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Anti-VEGF therapy for AMD inconsistently managed worldwide in real-life practice

Issue: November 10, 2014

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Anti-VEGF therapy for age-related macular degeneration has been a major breakthrough in the battle against vision loss. The pivotal MARINA and ANCHOR trials showed a mean increase of 7 to 11 visual acuity letters at 1 year, substantially maintained at 2 years, with monthly injections of ranibizumab. In clinical trial settings, optical coherence tomography-guided variable-dosing regimens achieved comparable results. In the VIEW trials, after three monthly loading doses, bimonthly administration of aflibercept produced similar improvement to monthly ranibizumab.

However, both the HORIZON and SEVEN-UP studies, which observed over the long term MARINA and ANCHOR trial patients, showed evidence that less rigorous follow-up patterns, with Lucentis (ranibizumab, Genentech) administered at the investigator’s discretion, led to a decline of the visual acuity gains achieved with monthly treatment. In the real world, as shown by numerous reports across continents, anti-VEGF treatment does not meet expectations and results are not up to the standards of clinical trials.

Such a discrepancy is obvious, simply because clinical trials are not a real-world situation, according to Jay S. Duker, MD, OSN Retina/Vitreous Board Member.

“Trials recruit a select motivated group of patients, and typically those patients get the opportunity to receive a treatment that they could not get otherwise. There are exclusion criteria, which prevent people with certain diseases or people who are sick or unable to comply with a strict follow-up schedule to be enrolled. This highly selected group of relatively healthy subjects are not the real world,” he said.

According to Sobha Sivaprasad, MD, ranibizumab had a definite beneficial effect, particularly the loading doses, but results are difficult to maintain; in the AURA study, initial visual acuity gain was followed by a decline to baseline at 2 years.

Image: Sivaprasad S

According to Francesco Bandello, MD, president of the European Society of Retina Specialists (Euretina), there are reasons for the gap between clinical trial and real-life outcomes that are inherent to the scope and nature of clinical trials themselves.

Multinational pharmaceutical companies are currently the only entities capable of producing evidence-based medicine data through large-scale, multicenter investigations. They have an interest in optimizing efficacy data to allow pharmacotherapies to be approved, registered and reimbursed, and therefore they may adopt inclusion and exclusion criteria as well as follow-up and treatment modalities that are not realistically applicable to the clinical practice.

“The result is that patients in real life do a lot worse than in the trials,” Bandello said.

On the other hand, independent studies that meet evidence-based medicine criteria have unaffordable costs, he said. Studies such as CATT and IVAN are unique standalone cases.

Overall positive view in U.S.

In a report recently published in the U.S., the patterns of anti-VEGF treatment for neovascular AMD were investigated among Medicare beneficiaries who initiated therapy between 2006 and 2010. A large database of 459,237 beneficiaries was made available. In the first year of treatment, a mean of 4.3 injections were administered. Frequency in the second year varied in proportion to the number of injections already received. Eyes that received seven or more injections in the first year received a mean of 4.8 injections, while eyes that received four or fewer injections in the first year received a mean of 0.9 injections. The majority of patients received no injections in the second year. Rates of anti-VEGF discontinuation were 57% within 12 months and 71% within 24 months. According to the authors, “the optimal treatment patterns were infrequently used in clinical practice, suggesting general under-treatment of patients with neovascular AMD.”

Although large real-life reports focusing on results of anti-VEGF therapy in the U.S. are lacking, and Medicare data show that the tight schedules suggested by clinical trials are not maintained, the overall perception of AMD management is positive among U.S. ophthalmologists.

“Anti-VEGF therapy is effective and certainly as effective as it can be in a real-life situation,” Duker said. “What we have learned is that many patients can be maintained with excellent VA in the long term by giving them injections less than monthly. Most patients don’t require monthly treatment. They do, however, require frequent visits to monitor for recurrence of the disease.”

Individualized therapy is the key to success, Duker said.

“U.S. results tend to be above average because we have more freedom to treat patients the way their disease requires and the way they choose to be treated. Like over 70% of specialists in the U.S., I use a treat-and-extend protocol most of the time. None of us in real-life practice have the number of patients or the excellent follow-up that you would get in a clinical trial, so it’s difficult to state with certainty, but the fair majority of my patients get stabilized and remain stable in the long term,” he said.

James A. Eadie, MD, a retina/vitreous consultant in Pittsburgh, agreed that, in general, it is not realistic, and often not indicated, to treat all patients monthly in the fashion of the ANCHOR and MARINA trials.

“I would like to think that, as a community, we tend to be aware of the literature and to make appropriate informed decisions for each patient. But many factors go into our management decisions in real life,” he said.

“Office capacity and waiting times may limit the sheer number of injections that we are able to provide. From a patient’s perspective, burden to family members and caregivers, cost of co-payments, pain and anxiety associated with injections, apathy, depression, parking and driving all can factor into a given patient’s informed decisions with regards to management of his or her AMD,” he said.

The government’s investment in AMD treatment has consistently grown over the years, Eadie said.

Medicare data for 2010 showed that $1.1 billion was spent on ranibizumab and $27 million on Avastin (bevacizumab, Genentech). Ranibizumab alone accounted for nearly 10% of the Medicare Part B drug budget.

“That being said, as the population ages and demand for services increases, these costs will present a serious challenge. Up to this point, Medicare has been very good about paying for anti-VEGF medications when they are indicated,” Eadie said.

As a result, access to anti-VEGF treatment has been ensured, and it is rare today that patients have to pay out of pocket.

Jay S. Duker

“In Massachusetts, we switched to universal health care many years ago. Almost 99% of adults in our state are covered by insurance, and the insurance pays for any of the three anti-VEGF agents. For those who are not covered or have a large co-pay, I will often use Avastin. It is so inexpensive that the cost of the drug is not an issue for the majority of people. In addition, Genentech and Regeneron have been generous in supplying our patients with free samples for those who have economic issues,” Duker said.

First-line treatment for most specialists

The widespread use of bevacizumab has been pivotal in making anti-VEGF treatment accessible to U.S. patients. The 2014 Preferences and Trends Survey from the American Society of Retina Specialists showed that 64% of U.S. providers use bevacizumab as their first-line treatment for AMD. The low cost per dose, $30 to $50 compared with $2,000 for ranibizumab and Eylea (aflibercept, Regeneron), greatly reduces the economic burden of the treatment compared with other parts of the world, such as Europe, where ranibizumab and aflibercept together account for 77% of the total injections.

Bevacizumab for ocular use has been at the center of major controversies, regulatory issues and legal cases in Europe, but it is well accepted in the U.S.

“The use of Avastin is not controversial here at all because we are experienced with it. More than 60% of U.S. retina specialists use it as their first-line drug for wet AMD. Prior to FDA approval, we had no access to Lucentis, and at that time we had significant anecdotal data that Avastin was effective, so U.S. retina specialists gained extensive experience with the drug and now are very comfortable with its use,” Duker said.

Discordant interpretations of safety outcomes in the CATT have led European specialists to express “concerns about an increased risk of ocular and systemic adverse events with bevacizumab,” as stated in the recently published guidelines for the management of neovascular AMD by Euretina. But specialists in the U.S. “do not generally believed that the risk rate is higher,” according to Duker.

“When you look at the side effects in the CATT study that you would expect from an anti-VEGF — hypertension, stroke, heart attack — there was no statistical difference between the two drugs. The higher number of hospitalizations ‘for all causes’ in the Avastin group is a data point that needs to be looked at, but not significant enough to change practitioners’ minds here about the safety of Avastin vs. Lucentis,” he said.

The risk of contamination with compounded bevacizumab is preventable when split doses are prepared under sterile conditions and tested carefully.

“There were scattered reports of infection outbreaks in the country due to the poor sterile practices of some pharmacies. But the reputable pharmacies do it in a sterile fashion and never had trouble,” Duker said.

Big picture of real-world studies

In the introduction to the Euretina guidelines, the authors underscored that the therapeutic benefit of anti-VEGFs “is accompanied by significant economic investments, unresolved medicolegal debates about the use of off-label substances and overwhelming problems in large population management.”

“The burden of disease has turned into a burden of care with a dissociation of scientific advances and real-world clinical performance,” the authors wrote.

In most of the contexts analyzed by real-world studies, irregular monitoring and undertreatment are reported. The big picture shows that a significantly lower number of injections compared with the recommended dose of seven to eight in the first year and five to six in the second year is administered in real life, patients are not monitored regularly, and discontinuation is frequent.

The AURA study retrospectively reviewed the follow-up and results of 2,227 patients treated in eight countries: Canada, France, Germany, Ireland, Italy, the Netherlands, the United Kingdom and Venezuela.

“What we found was that ranibizumab had a definite beneficial effect, particularly the loading doses, but it was hard to maintain the results at 1 year, and at 2 years, VA was back to baseline. Still good, because if left untreated, these eyes would have lost 15 letters, but we would like to do better,” Sobha Sivaprasad, MD, senior study author, said.

The lower visual acuity gain reported in some countries was partly due to a ceiling effect.

“However, monitoring and treatment practices had a high impact, reflected in the different outcome of countries with comparable baseline scores,” Sivaprasad said.

Overall, 10 visual acuity tests were performed over the study duration, and patients received a mean of five injections in the first year and two injections in the second year. Countries had substantial differences in injection frequency. More frequent visits and injections were associated with greater improvements in visual acuity.

The LUMINOUS study is the largest, observational, global study on ranibizumab in routine clinical practice to treat AMD, diabetic macular edema and retinal vein occlusion. Data collection is ongoing, and the aim is to enroll 30,000 patients from approximately 600 sites in 41 countries worldwide, followed for 5 years. The first interim analysis of 2,112 patients with wet AMD followed for 1 year was released at the 2014 Association of Research in Vision and Ophthalmology meeting. A mean gain of 4.1 letters was achieved at 1 year in the treatment-naïve subgroup, while previously treated patients maintained their initial higher baseline. A mean number of 5.2 injections and seven visits were recorded.

Great variation between countries

Focusing on individual countries within multinational real-life studies, remarkable differences emerge.

Australia contributed 44% of patients within the first 1-year global interim analysis for wet AMD in the LUMINOUS study. As shown in a poster presented at the Euretina meeting in London, the 938 Australian patients, mostly Caucasians, received a mean of seven injections and gained a mean of 5.6 letters if treatment naïve or maintained baseline vision if previously treated.

“The contrast between Australia and other countries in the Asia-Pacific region that do not have a national payment scheme is stark. If there is a system in the society that allows you to follow the intense clinical trial protocols, like in Australia, VA improves and is maintained. Where there is no support from the system, the effectiveness is lost,” Tien Y. Wong, MD, MPH, PhD, OSN APAO Edition Assistant Editor and professor and director of the Singapore National Eye Centre, National University of Singapore, said.

In the AURA study, the U.K. was top of the list for follow-up visits, injection frequency and consequently visual outcomes.

“Ours is quite an exceptional situation in which regular follow-up visits and free treatment are given under NHS coverage to all, even monthly if necessary. When insurance comes into it, or patients have to pay, results are very different. Other countries cannot cope with the workload and the frequency of treatment,” Sivaprasad said.

High burden, lack of funding in Asia

Due to the large population and lack of governments’ funding, Asia is the continent where the burden of care is greater. In most countries, including Singapore, China, the Philippines and India, the treatment for wet AMD is not covered by government insurance. Taiwan covers up to three injections per year, South Korea up to 10 injections of ranibizumab per lifetime and Thailand up to 12 injections of bevacizumab.

A retrospective analysis of treatment patterns at the Singapore National Eye Centre, which manages more than 50% of outpatient ophthalmology visits and surgeries in the country, found that a mean of three to four injections are administered per year.

“This is about half of the injections needed for best results because people have to pay for their own follow-up and treatment. Furthermore, most patients are given bevacizumab, which is a cheaper drug. And this happens in Singapore, which can be considered a high-income country, with good health care standards,” Wong said.

There are few studies that have examined treatment patterns and outcomes in a real-life setting in Asians, and more are needed to raise awareness, according to Wong. In addition, cost-effectiveness studies are needed to educate policymakers about the need to invest in AMD treatment.

“Effective health care policies for AMD are cost-saving in the long term, but these studies are not easy to do and most health care systems and governments are not interested because it does not bring a direct political capital in the shorter term of their mandate,” he said.

Hospital overload in Europe

European ophthalmologists report hospital overload as a major hurdle in the way of effective AMD management in Europe.

Other observational studies in individual countries, including the WAVE and COMPASS studies in Germany, the LUMIERE study in France and a study in Coimbra, Portugal, reached the same conclusions: The good visual results obtained during the loading phase are lost during the subsequent flexible maintenance phase. Only one-half to one-third of patients received further ranibizumab reinjections, with an average of one to two. Patients are not monitored monthly, OCT is seldom used, and the delay between upload and the first reinjection is several months. The LUMIERE study also found that less than 40% of patients received the recommended treatment of three initial monthly injections.

“The reason why French ophthalmologists didn’t observe the loading dose is unclear. I guess it was partly due to underestimating the importance of the loading phase and partly to the work overload in our retina units,” study investigator Hassiba Oubraham, MD, said.

A second observational study, the TWIN study, collected data from 2010. The same centers that participated in the LUMIERE study were included, and a few were added, for a total of 881 patients.

“The study showed that something was learned from experience. The interval between diagnosis and first injection was shorter and more than half of the patients received a loading dose. However, patients continued to be monitored and re-treated irregularly. Letter gain was slightly higher, although not significantly,” Oubraham said.

The authors of the WAVE study noted that deficiencies in the adherence to the recommendations of regular monthly monitoring and the insufficient implementation of optimal diagnostic and re-treatment criteria were the reasons for suboptimal treatment outcomes, “which have not only a potentially devastating personal impact but also considerable cost implications.”

Rufino Silva, MD, PhD, senior author of the Coimbra study, said that hospitals, overloaded by the increasing number of AMD patients needing treatment, may be unable to organize appropriate schedules for patients.

“It’s a widespread problem, which might become even greater in the future. We need to reconsider the way we treat,” he said.

Using the U.K. as a model, Sivaprasad believes that efficacy and efficiency can be increased by better planning and solid investments in health care. According to Bandello, the need for continuous, tight monitoring, the high number of examinations and the frequent reinjections required are a burden that can hardly be sustained, even by the most efficient system.

New options needed

Newer therapeutic options that make the burden of AMD management more sustainable are advocated by the ophthalmic community worldwide.

“A treatment that impacts so heavily on the countries’ medical resources cannot be the ultimate solution for AMD,” Wong said. “We need newer drugs, longer lasting, cheaper, easier to administer, ideally drugs that are capable of preventing AMD. These will be the longer-term solution, and it might be worth investing more money into research rather than continue draining resources for treatment.”

Francesco Bandello

“As long as such a high frequency of injections is required, efficiency cannot be guaranteed,” Bandello said. “To release the pressure, we need long-lasting drugs, sustained-release delivery systems, new molecules with increased efficacy and easier ways of administration.”

Significant changes in anti-VEGF compounds or delivery are not expected in the immediate future, but there are new options in the pipeline that seem promising, Duker said.

“We hope that combination with anti-PDGF, such as Fovista (Ophthotech), which we hope shows a benefit in phase 3 and subsequently gets FDA approval, may alter the way we administer anti-VEGF. Eye drops with anti-VEGF properties being studied by several companies (Ohr Pharmaceutical, PanOptica), another interesting approach, may allow us to reduce the number of injections,” he said.

Efforts are underway to develop more effective drug delivery systems that are able to provide sustained release of medications. Genentech is working on an implantable refillable device.

Finally, Avalanche Biotechnologies is using intraocular gene therapy to provide long-lasting anti-VEGF activity, a new approach that is many years from approval but could revolutionize disease management, Duker said. – by Michela Cimberle

Which individualized maintenance regimen offers better safety and efficacy with reduced treatment burden in real-life clinical practice?

Less treatment burden exists with treat and extend

Carl D. Regillo

There are three basic approaches to treating wet AMD with intravitreal anti-VEGF agents. There is the continuous fixed-interval approach with injections every 1 to 2 months. This is rarely practiced because it may represent overtreatment for many patients, and overtreatment translates into excessive treatment burden and increased risks. The next style of treatment is the “as needed” or pro re nata (PRN) approach. Treatment is rendered monthly at first until the macula is dry, and then you monitor closely and treat when there are signs of recurrent exudation. This is an individualized form of therapy and does minimize overtreatment, but it requires frequent monitoring, so the burden of frequent office visits is not reduced. Moreover, even with close monitoring, the best imaging technique, and a zero tolerance for any signs of recurrent exudation, it does not work as well in the long run, as shown in the CATT and IVAN trials. The problem with this style of therapy is that is allows for recurrences before re-treating, and multiple recurrences over time will ultimately lead to significant disease progression.

The third approach is the “treat-and-extend” strategy, which represents the best of both worlds in terms of disease control and treatment burden. It is both continuous and individualized therapy. With this proactive approach, treatment is rendered at every patient encounter, but it is the follow-up and treatment interval that is variable, adjusted for a given patient in order to maintain a dry macula and minimize recurrences. This strategy has been studied both retrospectively and prospectively. Although there are no comparative clinical trials available yet, all published studies show consistent, good visual outcomes with less treatment and fewer office visits. The visual results appear as good as what is seen in trials with monthly continuous fixed-injection regimens, and the most recently published studies indicate that the acuity gains hold up well out through 2 and 3 years of follow-up, something PRN studies fail to show.

Carl D. Regillo, MD, is an OSN Retina/Vitreous Board Member and director of retina services, Wills Eye Hospital , Philadelphia. Disclosure: Regillo is a consultant to Abbott Medical Optics, Acucela, Alcon Laboratories, Alimera Sciences, Allergan, Bausch + Lomb, Genentech, Notal Vision, Novartis Pharmaceuticals, Regeneron Pharmaceuticals and ThromboGenics.

PRN offers personalized treatment, rigorous monitoring

Anat Loewenstein

Evaluation of PRN anti-VEGF dosing started with the PrONTO study. Results were comparable to those of the pivotal phase 3 trials, with reduced treatment frequency. Other large studies, such as the VIEW studies, as well as many other smaller series, supported the use of this treatment schedule. In studies that failed to show good results after PRN therapy, such as the SUSTAIN trial, patients were not examined monthly or, as in the CATT and HARBOR, differences in visual outcomes were quantitatively small and not clinically significant. PRN therapy has a lot of good data to support it.

In contrast to this, there is a paucity of data on the use of treat and extend, and basic unanswered questions remain on what a treat-and-extend regimen should involve. Loading dose, treatment intervals and the way to deal with disease recurrence are still a matter of opinion.

PRN treatment uses visual and anatomic outcomes to determine treatment intensity and is thus based on clinical judgment. Patients can easily predict their next appointment, which makes it easier for them to organize their life around it. This may lead to better adherence with treatment and fewer missed appointments. In addition, closer monitoring may result in better care. PRN does not rely on the patient to report vision changes, there is less opportunity for disease recurrence to go unnoticed with monthly visits, and if disease recurs, it will be caught quickly and damage will be less severe. PRN also has advantages for the clinic. The fixed schedule of monthly appointments is easy to organize and may reduce cost because regular patterns improve adherence, and fewer missed appointments mean less clinic time and reduced costs.

In summary, PRN is a well-validated treatment regimen with a lot of advantages for our daily clinical practice.

Anat Loewenstein, MD, is an OSN Europe Edition Board Member and chairman of ophthalmology, Tel Aviv University, Israel. Disclosure: Loewenstein is a consultant to Alcon Laboratories, Alimera Sciences, Allergan, Bayer HealthCare Pharmaceuticals, ForSight Labs, Lumenis, Notal Vision, Novartis Pharmaceuticals, Ora Bio and Teva Pharmaceuticals USA.