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Current Controversies in the Management of Neovascular Age-Related Macular Degeneration

Current Controversies in the Management of Neovascular Age-Related Macular Degeneration. Anthony B. Daniels, MD, MSc. Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts.

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Current Controversies in the Management of Neovascular Age-Related Macular Degeneration

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  1. Current Controversies in the Management of Neovascular Age-Related Macular Degeneration Anthony B. Daniels, MD, MSc Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts A REPORT FROM THE 2012 ANNUAL MEETING OF THE ASSOCIATION FOR RESEARCH IN VISION AND OPHTHALMOLOGY © 2012 Direct One Communications, Inc. All rights reserved. 1

  2. Anti-VEGF Therapy for Exudative AMD Intravitreal injections of the anti-vascular endothelial growth factor (VEGF) agent ranibizumab has become the standard of care in treating exudative age-related macular degeneration (AMD) based on two trials: • The Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization (CNV) in Age-Related Macular Degeneration (ANCHOR) trial1 • The Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular Age-Related Macular Degeneration (MARINA)2 © 2012 Direct One Communications, Inc. All rights reserved. 2

  3. Anti-VEGF Therapy for Exudative AMD • Before the introduction of ranibizumab, loss of visual acuity was the norm, with only a small fraction of affected patients regaining a significant amount of vision. • With monthly intravitreal injections of ranibizumab: • 95% of AMD patients maintained their initial visual acuity. • 34%–40% of patients actually gained 15 Early Treatment Diabetic Retinopathy Study (ETDRS) letters.1,2 © 2012 Direct One Communications, Inc. All rights reserved. 3

  4. Scrutiny of Anti-VEGF Dosing • As expectations rose, so did frustrations with the burden of monthly injections. • The focus of clinical trials shifted to alternative dosing regimens, either: • Less frequently (PIER study)3 • On an “as-needed” basis (PrONTO study)4 • With successive extension of the between-injection interval (“treat-and-extend” protocol)5,6 • Investigators sought new drugs that targeted VEGF apart from ranibizumab based primarily on a less-frequent dosing regimen. • Every-other-month dosing with aflibercept7,8 © 2012 Direct One Communications, Inc. All rights reserved. 4

  5. Importance of Costs • The cost of ongoing monthly treatment with ranibizumab became prohibitive for some patients. • Interest shifted to less expensive alternatives, culminating in the head-to-head trial of ranibizumab versus bevacizumab in the Comparison of Age-Related Macular Degeneration Treatment Trial (CATT).9 © 2012 Direct One Communications, Inc. All rights reserved. 5

  6. Further Goals of AMD Therapy • As we enter the second decade of the 21st century, clinicians and researchers have set their sights on the two thirds of patients who, despite treatment, never regain a significant amount (ie, > 3 lines) of vision. • The international retina community is still trying to determine the best dosing regimen that maximizes outcomes with a lower burden of patient visits and injections. • Despite the publication of the first-year CATT results this past year,9 it is still unclear how bevacizumab use compares with ranibizumab administration, especially when the drugs are given as needed. © 2012 Direct One Communications, Inc. All rights reserved. 6

  7. New Insights into AMD Therapy • Research studies presented at this year’s ARVO meeting focused primarily on: • The best schedule for administering ranibizumab therapy • The prediction and treatment of patients who do not respond to anti-VEGF therapy • The comparison of VEGF-inhibitor treatments under various dosing protocols • Now that anti-VEGF agents have been used clinically for several years, attention also is being paid to: • Their long-term safety • The initial dramatic gains seen in treated patients • Long-term outcomes © 2012 Direct One Communications, Inc. All rights reserved. 7

  8. CATT Update © 2012 Direct One Communications, Inc. All rights reserved. 8

  9. CATT Update: History and Rationale • During the delay awaiting FDA approval of ranibizumab following publication of the dramatic ANCHOR1 trial and MARINA2 data, clinicians began using another anti-VEGF agent, bevacizumab, off-label to treat neovascular AMD. • A head-to-head trial of bevacizumab and ranibizumab was conducted with funding from the National Institutes of Health because: • Results with use of bevacizumab appeared to be comparable to those found with ranibizumab therapy. • Bevacizumab was significantly less expensive than ranibizumab to use. © 2012 Direct One Communications, Inc. All rights reserved. 9

  10. CATT Update: One-Year Results • One-year (primary endpoint) outcomes of the CATT results showed that visual acuity was better in the ranibizumab group than in the bevacizumab group. • There was no statistically significant difference between the two (ie, bevacizumab use was noninferior to ranibizumab therapy) if they were given on a monthly dosing schedule.9 • The data did not allow investigators to determine whether as-needed dosing of bevacizumab was inferior or noninferior to as-needed ranibizumab injections or to monthly dosing of either drug. © 2012 Direct One Communications, Inc. All rights reserved. 10

  11. CATT Update: Persistent Questions • Would the results demonstrating the equivalence of monthly ranibizumab and bevacizumab (and of monthly and as-needed ranibizumab dosing) continue to hold true at the 2-year mark? • Is as-needed bevacizumab use comparable to as-needed (or monthly) ranibizumab therapy? • Would the apparently increased rate of adverse events experienced by the bevacizumab group during the first year continue to be found through the second year, or was this simply a statistical aberration? © 2012 Direct One Communications, Inc. All rights reserved. 11

  12. CATT Update: Two-Year Results • With regard to the questions of efficacy and safety, the 2-year CATT results10 demonstrated persistent equivalence of the two drugs from the 1-year time point through the 2-year mark. • Bevacizumab use remained noninferior to ranibizumab therapy in terms of visual acuity at the 2-year study point. • The rate of adverse events in the bevacizumab group (treated either monthly or as needed) remained higher than that in the ranibizumab group (treated either monthly or as needed). © 2012 Direct One Communications, Inc. All rights reserved. 12

  13. CATT Update: Two-Year Results • The rates of death or arterial thrombotic events that could be linked pathophysiologically to anti-VEGF treatment were comparable between the two treatment groups. • Because of the lack of specificity to conditions associated with VEGF inhibition, interpretation of the relationship between bevacizumab therapy and higher rates of serious adverse events is unclear. © 2012 Direct One Communications, Inc. All rights reserved. 13

  14. CATT Update: Two-Year Results • With regard to the effect of the dosing regimen on visual acuity outcome, a pooled analysis of the 2-year CATT results demonstrated that as-needed dosing with either ranibizumab or bevacizumab was statistically inferior to monthly dosing with either drug. • However, the CATT study was initiated in the days of time-domain optical coherence tomography (TD-OCT). • Treatment decisions were based upon a decrease in visual acuity and the presence of fluid on TD-OCT. © 2012 Direct One Communications, Inc. All rights reserved. 14

  15. CATT Update: Two-Year Results • More recent as-needed regimens have much stricter criteria for retreatment, including the presence of any fluid on spectral-domain OCT (SD-OCT). • It is not known how much small amounts of fluid not seen with TD-OCT affect visual outcomes. © 2012 Direct One Communications, Inc. All rights reserved. 15

  16. CATT Update: Retinal Morphology • The CATT investigators also attempted to correlate retinal morphology with visual acuity.11 • Patients who received ranibizumab had a greater reduction in central subfoveal thickness than did those who received bevacizumab, despite the equivalence in visual acuity outcomes. • Specifically, the investigators looked at: • The presence of fluid (either intraretinal fluid [IRF], subretinal fluid [SRF], or subretinal pigment epithelium fluid [SRPEF]) • The thickness of the central foveal region • How these variables correlated with visual acuity outcomes © 2012 Direct One Communications, Inc. All rights reserved. 16

  17. CATT Update: Retinal Morphology • All four treatment regimens (monthly or as-needed ranibizumab and monthly or as-needed bevacizumab) decreased the amount of IRF, SRF, and SRPEF and overall subfoveal thickness from baseline. • More eyes treated with ranibizumab than those injected with bevacizumab were free of any fluid at 52 weeks. • However, the majority of patients in all four treatment groups still had persistent fluid 1 year after starting therapy. © 2012 Direct One Communications, Inc. All rights reserved. 17

  18. CATT Update: Retinal Morphology • Patients receiving monthly ranibizumab had the lowest rate of persistent fluid (55%) when compared with the other three groups (74%–80%) • At every time point, eyes with residual IRF had worse visual acuities than did eyes without IRF. • The presence of SRF or SRPEF did not appear to affect visual acuity. • By 4 weeks after the first injection was given, retinal thickness decreased. • A greater decrease was seen with ranibizumab than with bevacizumab. • The greatest reduction in retinal thickness was noted among the group given monthly ranibizumab injections. © 2012 Direct One Communications, Inc. All rights reserved. 18

  19. Aflibercept © 2012 Direct One Communications, Inc. All rights reserved. 19

  20. Aflibercept: Background • Some of the ongoing concerns with ranibizumab therapy involve pharmacokinetics and duration of action, resulting in the need for monthly therapy as long as exudative lesions remain active. • Ophthalmologists were excited that the results of the VIEW 17 and VIEW 28 trials showed equivalency between every-other-month treatment with aflibercept, also known as VEGF Trap-Eye, and monthly ranibizumab administration. • This introduced the prospect of fewer injections for patients and fewer patient office visits for retina specialists. © 2012 Direct One Communications, Inc. All rights reserved. 20

  21. Aflibercept: Efficacy According to Subgroups • Ho et al12 presented a subgroup analysis of the efficacy of aflibercept for neovascular AMD as noted during the VIEW 1 and VIEW 2 trials. • In all, 2,457 patients were randomized to receive either: • Ranibizumab monthly • 0.5 mg of aflibercept monthly • 2 mg of aflibercept monthly • Aflibercept every other month • The main outcomes were the percentage of patients maintaining vision (ie, losing < 15 ETDRS letters) and the mean change in best-corrected visual acuity. © 2012 Direct One Communications, Inc. All rights reserved. 21

  22. Aflibercept: Efficacy According to Subgroups • Regardless of how the cohort was subdivided, results of a noninferiority analysis showed no statistical difference in outcomes among the four treatment groups. • Subgroups were divided based on several criteria: • Age • Initial visual acuity • Lesion type • Lesion size • Central retinal thickness • No subgroup was at a disadvantage by using any one of the treatment regimens. © 2012 Direct One Communications, Inc. All rights reserved. 22

  23. Aflibercept: Time to Change in Visual Acuity • In a separate study presented by Roth et al,13 the cohorts from the VIEW 1 and VIEW 2 studies were analyzed with regard to: • The time until a gain or loss of 15 letters occurred (simple event) • The time until a sustained gain or loss was noted (sustained event, defined as that degree of gain or loss over two consecutive visits). © 2012 Direct One Communications, Inc. All rights reserved. 23

  24. Aflibercept: Time to Change in Visual Acuity • Gain of vision occurred equally rapidly between groups. • There was no difference among the four treatment groups with regard to the time until sustained vision gain of > 5 letters, > 10 letters, or > 15 letters. • Time to a gain of > 5 letters was 12 weeks. • Time to a gain of > 10 letters was 28 weeks in all four groups. © 2012 Direct One Communications, Inc. All rights reserved. 24

  25. Ranibizumab Dosing andLong-Term Response © 2012 Direct One Communications, Inc. All rights reserved. 25

  26. As-Needed Maintenance Therapy • Rees and colleagues14 reported on their experience with long-term structural and functional outcomes after three loading doses of ranibizumab were given to patients with neovascular AMD. • Further treatment was given as needed. • Outcomes were visual acuity and the presence of SD-OCT image abnormalities after the initial three injections were given and at 12 and 24 months afterward. © 2012 Direct One Communications, Inc. All rights reserved. 26

  27. As-Needed Maintenance Therapy • After three injections: • 97.1% of patients maintained their vision (lost < 15 ETDRS letters). • 20% gained  15 ETDRS letters (mean gain from baseline, +6.2  10.9 letters). • At 12 months: • 88.6% of patients maintained visual acuity. • 31.4% gained 15 letters (mean gain, +6.9  17.6 letters). • At 24 months: • 88.6% maintained acuity. • 51.4% gained 15 letters (mean gain, +11.2  20.1 letters). © 2012 Direct One Communications, Inc. All rights reserved. 27

  28. As-Needed Maintenance Therapy • Macular fluid was present on SD-OCT in: • 93% of eyes at baseline • 66% of eyes after three injections • 69% of eyes at 12 months • 59% of eyes at 24 months • These results demonstrate that patients can continue to experience improvements in visual acuity for a long time after ranibizumab therapy is initiated. • The improvement in visual acuity seen early in the treatment course is not necessarily indicative of the maximal effect that may be expected, even when an as-needed dosing regimen is used. © 2012 Direct One Communications, Inc. All rights reserved. 28

  29. As-Needed Retreatment • Gaucher et al15 reported on their experience with as-needed retreatment using a series of three intravitreal ranibizumab injections. • Each patient received initial induction with three monthly doses of ranibizumab. • When signs of activity were present, patients then received as-needed dosing based on the PrONTO retreatment criteria.4 • Patients were retreated with ranibizumab when visual acuity decreased by at least five letters or when OCT showed signs of exudation. © 2012 Direct One Communications, Inc. All rights reserved. 29

  30. As-Needed Retreatment • At 2 years, patients made a mean of three office visits annually and received a mean of five injections annually. • Using this treatment paradigm, visual acuity stabilized in 65.6% of eyes and improved in 28.8% of eyes, with a relatively low burden of patient visits and injections. • There was no mean gain in visual acuity over the 2 years of this study (year 1, 53.18 letters; year 2, 54.18 letters). © 2012 Direct One Communications, Inc. All rights reserved. 30

  31. Retreatment with Sequential Injections • Ceklic et al16 used a variation of this as-needed protocol involving three sequential injections. • After dose induction with ranibizumab, patients were monitored monthly, including with OCT. • If signs of exudation were present, a series of three monthly injections of ranibizumab was given. • If the macula remained dry, the patient continued to receive ranibizumab injections quarterly. © 2012 Direct One Communications, Inc. All rights reserved. 31

  32. Retreatment with Sequential Injections • Using this modified protocol, in which patients who remained dry still received low-frequency injections of ranibizumab, mean best-corrected visual acuity improved by seven letters at 12 months and eight letters at both 24 and 36 months when compared with baseline. • These gains were achieved with a mean of 7.4, 12.1, and 16 injections at each time point, respectively. © 2012 Direct One Communications, Inc. All rights reserved. 32

  33. Worsening Neovascularization • Dyer et al17 initially gave their patients either ranibizumab or bevacizumab until there was no leakage on fluorescein angiography and/or no fluid was found on OCT. • Thereafter, maintenance therapy with 0.3 mg of pegaptanib was administered every 6 weeks. • Retreatment with ranibizumab was given for signs of worsening neovascularization at the investigator’s discretion. • Induction therapy to achieve a dry macula required a mean of 3.5  1.3 injections. © 2012 Direct One Communications, Inc. All rights reserved. 33

  34. Worsening Neovascularization • A mean of 11.4 ±  2.4 maintenance injections were given over 24 months. • 79% of patients maintained visual acuity. • 26% gained > 15 letters. • 40% required retreatment with ranibizumab for breakthrough activity despite pegaptanib maintenance therapy. • Because pegaptanib has the advantage of being more selective than other VEGF inhibitors for VEGF165, treatment with this drug theoretically may cause fewer arterial thrombotic adverse events; however, this has never been tested. © 2012 Direct One Communications, Inc. All rights reserved. 34

  35. Benefits of the Induction Phase • Most as-needed ranibizumab protocols currently being advocated begin with a mandated induction phase involving three monthly injections before the as-needed portion of the protocol is begun. • Kloeckener-Gruissem and colleagues18 evaluated: • The benefits of the induction phase in a retrospective analysis • The predictive value of the initial rise in visual acuity as it pertains to visual acuity 12 and 24 months later • The effect of polymorphisms in the gene for complement factor H (CFH) in regard to response to ranibizumab and final visual acuity © 2012 Direct One Communications, Inc. All rights reserved. 35

  36. Benefits of the Induction Phase • Eyes showing an initial gain in visual acuity tended to retain improvement over the course of the study period. • Patients who were homozygous for the rs1061170 single-nucleotide polymorphism at CFH were more likely to belong to the group of poor responders. • However, whether or not patients received an induction phase of three monthly injections of ranibizumab before beginning as-needed maintenance therapy did not affect their long-term visual acuity at either 12 or 24 months. © 2012 Direct One Communications, Inc. All rights reserved. 36

  37. Treatment-Naïve Subfoveal CNV • Suner et al19 presented first-year data from the HARBOR study, which evaluated the efficacy and safety of 2.0 mg versus 0.5 mg of ranibizumab given for treatment-naïve subfoveal CNV from AMD. • 1,097 patients were randomized to one of four different groups given ranibizumab: • 0.5 mg of ranibizumab dosed monthly • 0.5 mg given as needed (with monthly monitoring) • 2.0 mg dosed monthly • 2.0 mg given as needed • Three loading doses were given in the as-needed protocol arms. © 2012 Direct One Communications, Inc. All rights reserved. 37

  38. Treatment-Naïve Subfoveal CNV • All four groups experienced improved visual acuity at the 12-month primary endpoint. • 95% maintained their vision (range, 93.4%–97.8%). • About one third of all patients gained 15 letters. • Patients given 0.5 mg monthly gained a mean of 10.1 letters (mean, 11.3 injections). • The 2.0 mg monthly group gained +9.2 letters (mean, 11.2 injections). • The 0.5 mg as-needed group gained +8.2 letters (mean, 7.7 injections). • The 2.0 mg as-needed group gained +8.6 letters (mean, 6.9 injections). © 2012 Direct One Communications, Inc. All rights reserved. 38

  39. Treatment-Naïve Subfoveal CNV • In a pooled analysis, the as-needed protocols did not meet the noninferiority endpoints when compared with monthly dosing at either dosage (ie, as-needed therapy was inferior to monthly dosing), and 2.0 mg of the drug was not superior to 0.5-mg dosing. • Thus, monthly injections of 0.5 mg of ranibizumab appeared to be at the top of the curve for treatment-naïve neovascular AMD. • Increasing the dosage to 2.0 mg monthly added no further benefit. • As-needed dosing with monthly monitoring still resulted in clinically meaningful gains in visual acuity. © 2012 Direct One Communications, Inc. All rights reserved. 39

  40. Long-Term Ranibizumab Therapy • In the Seven-Year Observational Update (SEVEN UP) study, Bhisitkul and others20 presented the most long-term data available for neovascular AMD patients receiving ranibizumab. • All patients initially had been enrolled in the ANCHOR and MARINA registration trials and then participated in the HORIZON extension study, where they were randomized to receive long-term ranibizumab maintenance therapy. • These patients began receiving ranibizumab 7–8 years ago—longer than any other AMD study participants have been exposed to the drug. © 2012 Direct One Communications, Inc. All rights reserved. 40

  41. Long-Term Ranibizumab Therapy • The first cohort of patients was re-evaluated with a complete ophthalmologic examination, fundus photography, autofluorescence, fluorescein angiography, SD-OCT, and serum collection for genetic analysis. • The primary endpoint was the percentage of neovascular AMD patients with a visual acuity  20/70. Sixty-three patients were included in the analysis. © 2012 Direct One Communications, Inc. All rights reserved. 41

  42. Long-Term Ranibizumab Therapy The investigators found that: • 35% of patients had a visual acuity of  20/70. • 23% of patients had a visual acuity of  20/40. • 37% had a visual acuity of  20/200. • 27% of the original study eyes had active leakage at the time of the SEVEN UP study visit. • 54% of the eyes had recent CNV activity in the 6 months before the study visit. • 52% of the eyes needed some treatment for disease activity during the previous 6 months. © 2012 Direct One Communications, Inc. All rights reserved. 42

  43. Long-Term Ranibizumab Therapy In the interim: • 51% of patients had developed exudative AMD in the other eye • 6% of patients were now legally blind (visual acuity  20/200 in both eyes). © 2012 Direct One Communications, Inc. All rights reserved. 43

  44. Long-Term Ranibizumab Therapy • Since exiting the HORIZON study: • Only 25% of eyes required no interim ranibizumab injections because of either disease quiescence or therapeutic futility. • 25% of eyes required  11 injections. • Only a minority of study eyes had excellent visual outcomes. • The majority demonstrated ongoing disease activity and poor visual outcomes. • Therefore, clinical vigilance and prolonged treatment may be required for these patients. © 2012 Direct One Communications, Inc. All rights reserved. 44

  45. Predicting Response and the Problem of Nonresponders © 2012 Direct One Communications, Inc. All rights reserved. 45

  46. Predicting Response to Anti-VEGF Therapy • The majority of patients with neovascular AMD who are receiving anti-VEGF therapy maintain their pretreatment visual acuity—that is, they lose < 15 ETDRS letters when compared with their presenting visual acuity. • Only one third gain a significant amount of vision (usually defined as a gain of  15 ETDRS letters). • Because most patients do relatively well, attention has turned to predicting who will not benefit from anti-VEGF therapy alone and how best to approach the management of these patients. © 2012 Direct One Communications, Inc. All rights reserved. 46

  47. Lesion Characteristics • Caprani and colleagues21 described the baseline lesion characteristics of ranibizumab nonresponders. • In a retrospective analysis, all patients were treated with three monthly ranibizumab injections. • Outcomes at month 4 were evaluated. • Patients were divided into three groups: • Those gaining at least one line of vision (responders) • Those losing at least one line of vision (nonresponders) • Those staying within one line of the initial presenting visual acuity (stable group) © 2012 Direct One Communications, Inc. All rights reserved. 47

  48. Lesion Characteristics • Overall, patients in the responder group had significantly smaller lesions than did patients in the other two groups (P < 0.05). • The presence of intraretinal fluid at baseline, which correlated with poor visual acuity in other studies, did not predict a poor prognosis. • Initial presenting visual acuity likewise did not predict whether a patient would gain or lose vision on ranibizumab therapy. © 2012 Direct One Communications, Inc. All rights reserved. 48

  49. Maintaining a Good Response • In patients who initially responded to ranibizumab therapy, Saldanha and Blyth22 attempted to ascertain the likelihood of maintaining this good response over a long period. • Patients were categorized as full responders, partial responders, nonresponders, and those with structural damage based on visual acuity and OCT findings. • Patients were treated with three monthly doses of ranibizumab and then followed an as-needed dosing protocol. © 2012 Direct One Communications, Inc. All rights reserved. 49

  50. Maintaining a Good Response • A good response at 16 weeks was associated with continued positive outcomes at 52 and 104 weeks. • Of patients categorized as being full responders at 16 weeks, 73% remained full responders at 52 weeks and 63% remained full responders at 104 weeks. • Only 3% of patients were deemed nonresponders at 52 weeks. • By 104 weeeks, 7% of patients were deemed nonresponders. • Structural damage occurred in 12% of patients at 52 weeks and 17% of patients at 104 weeks. © 2012 Direct One Communications, Inc. All rights reserved. 50

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