a far reduced cost. Whenever I initiate therapy in patients for whom cost is not an issue, I always discuss the available agents and many patients elect to go straight to the United States Food and Drug Administration-approved agents. Until recently, that was only ranibizumab. With the approval of aflibercept, we now have a third option. The potential of reduced treatment while following a proven regimen is appealing and it is likely its use will increase. Others prefer ranibizumab because of its track record of safety and efficacy. In patients who have suboptimal responses to (other) VEGF therapy, I am switching those patients to aflibercept to see if they achieve a greater response to that agent, which may have benefits over the current agents. The initial responses have been promising, but more time and patients are necessary to truly gauge the benefits. Q: Right. There hasn’t been a head-to-head trial yet. Dr. Heier: There has been a head-to-head trial comparing aflibercept with ranibizumab, as we discussed above. There have also been several trials comparing ranibizumab with bevacizumab. However, these trials have all been for treatment-naïve patients, not previously treated patients. Q: Is aflibercept on the Medicare formulary? Dr. Heier: Medicare in our region (region A) is covering it now. Q: Do you ever find yourself treating patients more frequently than every 4 weeks? Dr. Heier: Yes. I have a regimen for patients who are what I call suboptimal responders. Those are patients who either have increasing fluid and worsening vision (with treatment) or persistent fluid that does not really seem to be responding to anti-VEGF therapy. These patients typically are receiving ranibizumab, because I have a low threshold for switching from bevacizumab. Before aflibercept, I would switch them to ranibizumab. If the response was still suboptimal, I would try double-dose ranibizumab and bring them in at 2 weeks, rather than 4 weeks. By doubling the dose and shortening the interval, I should see an anatomic response. If I do not, then I assume that this is a patient who, for some reason, is not responsive to anti-VEGF agents. I look for other treatment alternatives, typically by first obtaining an indocyanine green angiography and then looking for choroidal neovascularization variants such as retinal angiomatous proliferation or polypoidal choroidal vasculopathy. If I do see a response (with the anti-VEGF agent), I bring the patient back 2 weeks later. Often, then, I will see that the fluid is back, and so that tells me that this is a patient who
S24
is anti-VEGF responsive but requires frequent therapy. In that patient, I may alternate ranibizumab and bevacizumab every 2 weeks, or I may treat them with double-dose ranibizumab every 4 weeks, or we try to find some other regimen that works for the patient. More recently, I have treated numerous suboptimal responders with aflibercept and have seen a significant anatomic response in many of them. To be fair, this is a relatively small subset, and over time it is very possible that we will see the reverse, with suboptimal aflibercept responders demonstrating a response to ranibizumab. However, my early impression of aflibercept in these hard-to-treat patients is a good one. Q: So it is very individualized treatment? Dr. Heier: Correct. Q: Have you noticed any characteristics of patients who tend to be unresponsive? Dr. Heier: I do look for characteristics, such as retinal angiomatous proliferation or polypoidal choroidal vasculopathy, that would explain poor responses. Some of the suboptimal responders are classified as sick retinal pigment epithelium syndrome, a disease with characteristics somewhat between exudative AMD and chronic central serous retinopathy. These patients in fact may have atypical central serous retinopathy, which is another disease that can be mistaken for exudative AMD but responds poorly to anti-VEGF agents. Q: That answers the question of when you would move to combination therapy, correct? Dr. Heier: Right. So, I have a suboptimal responder, we have done an indocyanine green angiography, and we found one of these variants that we think is amenable to combination therapy, which can be retinal angiomatous proliferation or polypoidal choroidal vasculopathy. Or we have seen what appears to be a typical occult or classic lesion that for some reason is not responding well or is requiring frequent therapy. For those patients, we consider combination therapy. My standard combination protocol is to isolate the area on an indocyanine green angiogram and to treat with reduced-fluence photodynamic therapy and intravitreal bevacizumab on the same visit. Then I bring the patient back 2 weeks later and gauge the response. Usually, we see a nice response, anatomically and, we hope, visually. In some patients, we see an improvement in the intraretinal fluid and an increase in the subretinal fluid. In those patients, we treat with an intravitreal steroid injection. So some patients require what has often been described as triple therapy. Q: When do you get to the point of putting patients into clinical trials? Dr. Heier: I may do that sooner than these other steps; it depends on the patient’s disease characteristics and what clinical trials are available. For instance, we have a trial right now that has a very strong anti-VEGF agent that is different from these (current) agents, so I would have a very low threshold for offering that trial to patients who are not responding to current agents. Q: Now you have 3 anti-VEGF options and there is so much coming down the pipeline. What does all this say to the community ophthalmologist? What is the ultimate message?
Heier 䡠 Individualizing Neovascular AMD Therapy Dr. Heier: It is outstanding that we have different agents to offer our patients. We are likely to have more in the future, not just anti-VEGF agents, but other agents as well. Although most patients respond to these agents—and most respond to all 3—there is still a small, but not in significant subset of patients who do not respond. So you need to treat patients as individuals. You need to recognize differences in patients, to know how to evaluate them, and to develop approaches to those patients who do not respond to best help them to achieve an adequate response. Acknowledgment. The author thanks Debra Gordon, MS, for writing and editing assistance, whose services were provided by Johns Hopkins in cooperation with ASiM. Responsibility for the content rests with the author.
2.
3.
4.
5.
References 6. 1. Regillo CD, Brown DM, Abraham P, et al. Randomized, double-masked, sham-controlled trial of ranibizumab for neo-
vascular age-related macular degeneration: PIER Study year 1. Am J Ophthalmol 2008;145:239 – 48. Abraham P, Yue H, Wilson L. Randomized, double-masked, sham-controlled trial of ranibizumab for neovascular agerelated macular degeneration: PIER study year 2. Am J Ophthalmol 2010;150:315–24, e311. Schmidt-Erfurth U, Eldem B, Guymer R, et al. Efficacy and safety of monthly versus quarterly ranibizumab treatment in neovascular age-related macular degeneration: the EXCITE study. Ophthalmology 2011;118:831–9. Lalwani GA, Rosenfeld PJ, Fung AE, et al. A variable-dosing regimen with intravitreal ranibizumab for neovascular agerelated macular degeneration: year 2 of the PrONTO Study. Am J Ophthalmol 2009;148:43–58, e41. Boyer DS, Heier JS, Brown DM, et al. A phase IIIb study to evaluate the safety of ranibizumab in subjects with neovascular age-related macular degeneration. Ophthalmology 2009; 116:1731–9. Heier JS, Brown DM, Chong V, et al. Intravitreal aflibercept (VEGF Trap-Eye) in wet age-related macular degeneration. Ophthalmology 2012;119:2537– 48.
Footnotes and Financial Disclosures Originally received: May 10, 2012. Final revision: January 8, 2013. Accepted: January 25, 2013.
Financial Disclosure(s): The author(s) have made the following disclosure(s):
tics, Paloma Pharmaceuticals, Pfizer, Inc., Regeneron Pharmaceuticals, Inc., and Sequenom, Inc.; Financial support - Alimera Sciences, Alcon Laboratories, Allergan, Inc., Genentech, Inc., Genzyme Corporation, GlaxoSmithKline, NeoVista, Inc., Notal Vision, Novartis Pharmaceuticals Corporation, Ophthotech Corporation, Paloma Pharmaceuticals, Pfizer, Inc., and Regeneron Pharmaceuticals, Inc. Supported by an educational grant from Regeneron Pharmaceuticals, Inc, Tarrytown, NY.
Jeffrey S. Heier - Consultant - Acucela, Alcon Laboratories, Allergan, Inc., ForSight Labs, Fovea Pharmaceuticals, Genentech, Inc., Genzyme Corporation, GlaxoSmithKline, NeoVista, Inc., Notal Vision, Oraya Therapeu-
Correspondence: Jeffrey S. Heier, MD, Ophthalmic Consultants of Boston, 50 Stanford Street, Suite 600, Boston, MA 02114. E-mail: [email protected].
Manuscript no. 2012-681.
Vitreoretinal Service, Ophthalmic Consultants of Boston, Boston, Massachusetts.
S25