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Intravitreal injections with anti-VEGF medications have been shown to improve vision in patients with neovascular age-related macular degeneration (nAMD) and have become the standard of care. Treatment with anti-VEGF injections has been shown in clinical trials to improve vision by 6 to 10 letters from baseline, but In contrast to pivotal studies, anti-VEGF intravitreal injections may be relegated to as-needed treatment after the initial loading phase. This activity focuses on the recent pivotal trials and reviews the most effective AMD treatment options.
Pre-1980 through 1990s
There has been a rapid revolution of treating nAMD the past few years. Prior to 1980, there was no effective treatment available and many natural history studies have shown rapid and progressive visual loss among nAMD patients during this time.1 Most patients were legally blind within a 2-year period. Between 1980-1990, benefits of thermal laser were realized, which while destructive did reduce the progression to vision loss in those patients who were studied.2,3 The Macular Photocoagulation study was the landmark study in this arena that showed a reduction in visual loss, albeit the treatment was thermally destructive and there was no visual improvement for these patients.
Early 2000s
In 2000, submacular surgery studies began to show a stability or preservation of vision, but not really an improvement of vision in those patients, especially in those with subfoveal neovascularization from AMD. Therefore, those results were less than ideal.
Several studies during the 1990s showed that photodynamic therapy (PDT) slowed the progression of the disease and when combined with Kenalog actually showed some additional benefits in reducing the progression, but did not have a significant proportion of patients who had a gain in vision.4-6
Mid-2000s to Present Day
From 2005 and onward, anti-VEGF treatments have been the mainstay of treatment for AMD. At this point, we are achieving significant improvements in vision from baseline, including a gain of 10 letters in some studies.7,8
The first treatment developed using a VEGF-neutralizing strategy was bevacizumab, approved by the FDA in 2004 for the treatment of colon cancer in combination with chemotherapy. Not long after, ophthalmologists began injecting bevacizumab directly into the vitreous cavity as an off-label use in the treatment of neovascular AMD because of its efficacy and minimal systemic adverse effects, which led to the first studies to demonstrate an improvement in visual function in patients with neovascular AMD (nAMD).9
If, ostensibly, the anti-VEGF era began in August 2005 with the first report of bevacizumab injection for wet AMD (”the shot heard around the world) by Dr. Phil Rosenfeld at the ASRS meeting in Toronto, we can see that the prevalence of AMD during that decade increased to more than 2 million cases by the year 2010.10
Starting with data from 2010, we can project the prevalence of AMD in the years 2030 and 2050, at which point the National Eye Institute predicts there will be more than 5 million US patients with AMD. Note: AMD is a disease of the Caucasian population.11
This image shows the current and emerging anti-VEGF agents, their format, molecular structure, molecular weight, and clinical dose used for treating wet AMD. Note the large size of bevacizumab and aflibercept. It was once hypothesized that large molecules, if delivered intravitreally, would not be able to penetrate the retina to treat choroidal neovascularization (CNV). Clearly that theory has been disproven and both bevacizumab and aflibercept are effective agents in treating wet AMD. Also note the small molecular weight of brolucizumab. This allows a high dose to be delivered. Finally, abicipar is a DARPin platform that is distinct from the other agents. DARPin molecules are a novel class of binding proteins with the potential to overcome some limitations of antibody-based therapeutics. DARPin molecules are small, highly stable proteins that contain engineered ankyrin repeat domain(s) and can be selected to bind any given target protein with high specificity and affinity.12-20
The studies listed in this image highlight all of the anti-VEGF dosing paradigms investigated in large, randomized clinical trials. It is important to note that monthly dosing is still the best AMD treatment21,5,6 and all other treatments are compared to this standard of care. Furthermore, no subsequent dosing paradigm has been found to be superior to monthly dosing. All paradigms have been tested in clinical trials with a primary endpoint of noninferiority.
While monthly dosing is believed to produce the best VA results in wet AMD patients over 1 and 2 years in large clinical trials, it has been felt that monthly dosing is not realistically possible to execute for patients in the real world.22,23 Thus, the various dosing approaches have been aimed at reducing the treatment burden while maintaining VA gains: bimonthly with aflibercept, PRN, and treat and extend with all currently available anti-VEGF agents.
The newest anti-VEGF to receive FDA approval is brolucizumab. According to the package insert, the recommended dose for brolucizumab is 6 mg (0.05 mL of 120 mg/mL solution) administered by intravitreal injection monthly (approximately every 25 to 31 days) for the first three doses, followed by 6 mg (0.05 mL) by intravitreal injection once every 8 to 12 weeks24 may help stretch the treatment interval. In two head-to-head clinical trials, brolucizumab was noninferior to aflibercept in visual function at week 48, and more than 50% of brolucizumab 6 mg-treated eyes were maintained on an every-12-week dosing interval through week 48. Anatomic outcomes favored brolucizumab over aflibercept. Overall safety with brolucizumab was similar to aflibercept (ClinicalTrials.gov; NCT02307682, NCT02434328).25
Outlined by Lanzetta and Lowenstein, the pillars of optimal treatment include early diagnosis; initiation of treatment using the loading dose; titrating treatment intervals; and sustained therapy. All of these have been validated in other studies where they’ve shown that early diagnosis leads to the better visual outcomes.26 Patients who present with better vision at earlier times have better outcomes than those who have worse vision at the first visit. The LUMINOUS study showed that loading doses matter be cause it has a 4 or 5 letter VA benefit over those patients who did not have a loading dose.27 Next is to titrate to the patient’s needs. The personalization of anti-VEGF has been important because we see a wide variety of treatment intervals for patients. And lastly that sustained proactive approaches have led to long-term visual outcome.26
Aflibercept, bevacizumab, and ranibizumab, are the most studied medications used to treat nAMD, even though bevacizumab is used off label.
The initial treatment trials of aflibercept and ranibizumab were conducted with a very fixed dosing paradigm. Based on FDA trial results, ranibizumab is typically used monthly, after three monthly loading doses either less than monthly or quarterly.6,21
Aflibercept is most effective either monthly or bimonthly, after 3 monthly loading doses and is also approved quarterly at year 2.28
In contrast to a fixed dosing regimen, the HARBOR trial introduced as needed (PRN) treatment and found equivalent outcomes. And they use SD-OCT to monitor those outcomes.
The study included 1,098 patients who were at least age 50 years with treatment-naïve subfoveal wet AMD. At month 24, the mean change from baseline in BCVA was (letters) +9.1 (0.5 mg monthly), +7.9 (0.5 mg PRN), +8.0 (2.0 mg monthly), and +7.6 (2.0 mg PRN). The change in mean BCVA from month 12 to 24 was (letters) -1.0, -0.3, -1.2, and -1.0, respectively. The proportion of patients who gained 15 letters from baseline in BCVA at month 24 was 34.5%, 33.1%, 37.6%, and 34.8%, respectively. The mean number of ranibizumab injections through month 24 was 21.4, 13.3, 21.6, and 11.2, respectively; 5.6 and 4.3 mean injections were required in year 2 in the 0.5 mg and 2.0 mg PRN groups, respectively. The average treatment interval in the 0.5 mg PRN group was 9.9 weeks after 3 monthly loading doses, and 93% of these patients did not require monthly dosing.
Results of the HARBOR trial revealed that monthly monitoring, but less than monthly injections of ranibizumab can be effective. However, many patients can do well with PRN treatment and results overall using SD OCT guidance such as in the HARBOR study were relatively good. But to achieve these results, monthly office visits and testing is necessary, but not practical in real-world settings.
Results of the HARBOR trial revealed that monthly monitoring, but less than monthly injections of ranibizumab can be effective. However, many patients can do well with PRN treatment and results overall using SD-OCT guidance, such as in the HARBOR study, were relatively good. But to achieve these results, monthly office visits and testing is necessary, but not practical in real-world settings.
Based on results of the ANCHOR, MARINA and HARBOR trials, there is a high interpatient variability in treatment frequency, suggesting a need for personalized treatment regimens.
For example, in the HARBOR trial, the total number of injections ranged from 3 to 24 per patient over 2 years (n=237).29
In a trial by Mantel and colleagues, the investigators found that retreatment intervals ranged from ~ 4 to 14 weeks in study eyes with at least two measured intervals (n=31). This prospective study enrolled 39 patients with treatment-naïve nAMD. After three loading doses of intravitreal ranibizumab, patients underwent an intensified follow-up for 12 months (initially weekly, then with stepwise increases to every 2 weeks and to monthly after each injection).30
A mean of 7.5 injections (range 0-12) were given between months 3 and 15. The mean visual acuity increased by 13.1 and 12.6 ETDRS letters at months 12 and 15 respectively. Two or more injection-retreatment intervals were found in 31 patients. The variability of their intra-individual intervals up to 14 weeks was small (SD 0-2.13 weeks), revealing a high regularity of the retreatment rhythm. The SD was correlated with the mean interval duration (r = .89, P < .001). The first interval was a good predictor of the following intervals (regression coefficient =0.81).
A proactive treat-and-extend (T&E) regimen aims to personalize treatment by finding the optimum treatment interval for each patient. Proactive treatment regimen begins with three loading doses. If the OCT shows stability or there is no fluid on the OCT, the interval between the injections is gradually extended and then the idea is to reach a steady interval of time by which you cannot extend the injections further. Therefore you keep the patient at extended T&E intervals for that period of treatment.31,26
This phase 3b, multicenter, randomized, controlled clinical trial was designed to assess prospectively a treat-and-extend (TREX) management strategy compared with monthly dosing of ranibizumab in 60 treatment-naïve nAMD patients. The main outcome measure was the change in ETDRS BCVA from baseline.32
A total of 60 patients with ETDRS best-corrected visual acuity (BCVA) from 20/32 to 20/500 (Snellen equivalent) were randomized to receive intravitreal 0.5 mg ranibizumab monthly or according to a TREX protocol. The TREX patients were treated monthly for at least three doses, until resolution of clinical and spectral-domain optical coherence tomography evidence of exudative disease activity; the interval between visits then was individualized according to a strict prospective protocol.
At baseline, mean age was 77 years mean BCVA was 20/60 (Snellen equivalent), and mean central retinal thickness (CRT) was 511 μm. Fifty-seven eyes of 60 completed month 12, at which point mean BCVA improved by 9.2 and 10.5 letters in the monthly and TREX cohorts, respectively (P = .60). The mean number of injections administered through month 12 was 13.0 and 10.1 (range, 7-13) in the monthly and TREX cohorts, respectively (P <.0001).
Among TREX patients, seven were maximally extended, four demonstrated fluid at every visit, and at month 12, 18 had achieved an extension interval of 8 weeks or more; the mean maximum extension interval between injections after the first three monthly doses was 8.4 weeks (range, 4-12 weeks). Most TREX patients who demonstrated recurrent exudative disease activity (17/24 [71%]) were unable to extend beyond their initial maximum extension interval.32
In the 2-year results of the TREX-AMD Study confirmed the original trial.33
In the 2-year follow up study, 50 of the original 60 patients completed month 24, at which point mean ETDRS BCVA letter gains were similar: 10.5 and 8.7 for the monthly and TREX cohorts, respectively (P = .64). At month 24, four patients and 12 patients in the monthly and TREX cohorts, respectively, gained at least 15 letters (P = .41). No monthly cohort patient lost more than 2 letters, whereas five TREX cohort patients lost at least 15 letters.33
The key to understanding the TREX study in AMD is that 10 injections were given in the first year, so there was not a significant reduction in injection number/treatment burden the first year.
Among TREX patients completing month 24, 14 patients were at an extension interval of 8 weeks or more, and the mean maximum tolerated extension was 8.5 weeks over the course of 2 years. Of the 26 TREX patients (65%) who demonstrated recurrent exudation upon interval extension, the first maximum extension interval was consistent in most eyes (n = 19 [73%]).33
The mean maximal extension interval was about 2 months, which is typically what is seen for most anti-VEGF agents in the real world.34
A Japanese study by Hanemoto and colleagues published in 2017 included not only patients but their caregivers to gain insight into the comprehensive treatment burden. The investigators found that treating patients with wet AMD with anti-VEGF agents following a T&E regimen reduced hospital visits compared with a PRN regimen, where associated monitoring visits were necessary to provide good patient outcomes. T&E was associated with a reduction trend in caregiver burden, including time and costs.
For patients with nAMD, T&E was associated with almost half the number of hospital visits and estimated annual productivity loss by caregivers in year 1 compared with PRN. Of the 91 eyes (71 patients), 89.0% (81 eyes) received aflibercept, 7.7% (seven eyes) received ranibizumab and 3.3% (three eyes) received aflibercept/ranibizumab.
Seventy-one patient-caregiver pairs were included in the study. Most caregivers were female (74.6%), spouse/partner (54.9%), employed (46.5%), and the primary caregiver (85.9%). Patients received anti-VEGF treatment as follows: T&E (n = 42), switch (PRN to T&E; n = 18), PRN (n = 10), and other (n = 1). Caregiver-related burden (total Burden Index of Caregivers [BIC-11] scores) were 4.29 (T&E) 4.60 (PRN), and 5.33 (switch) (P = NS).35
The LUMINOUS study revealed that loading doses matter because it has a 4- or 5- letter VA benefit over those patients who did not have a loading dose.36,27
The retrospective Fixed Dosing (FIDO) study enrolled patients from a single US practice dosed with ranibizumab every 4 to 8 weeks for up to 7 years to report on long-term visual outcomes in patients receiving continuous fixed-interval dosing.37
This is a proactive treatment approach, which is likely not reproducible in real-world settings, but does provide some long-term data indicating that it’s most effective to treat patients for the long term and treat them on a semi or a regular basis with a high frequency of injections.
The study included 109 eyes (89 patients) with exudative AMD. The treatment regimen was continuous fixed-interval dosing (every 4 to 8 weeks) of ranibizumab, bevacizumab, or aflibercept for at least 5 years. Eyes were excluded if they averaged fewer than 6.5 injections per year. The primary outcome measure was mean change in letter score at 5, 6, and 7 years; secondary outcomes included the percentage of patients with 20/40 vision or better at 7 years and the mean change in letter score at each yearly time point based on baseline visual grouping (20/40 or better, 20/50-20/100, 20/200 or worse).
Forty-four, 75, and 109 patients with 7, 6, and 5 years, respectively, of continuous treatment were identified. Mean change in letter score at year 5 was +14.0 letters (P = 3.9 × 10(-9)), +12.2 letters at 6 years (P = 1.5 × 10(-7)), and +12.1 letters at 7 years (P = 3.8 × 10(-5)). Driving vision (20/40 or better) was achieved in 43.2% of treated eyes.37
A FIDO subanalysis revealed that the greatest visual gains at 5 and 7 years were seen in those patients with baseline VA worse than 20/200 (+24.5 and +25.5 letters), followed by those with 20/50 to 20/100 vision (+6.7 and +6.9 letters), and finally those with 20/20 to 20/40 (+3.7 and +3.4 letters). Patients received an average of 10.5 injections per year.
The graph shows the mean (±standard error) and median change in ETDRS letter score at baseline and subsequent yearly time points for our cohort of patients who received continuous fixed-interval dosing (between 4 and 8 weeks).
Peden and colleagues concluded that continuous fixed-interval dosing of anti-VEGF therapy in patients with exudative AMD results in favorable long-term preservation out to 7 years, with vision stabilizing or improving in 93.2% of eyes. Additionally, 43.2% of patients maintained driving vision in the treatment eye at 7 years compared with 10.1% at baseline. This data suggest better outcomes with continuous therapy over published results with sporadic, as-needed therapy.37
A 2018 review study by Singh and colleagues summarized the findings of long-term outcomes of anti-VEGF therapy (at least 3 years) in patients with exudative AMD. The study looked at the relationship between the studies and the frequency of injections and the mean VA in studies lasting longer than 5 years.38
-OS: Dry AMD with pigment alterations of the RPE.
-VA 20/20
-6 months later, new onset wet AMD OS
-VA 20/20
-Anti-VEGF therapy initiated with monthly loading doses
-Does well with anti-VEGF injections and is extended to Q 12 weeks
-13 months later, worsening SRF
-VA remains 20/20
-Injection interval intensified to Q 8 weeks
-With intensified treatment interval of Q 8 weeks, lesion responds
-Less SRF, but still persists
-VA 20/20
-12 months follow-up
-Despite continued Q 8 week anti-VEGF injections, SRF persists
-Maintains good of VA 20/30
-Consideration given to Q 4 week dosing, but patient reluctant
Case Discussion
-Are 3 monthly loading doses necessary?
-Is the goal of treatment to control disease with q12 week dosing?
-Is q16 week dosing possible in AMD?
-If SRF is stable and vision is good, should the treatment interval be maintained? Or should “treat to dry” be a guiding principle.
-When SRF worsens, should the interval shorten by 2 weeks, 4 weeks, or go back to q4 week dosing? Does the VA matter?
-When should the anti-VEGF agent be switched as opposed to reducing the treatment interval?
Presentation 15 October 2015
-84 y/o female presents with new distortion and worsening vision in her left eye
-Medical History: HTN, Heart Disease, Carotid Artery Occlusion without CVA, Hypercholesterolemia, Osteoporosis
-Ophthalmic History: CE/IOL OU Remotely
-Prior Ocular Treatments: None
Baseline 15 October 2015
-VA: 20/25 OD, 20/32- OS
-Tp: 16 OD 17 OS
-Lens: PCIOL OU
-Treatment: Plan SF-PDT OS
Follow-Up 23 November 2015
-VA: 20/25 OD, 20/25 OS
-Tp: 16 OD 17 OS
-Lens: PCIOL OU
-Observation: Less Distortion
-Treatment: Observe
Follow-Up 16 January 2016
-VA: 20/25 OD, 20/25-2 OS
-Tp: 15 OD 17 OS
-Lens: PCIOL OU
-Observation: Recurrent Distortion
-Treatment: Ranibizumab + Plan SF-PDT #2 11 February 2016
Follow-Up 10 July 2017
-VA: 20/25+ OD, 20/32- OS
-Tp: 19 OD 21 OS
-Lens: PCIOL OU
-Observation: “The wave is back”
-Treatment: Plan ranibizumab #2 + PDT #3
Follow-Up 05 February 2018
-VA: 20/25-1 OD, 20/32-2 OS
-Tp: 13 OD 15 OS
-Lens: PCIOL OU
-Observation: Recurrent Distortion
-Treatment: ranibizumab #4
Follow-Up 02 May 2018
-VA: 20/25-1 OD, 20/25-2 OS
-Tp: 14 OD 16 OS
-Lens: PCIOL OU
-Observation: Good vision again
-Treatment: Observe
Follow-Up 07 February 2019
-VA: 20/25- OD, 20/25- OS
-Tp: 13 OD 15 OS
-Lens: PCIOL OU
-Observation: Decrease in visual quality
-Treatment: Ranibizumab #5
Follow-Up 06 May 2019
-VA: 20/25 OD, 20/25 OS
-Tp: 11 OD 14 OS
-Lens: PCIOL OU
-Observation: Improved vision
-Treatment: Observe
Follow-Up 29 August 2019
-VA: 20/32- OD, 20/32 OS
-Tp: 13 OD 15 OS
-Lens: PCIOL OU
-Observation: Unchanged vision
-Treatment: Observe
Case Discussion
-Are retinal angiomatous proliferation (RAP) lesions something that you characterize at diagnosis?
-Is it reasonable to treat RAP lesions with PDT?
-Is PRN treatment reasonable in RAP lesions?
-Is the GA in this case due to disease progression? PDT? Anti-VEGF? Or a little bit of everything?
-RAP lesions usually show intraretinal fluid more so than subretinal fluid. Do you think this affects the prognosis?
Based on the varying response rates and longevity to treatment seen in the trial results and case discussions presented here, an individualized treatment approach appears necessary for optimal patient outcomes. In addition, ongoing research is needed to evaluate novel therapies, injection dosing options, and the impact of residual fluid.
The graph shows on the bottom left that the PACORES39 and CATT40 studies had very low frequency of injections, but also a loss of vision over the course of a 5-year period. In contrast, the studies shown on the far right of the graph, the HORIZON, RANGE and PEDEN studies, had a very high level of VA in the trials, but also a heavy treatment burden.