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

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, has been approved by the U.S. Food and Drug Administration and has 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.

Image: Wong TY

“Monthly injections undoubtedly achieve the best efficacy but create an unsustainable burden for patients, physicians and health care systems. The need to develop new schedules that will reduce the number of injections has become priority, but there is concern about under-treatment using the as-needed injection strategies,” Tien Yin Wong, MD, said.

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.

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.

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,” Ursula Schmidt-Erfurth, MD, 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.

Dr. Wong 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.

Costs may become an important factor in the choice.

Real-life options

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.

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.

“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.

“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.”

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

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 -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.

For more information:

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.

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. 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.

 

 

Is intraoperative optical coherence tomography a useful guide for surgery?

Real-time information supports decision-making process

There are several advantages in combining an OCT system with the surgical microscope. By providing real-time information on the surgical procedure and on the behavior of vitreoretinal tissue, it facilitates surgery and supports the surgeon’s decision-making process, thus improving surgical outcome. It also allows us to examine patients who are unable to sit upright, such as infants with ROP and elderly patients, in a lying position, directly on the operating table. OCT examinations can be repeated during surgery, without losing sterility.

Intraoperative imaging is a common practice in other areas, such as neurosurgery, in which different technologies are used for real-time evaluation of structure and function and to guide surgical decisions. We started this new adventure in 2008 and now use OCT routinely for vitreoretinal surgery. In cataract surgery, we have a study ongoing in which intraoperative OCT is used to measure foveal thickness and evaluate optic nerve behavior.

I think that the disadvantage of using OCT for only postoperative examination is that you can no longer change what has been done without reopening the eye and doing repeat surgery. If there are residual membranes, you can certainly diagnose them postoperatively, but only intraoperative imaging allows you to peel them off in the same session. If you have a patient with opaque media, such as a dense cataract, you cannot do OCT before surgery, but can remove the cataract and do OCT on the table immediately after. This is even more important in patients with a history of AMD because you can evaluate the condition of the fovea, and if there is some fluid, you can treat the eye immediately with anti-VEGF at the end of surgery. Thanks to OCT, you can also see the impact of cataract surgery in patients with dry AMD. In patients with retinal detachment, you can differentiate between a macula-on and macula-off detachment with higher certainty.

 

Susanne Binder, MD, is an OSN Europe Edition Board Member and can be reached at Rudolph Foundation Clinic, Vienna, Austria. Disclosure: Dr. Binder has no relevant financial disclosures.

Current technology not ready for intraoperative use

Intraoperative OCT, despite being a very promising technology, is still in its infancy. Available devices have significant limitations regarding real-time imaging, microscope integration, time efficiency and analysis software. Moreover, the importance of this imaging modality in improving surgical outcomes has not yet been demonstrated.

Most intraoperative OCT systems are derived from diagnostic OCTs adapted to be integrated in the operating room instrumentation. Some of them require the procedure to be stopped in order to acquire images. This results in a non-real-time imaging of surgical maneuvers, with significant time delays and with the need of additional operators to control the instrument.

In addition, most of the surgical instruments that are in use today are metallic. This causes critical shadowing of the OCT image and affects the real-time visualization of ocular tissues.

Software analysis packages are still lacking in the fields of real-time analysis of OCT data and in the identification of critical feedback to the vitreoretinal surgeon. Moreover, we need to develop imaging protocols specifically designed for intraoperative use that can provide the surgeon with a simultaneous display of the surgical field and fast real-time OCT imaging.

In conclusion, it is uncertain how intraoperative OCT will change vitreoretinal surgery and what will be its impact on surgical outcomes and visual results. Extensive research is still needed to fix the inadequate areas of this technology. Nevertheless, real-time intraoperative OCT promises to be a useful adjunctive tool in surgical decision making, and it has also shown to be an ideal imaging technique to provide a real-time dosimetry of subthreshold laser retinal photocoagulation, in which fast scanning and proper aiming are much easier to obtain.

 

Daniele Veritti, MD, can be reached at Department of Ophthalmology, University of Udine, Udine, Italy. Disclosure: Dr. Veritti has no relevant financial disclosures.