Breakthrough studies revive discussion of anti-VEGF treatment regimens for AMD

Anat Loewenstein, MD, said it is important to emphasize the need for re-treatment for best patient compliance, especially in light of CATT trial results. Image: Loewenstein A

Anti-VEGF therapy has been a major breakthrough in the treatment of age-related macular degeneration.

Five years after the approval of the blockbuster drug Lucentis (ranibizumab, Novartis/Genentech) with the pivotal MARINA and ANCHOR trials, its sister drug, Avastin (bevacizumab, Roche/Genentech), has taken a new turn following the results of the CATT. Meanwhile, Eylea (aflibercept, Bayer/Regeneron), also known as VEGF Trap-Eye, has undergone the phase 3 VIEW I and VIEW II trials, been approved by the U.S. Food and Drug Administration and been submitted for European Union market approval.

While welcoming the new therapies as one of the most significant advances in modern medicine, retina specialists are still discussing therapeutic regimens. No consensus on optimal practice has been reached. Monthly injections may achieve the best efficacy, but they create an unsustainable burden for patients, physicians and health care systems. The need to develop new treatment schedules that would reduce the number of injections has become a priority, but there is concern about under-treatment using the as-needed injection strategies.

The LUMIERE study, a retrospective observational study carried out at 16 centers in France, looked at current practices of ranibizumab treatment. The results, presented at the 2011 Association for Research in Vision and Ophthalmology meeting, unveiled an alarming real-life scenario. Only 40% of patients received the recommended induction phase of three monthly injections, and only 4% had a regular follow-up. No patients had monthly monitoring. The average number of yearly visits was eight, the average injection rate was five, and the average letter gain was three.

Only 20% of patients gained more than three lines at 1 year.

“The real world appears to be far behind what recommended treatments indicate,” Ursula Schmidt-Erfurth, MD, said. “And the real world happens everywhere, not just in France. It’s a global problem that requires a global approach.”

Ursula Schmidt- Erfurth

Hassiba Oubraham, MD, first author of the ARVO study, said that the causes of patients’ irregular monitoring and under-treatment were rarely related to the patients themselves.

“It’s our overloaded hospitals that are unable to guarantee regular access to visits and treatment. Appointments are normally delayed, and very few patients can have them according to the recommended schedule,” she said.

The induction phase is spread over an inappropriately longer time, with intervals longer than 1 month.

“And yet, we were able to prove that visual acuity is better if the induction phase is followed correctly,” Dr. Oubraham said.

The same applies to the number of visits. In the 2 years of the study, the number of visits increased from 8.6 in 2008 to 8.8 in 2009, with a consequent increase in the number of yearly injections from 5.1 to 5.6.

“We were able to see that a few more visits, leading to a few more injections, resulted in better outcomes. It’s not the PRN regimen that doesn’t work, but our bad management of it,” she said.

Anat Loewenstein, MD, said that her patients’ compliance changed dramatically the moment that she changed her attitude to the treatment.

“At the beginning, I was not emphasizing enough that they would have to be re-treated, that they had to come every month, that this would be for a long time, that they would need at least eight injections per year and most likely for a few years,” she said. “If you don’t explain this from the beginning, making clear that coming back to regular monthly appointments is a sine qua non to save their vision, it’s difficult to convince them later.”

Under-treatment, in her opinion, results mostly from physicians who do not see patients monthly and do not adopt the correct criteria for re-treatment.

“If you ask me what the CATT trial changed in my clinical practice, I’ll say that I am now even more convinced of the mandatory need to keep strictly to monthly visits when a PRN regimen is adopted. Also, if I see the presence of any fluid, I re-treat immediately,” Dr. Loewenstein said.

CATT results

The Comparison of Age-Related Macular Degeneration Treatments Trials showed that the results of closely followed as-needed regimens were non-inferior to monthly administration.

“Monthly therapy was compared to quite an aggressive PRN regimen of treatment,” Paul Mitchell, MD, PhD, said. “Most of the PRN trials to that point had not been aggressive enough and had used the 75 µm or 100 µm central retinal thickening parameter as a criterion for re-treatment rather than the presence of any fluid on the OCT.”

That is why, he said, the result of the as-needed treatment administration in the CATT was reasonably good compared with monthly treatment.

An equally important achievement of the study was to show that ranibizumab and bevacizumab had comparable results when administered monthly or as-needed. Comparison of as-needed bevacizumab with monthly ranibizumab failed to show non-inferiority and was therefore essentially inconclusive.

“This may suggest that if you use bevacizumab you should consider using it monthly rather than as-needed,” Dr. Mitchell said.

However, some deviation of the as-needed arms of the study was reported in the last quarter of the first year, suggesting failure to maintain visual gain over a long period.

“Is this going to be a marker of some loss of vision in the second year with PRN? Is it the beginning of a trend? We are waiting for further data,” Dr. Mitchell said.

VIEW results

The VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD trial was designed to compare ranibizumab with aflibercept, an anti-VEGF molecule with greater binding affinity and, therefore, theoretically longer-lasting activity in the eye, up to 10 weeks to 12 weeks. It was the largest AMD trial ever performed, with more than 2,500 patients. Two dosages — 0.5 mg and 2 mg — and two treatment strategies — every 4 weeks and every 8 weeks — were evaluated for aflibercept and compared with monthly ranibizumab.

“The great news is that a new treatment strategy, ie, a fixed regimen of injections at 2-month intervals, has proven as safe and effective as the monthly administration of both the same agent and ranibizumab. Mean visual gain, mean change in retinal thickness and stability of results over time were comparable,” Dr. Schmidt-Erfurth, principal investigator, said.

These findings open another potential for clinical practice. The same efficacy as monthly ranibizumab can be achieved with half the number of injections, and the hassle of monthly visits, examinations and decision making can be avoided.

Ten percent of the patients in the study were Asian and showed identical benefits.

“This is important because AMD is increasing in the Asian population due to the changes in nutrition habits,” Dr. Schmidt-Erfurth said.

Tien Yin Wong, MD, PhD, of Singapore, said that results are exciting, although some areas of uncertainty remain, as full data have not yet been analyzed.

“The 2-year results of the study that have been recently disclosed in a press release by Bayer and Regeneron show that, when switching to a PRN approach, the number of injections required with VEGF Trap-Eye is equivalent to the number of injections needed with Lucentis,” he said. “This suggests that the advantages of VEGF Trap-Eye after the first year may not be as marked as initially thought.”

Paolo Lanzetta, MD, who is also involved in the trial, explained that in the aflibercept group, the 8.4 letter gain with injections every other month at 1 year decreased to 7.6 letters with as-needed administration in the second year of the study. The total number of injections was 11.2 over the 2 years, with 4.2 injections given in the second year.

“The number of injections in the ranibizumab group was 4.7 in the second year and therefore quite comparable. Letter gain was 8.7 in the first year and 7.9 in the second year. In other words, once we switch to a PRN regimen, the VEGF Trap-Eye seems to require the same number of injections as Lucentis, and a PRN regimen seems to lead to a lesser visual gain,” he said.

However, the press release announcing the results said that the proportion of people who needed fewer injections was higher in the aflibercept group, suggesting that the new molecule may indeed have a longer half-life in the eye.

How aflibercept will change the current clinical practice is not yet clear, according to Dr. Wong. If patients have benefited from ranibizumab or bevacizumab, will they be switched to the new drug?

“Many physicians will be reluctant to change, particularly if previous treatments have been effective in controlling the disease. Some retinal physicians may also want to wait and see longer-term results before they start using the drug. Nevertheless, I expect that in the next 1 to 2 years quite a few patients, particularly those who do not respond to Lucentis or Avastin, will be given VEGF Trap-Eye,” he said.

Another question: Will people stop using as-needed dosing? Dr. Loewenstein wondered if the two options, aflibercept at fixed 2-month intervals and as-needed ranibizumab, will both become state-of-the-art strategies. Costs may become an important factor in the choice, she said.

Real world response

A constant encountered in all studies in which as-needed treatment is administered is the variability of individual response to therapy, Dr. Wong said.

“This is one of the reasons why our clinical practice and also the big trials now focus so much on as-needed treatment schedules. Results are quite good and most patients are happy with this approach, although there is increasing evidence that such an approach does not lead to the best results in terms of vision as compared to monthly treatment,” he said.

The second year of the VIEW study showed that for many patients a treatment interval close to 3 months can be achieved with both ranibizumab and aflibercept, Dr. Mitchell said.

“Interestingly, that trial also showed that half of the patients either needed significantly more or significantly less than the average number of injections. The top 25% typically needed six injections to eight injections and another quarter only three injections. There is quite a wide difference in the amount of individual therapy, and it does make sense to individualize treatment,” he said.

According to Dr. Lanzetta, the as-needed concept might be appealing. However, the criteria to tailor it to the individual patient’s response are still lacking, re-treatment parameters and the interpretation of these parameters are still unclear, and the real world scenario of as-needed treatments outside clinical trials is disappointing.

“Once the VEGF Trap-Eye becomes available, it makes sense to consider treating patients on a fixed schedule, every 2 months,” he said.

Although Dr. Lanzetta has not yet published his results, an exploratory analysis of the efficacy of ranibizumab administered at fixed 8-week intervals in his own patients suggests that this treatment schedule may also work with aflibercept.

In some cases, and only if patients are good responders, treat-and-extend might be an alternative, according to Dr. Oubraham.

After a loading phase of three monthly injections, all patients are seen at 6 weeks to receive a fourth injection. Subsequent visits are adapted to individual patients, extending or shortening the interval by 2 weeks according to the presence or absence of subretinal fluid. At all visits an injection is given, regardless of the state of the lesion, Dr. Oubraham explained.

This schedule has the advantage of decreasing the trauma of repeated monthly injections and the burden of fixed, multiple controls.

In a study, this method was retrospectively compared with the as-needed regimen and showed better efficacy. While the number of visits and injections was according to plan in the treat-and-extend group, the as-needed group missed a considerable number of visits.

“This explains why results were inferior,” Dr. Oubraham said.

“Treat-and-extend is an approach that many of us use, including myself,” Dr. Mitchell said. “It is convenient for clinicians and easy for patients to understand. People know they are going to have an injection at each visit, and therefore they can reconcile to that rather than saying to the nursing staff, ‘I hope the doc does not give me an injection today.’”

Whatever the choice, surgeons agree that reducing the treatment burden is a priority.

Tien Yin Wong

“Monthly injections for an unpredictable number of years are an unsustainable burden for patients, physicians and health care systems,” Dr. Wong said.

“We need to reduce this burden and with it the risk of adverse events and the social costs involved,” Dr. Mitchell said.

Role of OCT

In the era of anti-VEGF therapy, optical coherence tomography plays a key role in the diagnosis and management of AMD and other retinal diseases.

“The new spectral-domain technology allows us to detect subtle structural damage and fluid in particular, which is a sign of the activity of many retinal diseases. And this allows us to tailor the treatment according to the damage and the amount of activity and fluid that can be seen,” Dr. Wong said.

Treating in the presence of any fluid is the recommended practice, and new parameters, based on the status of the external limiting membrane and photoreceptors, in particular in the inner segment/outer segment junction, might be developed.

OCT has been used to monitor the effects of treatment and, based on this, to decide whether to re-inject or not. However, in the last 3 years, spectral-domain OCT technology has also been used to investigate prognostic factors that might help differentiate between responders and non-responders to anti-VEGF treatment, Christian Simader, MD, said.

Responders are defined, in most cases, as patients who gain vision, he said. The lack of photoreceptor integrity has been identified in some studies to be a factor for worse visual prognosis even after resolution of fluid.

“An intact photoreceptor layer and an intact pigment epithelial layer appear to be correlated with best visual prognosis. OCT allows us to analyze these layers, even if CNV makes visualization difficult,” he explained.

The EXCITE study, in which Dr. Simader was involved, and other OCT studies are progressively categorizing the morphological criteria, including retinal and vitreomacular structures, which are correlated with a different response to anti-VEGF treatment.

“These findings will help us defining more precise and individualized PRN re-treatment criteria,” Dr. Simader said. “I am sure that we will eventually achieve a PRN re-treatment modality that is comparable to monthly.”

Prevention, early treatment

The investigation of modifiable risk factors for AMD has spurred the interest of researchers for many years. Large studies such as the AREDS, the Rotterdam Study and the Blue Mountains Eye Study have demonstrated how lifestyle habits may influence and contribute to AMD.

“Recent data have also shown an interaction between genetic and environmental factors. The Rotterdam Study has demonstrated that people who have a better diet, though they carry the genes for AMD, have a reduced incidence, close to the non-carriers. And the Blue Mountains Eye Study teaches us that between the development of large soft drusen and late-stage AMD there is quite a long window in which we could advise people about modifying risk factors that might be quite important in terms of their ultimate risk,” Dr. Mitchell said.

The correlation between an early diagnosis and a better outcome was also clarified by studies. Both the MARINA and ANCHOR trials have shown that better baseline visual acuity and smaller lesion size are associated with better outcomes. The CATT recruited patients at the early stage of the disease, with a higher baseline and upper limit of vision and a smaller lesion size. Even more important, in 40% of the CATT cases, choroidal neovascularization did not involve the center of the fovea.

“We would expect that these cases in CATT, those who did not involve the center of the fovea, those who had a much better vision and those who had a smaller lesion, should do extremely well in particular in a PRN approach. They should require less frequent treatment and have a much better overall vision gain and stability than eyes at a more advanced stage,” Dr. Mitchell said.

Dr. Lowenstein was involved in the development of a device for early detection of CNV and CNV recurrence. The Preferential Hyperacuity Perimeter (Notal Vision) is able to detect minute changes in the relative localization of objects in space.

“We are now using this device as a part of the AREDS trial. The device is also conceived for home use, so that patients can self-detect changes. Home monitoring may help reduce the need for monthly visits,” Dr. Loewenstein said.

A worthwhile investment

Anti-VEGFs have found application in the treatment of other retinal conditions, such as diabetic macular edema, macular edema following retinal vein occlusion and myopic CNV.

“I am quite surprised that the developers of anti-VEGF therapy have not been awarded the Nobel Prize for ophthalmology. Having such an extraordinary success is extremely gratifying,” Dr. Mitchell said.

On one hand, anti-VEGFs have offered sorely needed effective treatment, but on the other hand, they have created an emergency situation for health care systems worldwide because of the cost, Dr. Lanzetta said.

“If preserving vision is the issue at stake, ophthalmology becomes necessarily a field [in] which to invest considerable resources,” he said.

“We are in the lucky situation of being able to treat many patients with a lot of efficacy, but a huge burden as well,” Dr. Schmidt-Erfurth said. “It is easy to prove that it is worth it, that it is an excellent investment, but old budgets are totally inadequate to these new therapies. If societies care for the vision of their citizens, this investment is out of discussion and we’ll continue fighting for it.” – by Michela Cimberle

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References:

• CATT Research Group, Martin DF, Maguire MG, Ying GS, Grunwald JE, Fine SL, Jaffe GJ. Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med. 2011;364(20):1897-1908.
• Dixon JA, Oliver SC, Olson JL, Mandava N. VEGF Trap-Eye for the treatment of neovascular age-related macular degeneration. Expert Opin Investig Drugs. 2009;18(10):1573-1580.
• Do DV, Schmidt-Erfurth U, Gonzalez VH, et al. The DA VINCI Study: phase 2 primary results of VEGF Trap-Eye in patients with diabetic macular edema. Ophthalmology. 2011;118(9):1819-1826.
• Golbaz I, Ahlers C, Stock G, et al. Quantification of the therapeutic response of intraretinal, subretinal, and subpigment epithelial compartments in exudative AMD during anti-VEGF therapy. Invest Ophthalmol Vis Sci. 2011;52(3):1599-1605.
• Ho L, van Leeuwen R, Witteman JC, et al. Reducing the genetic risk of age-related macular degeneration with dietary antioxidants, zinc, and ù-3 fatty acids: the Rotterdam study. Arch Ophthalmol. 2011;129(6):758-766.
• Holz FG, Korobelnik JF, Lanzetta P, et al. The effects of a flexible visual acuity-driven ranibizumab treatment regimen in age-related macular degeneration: outcomes of a drug and disease model. Invest Ophthalmol Vis Sci. 2010;51(1):405-412.
• Kawasaki R, Yasuda M, Song SJ, et al. The prevalence of age-related macular degeneration in Asians: a systematic review and meta-analysis. Ophthalmology. 2010;117(5):921-927.
• Loewenstein A. Macular diseases: moving the battlefield to the patient’s home. Retina. 2011;31(8):1445-1448.
• Loewenstein A, Ferencz JR, Lang Y, et al. Toward earlier detection of choroidal neovascularization secondary to age-related macular degeneration: multicenter evaluation of a preferential hyperacuity perimeter designed as a home device. Retina. 2010;30(7):1058-1064.
• Loewenstein A; Richard & Hinda Rosenthal Foundation. The significance of early detection of age-related macular degeneration: Richard & Hinda Rosenthal Foundation lecture, The Macula Society 29th annual meeting. Retina. 2007;27(7):873-878.
• Ni Z, Hui P. Emerging pharmacologic therapies for wet age-related macular degeneration. Ophthalmologica. 2009;223(6):401-410.
• Oubraham H, Cohen SY, Malbrel C, Mimoun G, Zourdani A. The LUMIERE study; changes in visual acuity in patients with wet AMD treated with ranibizumab in real-life conditions of use in France. Poster presented at: Association for Research in Vision and Ophthalmology meeting; 2011; Fort Lauderdale, Fla.
• Oubraham H, Cohen SY, Samimi S, et al. Inject and extend dosing versus dosing as needed: a comparative retrospective study of ranibizumab in exudative age-related macular degeneration. Retina. 2011;31(1):26-30.
• Pai AS, Mitchell P, Rochtchina E, Iyengar S, Wang JJ; Blue Mountains Eye Study. Complement factor H and the bilaterality of age-related macular degeneration. Arch Ophthalmol. 2009;127(10):1339-1344.
• Schmidt-Erfurth U, Eldem B, Guymer R, et al; EXCITE Study Group. Efficacy and safety of monthly versus quarterly ranibizumab treatment in neovascular age-related macular degeneration: the EXCITE study. Ophthalmology. 2011;118(5):831-839.
• Tan JS, Wang JJ, Flood V, Mitchell P. Dietary fatty acids and the 10-year incidence of age-related macular degeneration: the Blue Mountains Eye Study. Arch Ophthalmol. 2009;127(5):656-665.
• Two year results of Phase III Studies with VEGF Trap-Eye in Wet Age-related Macular Degeneration Show Sustained Improvement in Visual Acuity. Bayer HealthCare website. http://www.animalhealth.bayerhealthcare.com/4007.0.html?&no_cache=1&tx_ttnews%5Btt_news%5D=2606&cHash=73d59bca19fa5378c387def35d72ad10. Dec. 5, 2011.
• Waisbourd M, Goldstein M, Loewenstein A. National survey of the ophthalmic use of anti-vascular endothelial growth factor drugs in Israel. Isr Med Assoc J. 2011;13(3):141-146.
• Wang JJ, Rochtchina E, Lee AJ, Chia EM, Smith W, Cumming RG, Mitchell P. Ten-year incidence and progression of age-related maculopathy: the blue Mountains Eye Study. Ophthalmology. 2007;114(1):92-98.
• Wang JJ, Rochtchina E, Smith W, et al. Combined effects of complement factor H genotypes, fish consumption, and inflammatory markers on long-term risk for age-related macular degeneration in a cohort. Am J Epidemiol. 2009;169(5):633-641.

• Paolo Lanzetta, MD, can be reached at University of Udine, Department of Ophthalmology, Piazzale S. Maria della Misericordia, 33100 Udine, Italy; +39-0432-559-905; fax: +39-0432-559-904; email: paolo.lanzetta@uniud.it.
• Anat Loewenstein, MD, can be reached at Tel Aviv Sourasky Medical Center, Department of Ophthalmology, 6 Weizmann St., Tel Aviv, Israel 64239; email: anatlow@tasmc.health.gov.il.
• Paul Mitchell, MD, PhD, can be reached at University of Sydney, Eye Clinic, Westmead Hospital, Hawkesbury Road, Westmead, 2145, Australia; +61-2-9845-7960; fax +61-2-9845-6117; email: paul.mitchell@sydney.edu.au.
• Hassiba Oubraham, MD, can be reached at Department of Ophthalmology, Centre Hospitalier La Source, 14, avenue de l’Hôpital, 45 067 Orléans Cedex 2, France; +33-2-38-74-43-77; fax: +33-2-38-74-48-28; email: hassibaoubraham@gmail.com.
• Ursula Schmidt-Erfurth, MD, can be reached at Medical University Vienna, Department of Ophthalmology, Waehringer Guertel 18-20, A-1090 Vienna, Austria; +43-1-40400-7931; fax: +43-1-40400-7932; email: ursula.schmidt-erfurth@meduniwien.ac.at.
• Christian Simader, MD, can be reached at Medical University Vienna, Department of Ophthalmology, Waehringer Guertel 18-20, A-1090 Vienna, Austria; +43-1-40400-3307; email: christian.simader@meduniwien.ac.at.
• Tien Yin Wong, MD, PhD, can be reached at Singapore Eye Research Institute, Singapore National Eye Centre, 11 Third Hospital Avenue, Singapore 168751; +65-63224571; fax: +65-63231903; email: tien_yin_wong@nuhs.edu.sg.
• Disclosures: Dr. Lanzetta is a consultant for Allergan, Bayer and Novartis. Dr. Loewenstein is a consultant for Notal Vision, Allergan, Novartis, Alimera. Dr. Mitchell is a consultant for Novartis, Bayer, Pfizer, Allergan, Alcon and Solvay. Dr. Oubraham is a consultant for Novartis and Allergan. Dr. Schmidt-Erfurth is a consultant for Carl Zeiss, Novartis, Heidelberg Engineering, Bayer Schering and Genentech. Dr. Simader has no relevant financial disclosures. Dr. Wong is a consultant for Novartis, Allergan, Bayer, Pfizer and Solvay.