Age-Related Macular DegenerationóDetermining Appropriate Use of Treatments: A Stakeholder Summit


Clinical Background of Wet Age-Related Macular Degeneration
The difference between dry and wet AMD can be confusing, Wykoff acknowledged. “Everybody with macular degeneration has dry macular degeneration. That’s sort of a baseline mild or intermediate form, and then if you develop the advanced form, you either develop wet macular degeneration with bleeding, or advanced dry. It’s unfortunate that the early and the advanced forms can both be called dry,” he said. One classification system used to characterize AMD is taken from the Age-related Eye Disease Study (AREDS), which classifies AMD stages as: 1) no AMD; 2) early AMD; 3) intermediate AMD; and 4) advanced AMD (Table 1).1

A second way to classify AMD is a more broad approach, dependent on abnormal neovascularization.2 Wet AMD refers to the presence of bleeding in the back of the eye, which ultimately destroys the central retina. The majority of cases of AMD are considered of the atrophic variety. However, the neovascular subtype, or wet AMD, while only affecting 10% to 20% of patients with AMD, is responsible for approximately 90% of AMD-related severe vision loss.3

In developed countries, age-related AMD is among the leading causes of severe and irreversible visual impairment.1,3-5 Often overshadowed by the impact of diabetes on vision loss in working-age individuals, AMD takes over as the leading cause of blindness after the age of 55 years.3,6 In fact, the prevalence skyrockets in people aged more than 80 years; it affects an estimated 1 in 10 individuals. Salgo noted that although AMD is “a massive problem…I’m not sure…that a lot of primary care docs are aware of it.” Nielsen agreed. “I think it does not have the same recognition outside of ophthalmology that certainly we see on a daily basis with our patients,” he said. “By 2050, there will be [an estimated] 80 million people worldwide affected by this disorder, and that’s staggering.”

The earliest symptom people usually notice of AMD is light/dark disassociation. That means problems, Wykoff explained, “if you go from a bright area outside, or a brightly lit room, into a darker room—the classic example is going [from outside] into a restaurant. People just won’t be able to adapt to darker settings as quickly as others. That’s the most common symptom if you look across all types of AMD,” he continued. “That mostly represents the early mild or intermediate forms of dry AMD. But then when you get into significant visual acuity loss, you’re talking about either bleeding in the back of the eye, which is wet macular degeneration, or geographic atrophy, which is death of the central macula.”

Given the size of the aging US population combined with improved longevity, the prospect of an increasing elderly population with blindness carries with it a severe economic burden, not only for the individuals affected, but society as a whole.4 “As you can imagine, patients who suffer with loss of central vision can’t drive, can’t do many of the things that they like to do, and it really affects their quality of life,” said Nielsen. “Unfortunately, the person who suffers from AMD isn’t the only victim of this disease. It affects caregivers and families who then have to step in and help somebody who’s lost their independence and ability to take care of themselves.”

In terms of overall cost to the healthcare system, visual disorders rank seventh among all diseases, placing it in front of stroke, diabetes, coronary heart disease, and depression in Australia.5 Unfortunately, similar data for the United States is lacking. In 2014, the economic burden of eye disorders among the US population was estimated to be $145 billion per year, and by 2050, the cost is expected to rise to $717 billion.7 Nielsen noted that the “economic burden of someone who’s visually impaired is staggering. And if we can [diagnose] somebody early and keep them productive, keep them working in the job that they want to continue to work in, that has a huge societal benefit.” With the drive toward better management of scarce healthcare resources and cost containment efforts, a further examination of AMD, along with its current and future treatment options, is warranted.

While 80% of AMD patients have atrophic, or dry, AMD, 90% of severe AMD-related loss of visual acuity is related to wet AMD, caused by neovascularization.1 Landmark advances involving trials of intravitreal injections of compounds that inhibit vascular endothelial growth factor (VEGF) have been shown to impact the pathophysiology of neovascularization.4 The results from these early treatments of wet AMD were remarkable, altering the course of a disease once believed incurable.4 Since that time, further advances in diagnostics, earlier detection, and monitoring have been made, and new drugs in varying stages of development have been steadily introduced into the pipeline. However, while the improvements in visual acuity that were achieved during clinical trials with anti-VEGF drugs were substantial, they have also been difficult to fully replicate in typical practice settings.4,8 “If we look at the results of these phase 3 trials, they’re spectacular,” Nielsen confirmed. “We have a cure for neovascular or wet AMD, but when we look at what happens in the real world, when we look at a very influential paper in our field that was published looking at what happened in Europe, patients just don’t have the outcomes [in the real world] that they do in these clinical trials. The main underlying reason is that they don’t get treated enough. It’s tough for family members [and] for patients to come on a regular basis, to have these treatments in the eyes.”

Indeed, studies have shown that the inability to achieve the outcomes seen in clinical trials can be attributed to the frequency of the treatment regimens, which often require monthly intravitreal injections for extended periods of time.9 Long-term follow-up studies have also identified the need for additional research and development, sparked by a large percentage of patients who lost the early gains they made in visual acuity.

Risk Factors
AMD predominantly affects Caucasians and Asians; they have a higher risk profile than individuals of African or Hispanic descent.1 Other risk factors include increasing age, dietary fat intake, and family history.1 Smoking is an environmental risk factor that has been consistently shown in studies to be linked to AMD.1 It is remarkable, Salgo noted, that for AMD and “disease after disease after disease, you come up with the same basic prevention recommendations: They’re all the cardiovascular risk prevention strategies, which are watch your LDL [low-density lipoprotein cholesterol], watch your smoking, watch your hypertension, all of that stuff. It applies to the eyes, too.”

Treatment
Management of AMD focuses on treating patients with choroidal neovascularization, or wet AMD; to date, no therapy exists to treat dry AMD.2 AREDS and AREDS2 (the same research group’s second study to improve the original AREDS formulation) were designed to test benefits of antioxidant vitamins and minerals in patients with intermediate or advanced AMD in at least 1 eye to slow the progression to wet AMD.1 Both are prospective, randomized controlled trials, and both studies determined that supplementation with antioxidant vitamins and minerals should be considered for patients with AMD.1 AREDS showed that the effects on AMD were most pronounced in patients who received antioxidant vitamins with both zinc and copper; the benefits were a 19% reduction in the risk of losing vision (3 or more lines) and a 25% reduction in progressing to advanced AMD.1 AREDS2 further refined the recommended regimen; its results demonstrated the benefit of replacing beta-carotene with lutein and zeaxanthin. In other study results, in other populations, beta-carotene has been associated with a decrease in the absorption of nutrients and higher incidence of lung cancer. AREDS2 also showed the noninferiority of reducing the amount of zinc from the original formulation and the lack of benefit from the addition of 2 supplemental omega-3 fatty acids, docosahexaenoic and eicosapentaenoic acids.1

However, Wykoff cautioned that the decision whether to treat AMD with vitamins comes with caveats. “The challenge is that not all people at risk of AMD should be on the vitamins,” he said. “It’s a relatively small [percentage] of our entire global population who should be on them, so don’t put everybody on vitamins just because they’re at the age where they could have macular degeneration. You [still have] to get the dilated eye exam. Every year, all adults over 50 should at least get 1 exam.”

According to retina specialist Nielsen, his primary goal for wet AMD patients is to try to get the lesions to dry out as quickly as possible, for the disease to become as inactive as possible, and to try to administer the least number of treatments possible. The patients’ treatment options include laser photocoagulation, photodynamic therapy, surgery, and the current standard of care, pharmacologic treatment with anti-angiogenic drugs, which are anti-VEGF agents.2

Intravitreal Injections of Anti-VEGF
The anti-angiogenic drugs are VEGF-blocking agents, injected intravitreally. VEGF proteins selectively bind their native vascular endothelial cell surface receptors and activate cell signaling pathways, which induce angiogenesis, and increase vascular permeability and inflammation. Anti-VEGF agents are designed to inhibit the activation of VEGF receptor–mediated downstream effects, which, untreated, contribute to the pathogenesis of wet AMD. Patients may be fearful at first that the treatment involves an injection into the eye.2 “I tell patients, look, it’s a teeny needle,” Wykoff explained, “It’s hard to [even] see [it] without a microscope. It goes into the white part of the eye and it really doesn’t hurt. And that’s true for the vast majority of patients.”
This era of AMD treatment began in 2004 with the approval of pegaptanib, the first anti-VEGF drug approved for wet AMD.10 Pegaptanib is a 28-base ribonucleic acid aptamer, a pegylated modified oligonucleotide, that binds to extracellular VEGF 165, thus inhibiting VEGF165 from binding to VEGF receptors.11 As an aptamer, pegaptanib is less immunogenic than other anti-VEGF drugs currently available. Unfortunately, aptamers also have a weaker binding affinity than antibodies do, resulting in shorter physical and functional half-lives.10 Later, other anti-VEGF drugs were developed and recognized as having superior efficacy (although no head-to-head studies are available), so pegaptanib did not remain the standard of care for very long.10

Long-Term Efficacy of Anti-VEGF Treatments
Both the CATT Follow-up Study and the VIEW 1 Extension Study were long-term efficacy studies, which provided insight into the safety and efficacy of anti-VEGF treatment for the management of wet AMD. (CATT stands for Comparison of Age-related Macular Degeneration Treatments Trials; VIEW for VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD.)
The CATT Follow-up Study investigated long-term clinical outcomes in 647 patients with AMD treated with either ranibizumab or bevacizumab in the initial CATT study. To enroll in this follow-up investigation, patients must have had visual acuity measurement within 4.3 years to 7.1 years following assignment of study treatment in CATT. After a mean follow-up of 5.5 years, 91.3% of patients enrolled in the first CATT study had continued receiving care at a CATT center after release from trial protocol. However, the majority of patients (60%) were receiving a different treatment than their assigned study drug.12,13

Over the 5 years of follow-up after the initial CATT study, 50% of patients had visual acuity of 20/40 or better. From baseline to 2 years’ follow-up, only 5% to 6% of patients had visual acuity of 20/200 or worse. However, the improvements in visual acuity achieved at 2 years’ follow-up from baseline were not sustained; 20% of patients had visual acuity of 20/200 or worse by the CATT Follow-up Study visit. At the CATT Follow-up Study visit, results indicated that patients experienced declines in visual acuity from baseline by a mean of 3.3 letters (ie, Early Treatment Diabetic Retinopathy Study chart letters), and declined by 11 letters from 2 years.12 Ranibizumab treatment was associated with significant declines in visual acuity, compared with bevacizumab; ranibizumab-treated patients lost 4 letters more than did bevacizumab-treated patients at the CATT Follow-up Visit at year 5 following the original 2-year assessment (–12.7 letters vs –8.8 letters, respectively; P = .008).

Among patients originally assigned to ranibizumab, 7.6% experienced an arteriothrombotic event, compared with 4.5% of patients originally assigned to bevacizumab (P = .04). Otherwise, there were no statistically significant differences found in serious safety events among the drug and dosing regimen groups.13 From the results of this long-term study, investigators concluded that there is an unmet need for better therapeutic options as the mean visual acuity loss with ranibizumab worsened from baseline by 3 letters. Because half of patients achieved visual acuity of 50% or better, these results indicate that anti-VEGF therapy serves as a beneficial treatment to maintain vision in patients with wet AMD.

The VIEW 1 Extension Study evaluated long-term maintenance of visual acuity improvements with aflibercept treatment over approximately 4 years. In this extension trial of 323 patients with AMD, all patients received 2 mg of intravitreal aflibercept within 12 weeks of the last dose in the VIEW 1 study. They then continued treatment, for a median duration of 116 weeks, through week 212 total.
In the VIEW 1 trial, patients treated with aflibercept had achieved improvements in visual acuity, with a mean gain of 10.2 letters from baseline to week 96. Visual acuity improvements in the VIEW 1 study were maintained, with slight reductions, over a median of 116 weeks in the extension trial to week 212, with a net gain of 7.1 letters and a mean loss of 2.7 letters. Over the course of the trial, the majority of eyes treated with aflibercept maintained visual acuity; a greater number of patients achieved improvements of at least 15 letters over the 212-week extension trial than did those who suffered a loss of at least 15 letters (29.8% vs 8.4%). The mean loss of visual acuity over the 4-year extension treatment with aflibercept was less than loss in the CATT Follow-Up Study from baseline, by a mean loss of 3.3 letters over 5 years.14 Importantly, long-term treatment with aflibercept may offer an advantage for patients with wet AMD who have relatively worse visual acuity when initiating treatment. By the end of the VIEW 1 extension study, aflibercept treatment demonstrated a mean improvement of approximately 10 letters more in eyes with poor vision (defined as less than 50 letters) than in eyes with better vision at baseline of VIEW 1 (defined as more than 50 letters).14

Long-term treatment with intravitreal aflibercept was well tolerated and consistent with the known safety profile from short-term trials. The most common ocular adverse events (AEs) occurring in the extension study were retinal hemorrhage (10.8%), conjunctival hemorrhage (9.3%), and cataract (5.6%); 12 patients (3.7%) experienced serious ocular AEs in the study eye during the extension study.14

Anti-VEGF Treatment Options
Bevacizumab
Despite not having FDA approval for the treatment of wet AMD and no randomized controlled trials to support its use, bevacizumab has become the standard for treating wet AMD and remains the most widely used anti-VEGF therapy for its treatment.11 Bevacizumab is a full-length humanized recombinant monoclonal immunoglobulin G (IgG) anti-VEGF antibody that inhibits all VEGF-A isoforms. It is FDA-approved to treat several solid tumors and glioblastomas, but is used off-label to treat wet AMD. The cost of treating with bevacizumab is much lower than with FDA-approved drugs indicated for wet AMD.11

While randomized controlled trials have not evaluated the efficacy of bevacizumab for the treatment of wet AMD, reports of uncontrolled studies and case reports have been described since 2005.4,10 Evidence for its use can be derived from several noninferiority trials comparing bevacizumab with ranibizumab.4 Compounded bevacizumab has been associated with clusters of ocular inflammation and infectious endophthalmitis, although the endophthalmitis has been attributed to compounding procedures used to make the injections, rather than the drug itself.4
Bevacizumab, Nieson explained, must “be repackaged by a compounding pharmacy and …issues [may be] associated with the repackaging. Prior to recent endeavors, compounding in the ocular world was sort of a Wild West endeavor. Unfortunately,” he continued, “sentinel events happened that have brought in additional regulations, which have helped. But even after these regulations have been in place, [with] oversight over these compounding pharmacies, we’ve had issues with the repackaging of this medicine. I have a hard time using this medication when I have to worry about some of the risks associated with repackaging.”

Compounding Risks of Bevacizumab
While undeniably the most cost-effective treatment available on the market to treat wet AMD, intravitreal-administered bevacizumab does not come without risks. The risk of endophthalmitis, in particular, received attention and scrutiny on the national stage with its off-label use and its repackaging by compounding pharmacies. Clusters of bacterial contamination in bevacizumab have been traced to several compounding pharmacies throughout the country.4 In fact, 8 cases of fungal infection were traced back to the same compounding pharmacy after patients received a combination bevacizumab-triamcinolone product prepared at that pharmacy.15 However, it was the New England Compounding Company (NECC) tragedy that forced the federal government into action.16 In 2012, more than 700 patients were infected with contaminated products compounded by NECC, with 64 cases resulting in death.15 In response to the perceived widespread lapses in safety and oversight of compounding pharmacies (Table 215), the government legislated changes. In November 2013, the Drug Quality and Security Act was signed into law by President Obama; it amended the Federal Food, Drug, and Cosmetic Act, and gave the FDA additional authority to monitor and regulate compounded drugs (Table 317). Prior to this enactment, much regulation had been left to the states’ Boards of Pharmacy, with little consistency in oversight among states. While the final guidance is still evolving, with many stakeholders weighing in, compounding falls under either section 503A, which addresses all drug compounders, or section 503B, which adds regulations for outsourcing facilities.17 In either case, there is an expectation that United States Pharmacopeia guidelines and state laws be followed, and in the case of 503B, which includes the outsourced facilities as well, that they follow good manufacturing practices.17

While much attention has been paid to the oversight of pharmacies, relatively little attention has been given to physician practices that perform in-office compounding.17 Both the FDA and CDC have encouraged greater monitoring of in-office compounding, due to the risk that AEs similar to those caused by compounding pharmacies could occur.17 However, in the case of compounded bevacizumab specifically, retinal specialists are much more likely to use supplies from an outsourced pharmacy than they are to perform in-office compounding.17

Both the American Academy of Ophthalmology and the American Society of Retina Specialists continue to lobby to ensure that the final federal guidance does not restrict the availability of critical drugs used to treat ocular diseases, nor the ability of its membership to prepare and administer treatment for those diseases.18 Despite the controversies, the changes should ultimately result in safety improvements and reductions in infectious contaminations by providing additional oversight and standardization to compounding practices nationwide. In a review of the available research on the subject, VanderBeek et al in 2015 examined the relationship between compounding pharmacies and the occurrence of endophthalmitis, but failed to find a significant difference between injections of bevacizumab and ranibizumab. The rates of endophthalmitis seen were relatively low with both bevacizumab and ranibizumab: 0.017% and 0.025%, respectively.18 The authors also pointed out that Flynn et al found similar rates between bevacizumab and ranibizumab (0.13% and 0.020%, respectively).18

Multiple studies have investigated the quality and consistency of compounded products, although they have typically examined only a small number of samples. In 2011, Liu et al found that product mishandling and long-term storage can increase the number of protein aggregates and increase the presence of silicone microdroplets.19 In 2015, Yannuzzi also studied compounded bevacizumab from 11 different pharmacies. However, the study had a number of limitations, including only a small number of samples, which prevented the authors from analyzing the samples for silicone oil contamination.20 While the results of the studied samples indicated a lack of microbial contaminants and endotoxins, it did show that protein concentrations were highly variable.20 Unfortunately, none of the studies to date, including Yannuzzi et al, attempted to understand the compounding materials and procedures used by each of the pharmacies studied. The authors did speculate that variations could be related to filtration or to the packaging methods used during compounding. Polymer-based stop-cock devices that are used to remove bevacizumab from a vial are thought to result in drug adherence to the polymer as aliquots are prepared resulting in a decrease of proteins. Also, the authors suggest that pharmacies should not employ low-protein-binding sterilization filters. Adherence of proteins to glass syringes that have silicone-based lubricant; molecules from rubber stoppers; and stainless steel from filling pumps may also contribute to inconsistencies of compounded products.20 First and foremost, any provider who treats patients with bevacizumab has the responsibility to identify a reputable compounding pharmacy that follows Unites States Pharmacopeia 797 guidelines and is in good standing with its own state Board of Pharmacy. A review of the literature underscores the need for increased oversight, standardization, and a cost-effective commercial option.

Ranibizumab
Ranibizumab is a recombinant, humanized, monoclonal antibody antigen-binding fragment that has been shown to neutralize all active forms of VEGF-A.21 Because of ranibizumab’s smaller molecule size compared with bevacizumab, its half-life is half that of bevacizumab.11 The results of 2 pivotal clinical trials played a role in the FDA approval of ranibizumab for the treatment of wet AMD. The Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular Age-Related Macular Degeneration (MARINA) and Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in Age-Related Macular Degeneration (ANCHOR) trials were both randomized, double-blind studies evaluating ranibizumab in patients with wet AMD.2 Rosenfeld et al evaluated the safety and efficacy of repeated ranibizumab monthly injections in patients with wet AMD in the MARINA trial.21 Patients were randomly assigned to either receive ranibizumab (either 0.3 mg or 0.5 mg) or sham injections.21 At 12 months, 94.5% of the patients receiving ranibizumab 0.3 mg and 94.6% of those receiving ranibizumab 0.5 mg had lost fewer than 15 letters from baseline visual acuity, compared with only 62.2% in the sham-injection group who lost letters at that rate. At 24 months, the percentages decreased to 92%, 90%, and 53%, respectively.21 The ANCHOR study, a randomized, double-blind, active-treatment, controlled trial, allowed Brown et al to compare the efficacy and safety of monthly ranibizumab intravitreal injections with photodynamic therapy with verteporfin in patients with wet AMD.22 Patients were randomly assigned to either receive ranibizumab (either 0.3 mg or 0.5 mg) plus sham verteporfin therapy or sham intravitreal injections plus active verteporfin therapy.22 At 12 months, 94.3% of the patients receiving ranibizumab 0.3 mg and 96.4% of those receiving ranibizumab 0.5 mg had lost fewer than 15 letters from baseline visual acuity compared with only 64.3% of patients in the verteporfin group. More patients in the ranibizumab group had improved visual acuity by 15 or more letters compared with verteporfin (35.7% [0.3 mg] and 40.3% [0.5 mg] vs 5.6%).22 Rates of endophthalmitis were very low in both the ANCHOR and MARINA studies.

Aflibercept
Aflibercept is a novel VEGF inhibitor designed to bind all VEGF-A isoforms and VEGF-B with higher affinity than do native VEGF receptors (VEGFRs), Aflibercept is a soluble, decoy receptor fusion protein engineered from the extracellular VEGF binding domains from the human VEGFR-1 and VEGFR-2 fused to the Fc domain of human IgG. Aflibercept binds VEGF-A, inhibiting VEGFR binding and activation on the surface of endothelial cells. This aflibercept-mediated blockade of VEGFR activation pathways is important— because they are pathways that promote neovascularization and vascular permeability, processes involved in the pathogenesis of AMD. Importantly, this novel design allows a higher binding affinity of aflibercept compared with the VEGF binding affinity of the other wet-AMD therapies, ranibizumab and bevacizumab. Due to its large molecular weight, aflibercept is characterized by a long intravitreal half-life of 7.1 days, and its bioactivity in human eyes lasts 2.5 months.4,11,23

The safety and efficacy of aflibercept were demonstrated across 2 pivotal phase 3 randomized clinical trials, which led to its indication for patients with wet AMD. The VIEW-1 and VIEW-2 studies were prospective, double-masked, parallel-group, active controlled trials evaluating initial treatment with intravitreal aflibercept injections dosed monthly or every 2 months compared with monthly ranibizumab for 52 weeks.24 Across both trials, a total of 2457 treatment-naïve patients with wet AMD were randomized (1:1:1:1) to receive injections of 0.5 mg or 2 mg aflibercept every 4 weeks; 2 mg aflibercept every 8 weeks following 3 initial injections at week 0, –4, and –8; or 0.5 mg ranibizumab every 4 weeks.

The primary endpoint of both studies aimed to establish noninferiority of aflibercept compared with ranibizumab in the proportion of patients maintaining visual acuity, defined as losing less than 15 letters from baseline to week 52.24 Aflibercept did demonstrate noninferiority in the primary endpoint compared with ranibizumab. At the end of the VIEW 1 and VIEW 2 trials, maintenance of vision was achieved by 95.1% and 95.6% of patients treated with 2 mg aflibercept every 4 weeks, 95.9% and 96.3% of patients treated with 0.5 mg every 4 weeks, and 95.1% and 95.6% of patients treated with 2 mg aflibercept every 8 weeks, all compared with 94.4% and 94.4% of patients treated with ranibizumab every 4 weeks.24

In the VIEW 1 and VIEW 2 trials, intravitreal aflibercept had similar safety and tolerability across all doses and dosing regimens. Ocular treatment-emergent AEs, including serious ocular AEs, were similar in both monthly ranibizumab and aflibercept treatments. The combined AE rates for every 1000 injections from both trials, including eye disorders, endophthalmitis, procedural complications, and increased intraocular pressure, were lower with aflibercept treatment compared with ranibizumab: 1.1 for the ranibizumab group; 0.8 and 0.1 for the groups treated with 2 mg intravitreal aflibercept every 4 weeks; and 0.2 for the group treated with 2 mg aflibercept every 8 weeks.

Among the aflibercept treatment groups, there was no evidence of a dose-response for AEs; the group with the highest, most frequent dosage (2 mg every 4 weeks) experienced the lowest rates of AEs. There was a similar overall incidence of nonocular systemic AEs, serious systemic AEs, specific arterial thromboembolic end points, and deaths, comparing intravitreal aflibercept with ranibizumab. Additionally, immunogenicity was not demonstrated to be associated with intravitreal aflibercept.24

Comparison of Age-Related Macular Degeneration Treatments Trials
In 2011, year 1 results from the CATT trial were reported. The CATT study set out to determine the efficacy and safety effects of intravitreal ranibizumab compared with bevacizumab in patients aged 50 years and over with previously untreated active choroidal neovascularization due to AMD who had visual acuity between 20/25 and 20/320 on electronic visual-acuity testing.12 Patients were assigned to 1 of 4 treatment groups: 1) monthly ranibizumab; 2) monthly bevacizumab; 3) as-needed ranibizumab; or 4) as-needed bevacizumab. Ranibizumab was considered the standard of care in this study.12 Patients in the as-needed (PRN) treatment groups were evaluated every 28 days for signs of active neovascularization.12

The study found that after 1 year, visual acuity was improved in all 4 treatment groups, with most improvement occurring during the first 6 months. Bevacizumab and ranibizumab were found to be equivalent when given monthly and PRN. Additionally, ranibizumab monthly versus bevacizumab PRN proved to be equivalent, as did ranibizumab PRN versus bevacizumab monthly.12 The percentages of patients not experiencing a decrease in visual acuity from baseline of 15 or more letters was 94.4% in the ranibizumab monthly group, 94.0% in the bevacizumab monthly group, 95.4% in the ranibizumab PRN group, and 91.5% in the bevacizumab PRN group (Figure 1).12

AEs in each treatment group were also evaluated, and no significant differences were noted among the groups for rates of death from any cause. Serious AEs were observed more often with bevacizumab than with ranibizumab. One or more serious AE occurred in 17.6% of patients in the ranibizumab monthly group, 22.4% in the bevacizumab monthly group, 20.5% in the ranibizumab PRN group, and 25.7% in the bevacizumab PRN group.12 The rate of arteriothrombotic events was similar for all treatment groups (2%-3%). Endophthalmitis occurred in the monthly treatment groups (2 with ranibizumab and 4 with bevacizumab) but not in the PRN treatment groups.12

Based upon results of this study, the efficacy and safety of ranibizumab and bevacizumab intravitreal injections in wet AMD can be deemed similar. In 2012, CATT researchers reported year 2 results. For the second year of the study, researchers continued to evaluate monthly versus as-needed treatment, but also investigated the effect of switching to as-needed treatment after 1 year of monthly treatment. Patients from the year 1 trial assigned to monthly treatments were randomly reassigned to either monthly or PRN treatment with the same drug. For patients receiving the same treatment for 2 years, most improvement in mean visual acuity was observed in year 1, with little change noted during the second year.12 The difference in mean improvements was lower with bevacizumab compared with ranibizumab (– 1.4 letters) and with PRN dosing compared with monthly dosing (–2.4 letters).12 Rates of patients who experienced no decrease in visual acuity from baseline of 15 or more letters were similar among treatment groups (Figure 2). In patients moving from monthly to PRN dosing, changes in mean visual acuity were −1.8 letters in ranibizumab-treated patients and −3.6 letters in bevacizumab-treated patients. Mean visual acuity was similar at 2 years for patients in the PRN groups and in those who switched from monthly to PRN treatment.12 At year 2, no significant differences were noted among treatment groups for rates of death from any cause or arteriothrombotic events.12 As with year 1 results, serious AEs were observed more often with bevacizumab. One or more serious AE occurred in 31.7% of patients treated with ranibizumab, compared with 39.9% of patients treated with bevacizumab.12 No significant differences in endophthalmitis events were noted.12 To determine outcomes 5 years after initiating treatment, a cohort study was designed to include patients in the previously mentioned studies. At the end of year 2, patients were released from the clinical trial protocol.

A total of 647 patients from the initial CATT study were included in the CATT Follow-up Study.13 Of those, 91% continued to receive care at a CATT center even after being released from trial protocol, although more than half of the patients received a treatment different than their assigned study drug. Five patients received no eye care after the study.13 Improvements in visual acuity seen at 2 years were not maintained through year 5; however, at the end of year 5, 50% of patients had visual acuity of 20/40 or better and almost 10% had 20/20 vision (Figure 313). Twenty percent of patients had visual acuity of 20/200 or worse.13 The authors concluded that although visual acuity was less than at baseline, the follow-up study demonstrated that anti-VEGF therapy preserves vision for a majority of patients.

When asked by Salgo to compare the clinical difference between the on-label drugs and bevacizumab, Wykoff replied, “Bevacizumab works exceptionally well in many eyes. Let’s take the safety issues off the table that we’ve already explored. Let’s look at just efficacy for a second. There are very good data from all of the comparative trials put together that ranibizumab and aflibercept are better drying agents. Which means that they get the retina drier, faster, and they require fewer shots long-term.”

Wet AMD Treatment Costs
Ranibizumab is manufactured by Genentech and is currently marketed under the brand name Lucentis for the treatment of neovascular AMD.4 While retinal specialists hailed FDA approval of ranibizumab in June 2006 as revolutionary, the enthusiasm was quickly tempered by the associated cost of the drug set by the manufacturer. Wholesale acquisition cost (WAC) for a single-dose 0.5-mg vial is $1950; therefore, the annual cost of treatment, not including office visit, is an estimated $11,950.25 The cost can be doubled when both eyes are affected. For patients in the United States who are Medicare beneficiaries, ranibizumab is covered under the Medicare Part B benefit.26 The patient is responsible for 20% of the drug cost for each injection.

The situation is similar for aflibercept. In 2011, Regeneron received approval for the use of aflibercept as an ophthalmic solution in the treatment of wet AMD.6 Marketed under the brand name of Eylea, it has a WAC cost per 2-mg dose of $1850.26

For individuals on a fixed income, these co-payment costs can add up very quickly given the typical monthly treatment schedule.26 Nielsen elaborated, “It would be nice to be in a world where our only consideration is efficacy. In that world, this decision becomes very easy, I think, and you use the on-label medications. But the world that we live in is such that there is a very disparate cost for these medications, and so that plays a huge role. I think no one would use Avastin to treat patients if it weren’t cheap. If the agents were all the same price, there would be no one who would use bevacizumab to treat their patients.”

Given these choices, it is no surprise that retinal specialists, patients, and payers have been driven toward a cheaper alternative in the form of off-label administration of intravitreal bevacizumab.27 Originally developed by Genentech for the treatment of colon cancer, bevacizumab is marketed under the brand name Avastin and is also FDA-approved for the treatment of a number of other cancers.11 With a WAC price of $758.54 for a 100-mg vial that can be further repackaged to approximately 65 1.25-mg doses priced at approximately $55 a dose, it is hard to argue that it is not a valuable therapeutic option.27,28

Although consistent market competition has arisen over the last 5 years, the costs of ranibizumab and aflibercept have remained relatively constant. Given the inability of the marketplace to produce a cost-effective, commercially manufactured product, it is likely that there will be the same repackaging trend with aflibercept now that ziv-aflibercept (Zaltrap) has been approved. Marketed by Sanofi Genzyme as second-line treatment for metastatic colorectal cancer, Zaltrap contains the same active ingredient as Eylea.

In 2020, the US patents for ranibizumab and aflibercept are set to expire, and several biosimilars are already under development. Intas Pharmaceuticals has been working to bring Razumab, a biosimilar of ranibizumab, to market, with initial approval received in India in 2015. However, the first 3 batches of product showed an ocular inflammation rate of 10%, which serves to highlight the difficulties in maintaining quality and stability in the complex development process of large molecules. Since that time, the manufacturing process has been revised and the previous problems have been resolved.29

Formycon has also developed 2 biosimilars, FYB201 and FYB203, representing biosimilars to ranibizumab and aflibercept, respectively. A phase 3 trial expected in 2020, comparing safety, efficacy, and immunogenicity, has been enrolling patients, with final data collection as the primary outcome measure.29

In a review of the pipeline, there is certainly demonstrated need to find a therapeutic regimen that is sustainable and lowers the risk to the patient. The 3 main risks at this time are injection-site complications, such as infection or inflammation; long-term effects of multiple injections, such as increased risk of glaucoma surgery; and the recently described complications related to compounding of bevacizumab, connected to silicone oil microdroplets and protein aggregates.

Conclusion
Despite very important advances that have been made in the treatment of wet AMD over the past 15 years with new drugs directed at VEGF targets, not all patients benefit from treatment. Furthermore, existing treatments with the FDA-approved drugs ranibizumab and aflibercept are not only expensive, they require frequent office visits for drug administration and monitoring; this regimen is not always achievable in a real-world setting. Treatment with bevacizumab is less expensive; however, its use does come with additional risks associated with the compounding and repacking of the drug. In the CATT study, the 2-year drug cost per patient ranged widely, from $705 with the PRN bevacizumab regimen up to $44,800 with the monthly ranibizumab regimen.12 With bevacizumab and ranibizumab shown to be the 9th- and 19th-ranking drugs, respectively in terms of global sales in 2013, combined with a growing, aging population that will be candidates for therapy, these facts cannot be ignored by third-party payers.6 While there may be some relief in the form of biosimilars down the road, the cost and adherence issues need to be managed today. Future research is needed to identify an optimum maintenance strategy utilizing fewer injections and monitoring in order to improve adherence to treatment regimens and improve patient outcomes. While price alone should not dictate, nor limit, the physician’s choice of product, it should certainly play an integral role given the limited healthcare dollars at stake. •
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