AMD treatment in Europe focuses on combination therapies, new innovations

The use of anti-VEGF agents as a treatment for the neovascular form of age-related macular degeneration has been one of the most significant advances in ophthalmology in recent years.

Although AMD is non-neovascular in the majority of cases — around 80%, according to several studies — the neovascular form is responsible for about 90% of the cases in which the disease leads to severe visual loss of 20/200 or worse.

Previously, only a minority of these patients were eligible for treatment, and the best that could be achieved was to slow down the progression of the disease and stabilize vision. But now, the majority of patients qualify for the new anti-VEGF treatments and can expect an improvement in visual acuity.

Two anti-VEGF agents, Macugen (pegaptanib sodium, Eyetech/Pfizer) and Lucentis (ranibizumab, Genentech), have been subjected to randomized controlled trials, known as level 1 evidence. Because vision outcomes proved to be significantly better with ranibizumab, pegaptanib is rarely used as a therapy.

A third agent, Avastin (bevacizumab, Genentech), the “mother” molecule of ranibizumab and an approved cancer treatment, is widely used off-label worldwide in the treatment of neovascular AMD. A number of small studies — levels 2 and 3 evidence — suggest that it is well tolerated and effective, and the price is appealing: One injection of bevacizumab costs 40 times less than an equivalent dose of ranibizumab.

However, because no randomized clinical trial has established its safety and long-term efficacy as an intraocular medication, its use is controversial and has been a topic for debate for the last 2 years, particularly after the approval of ranibizumab by both the European Medicines Agency and the U.S. Food and Drug Administration.

To cut down on both costs and number of re-treatments, and to obtain even better visual outcomes, multi-modal treatment protocols have been suggested, such as the use of anti-VEGF agents in combination with photodynamic therapy and/or corticosteroids.

More recently, new lines of treatment have been investigated. Some of them remain within the mainstream of VEGF inhibition and are already undergoing phase 3 trials. Other drugs are attacking the disease with a different strategy and may be promising new options.

Recommendations on anti-VEGF therapy

The safety and efficacy of ranibizumab was proven in the ANCHOR and MARINA studies.

The combined results of these trials showed that approximately 90% of the treated patients lost fewer than 15 letters, more than 70% maintained baseline vision and 30% improved by 15 letters or more. The difference compared with controls was statistically significant.

A number of subsequent studies, such as PIER, EXCITE, PrONTO and SUSTAIN, investigated different regimens of administration in terms of dosing and frequency of re-treatment.

“Based on this large body of evidence, we are now able to draw some conclusions on how to deal with AMD patients in our daily practice,” said Paolo Lanzetta, MD, associate professor at Udine University in Italy.

Paolo Lanzetta

“First of all, we have learned that all subtypes of neovascular AMD lesion can benefit from ranibizumab treatment,” he said. “This includes classic, minimally classic and occult CNV lesions.”

The means for diagnosis also have been clarified. The type, stage and severity of the lesion should be evaluated on the basis of visual acuity, fundus biomicroscopy, fluorescein angiography and optical coherence tomography.

Treatment entails an induction phase with three consecutive monthly injections and a maintenance phase.

“Most of the visual gain is obtained with the first three injections, with a peak after the first one, which should be performed as early as possible after diagnosis. In between injections, visual acuity and ocular fundus should be examined in all the cases, while fluorescein angiography should be repeated only in presence of a significant visual acuity loss. The role of OCT is becoming more relevant with the advent of high-resolution scan,” Dr. Lanzetta said.

Maintenance is still open for debate because the studies have come up with a variety of suggestions.

“If we look at the overall results, statistically, the best outcomes were obtained with monthly injections also at this stage. This approach is what I would recommend whenever possible,” Dr. Lanzetta said.

However, an as-needed regimen can be adopted, provided that a regular monitoring of the patient is done at monthly intervals, he said.

Ursula Schmidt-Erfurth, MD, professor of ophthalmology at Vienna University, Austria, said that by adopting this more flexible, individualized attitude, a significant reduction in the number of intravitreal injections can be achieved, with beneficial effects on the patient’s quality of life and a significant reduction of the public costs involved.

“As the SUSTAIN study results have recently demonstrated, after the first three monthly injections, re-treatment should be performed when patients show the typical signs of an active lesion, like deterioration of vision and increased retinal thickness,” she said.

Patients should be evaluated once a month, possibly with the use of high-resolution OCT technologies.

“By showing and objectively measuring the individual response to the treatment, this technology can precisely suggest the appropriate timing for re-treatment in individual cases,” she said.

Following this treatment schedule, “excellent improvement and excellent maintenance have been achieved,” she said.

Jordi Mones, MD, who works in a private clinic, the Teknon Macula Retina Institute of Barcelona, Spain, applies the as-needed concept to the entire course of the treatment.

“Some patients do well even after one injection, so I am not injecting strictly three loading doses in every patient. It depends entirely on the case I am dealing with. The disease seems to follow a different rhythm in each patient and may recur every 3 weeks or every 3 months or not at all. Of course, it’s important to know what lesion you are dealing with and adjust your follow-up to the type of lesion,” he said.

Combination therapy

AMD has a complex pathogenesis, involving vascular, nonvascular and inflammatory components. This suggests that a combination of agents, allowing more than one disease factor to be addressed, could be a successful strategy.

“Different agents target different pathways and together might have a synergistic effect,” Dr. Lanzetta said.

In addition, although no official evidence has yet been provided from large-scale trials, “combination therapies might offer the potential to reduce the burden of patient monitoring, as well as reduce the frequency and prolong the effects of single treatments,” Dr. Schmidt-Erfurth noted.

According to Drs. Lanzetta and Schmidt-Erfurth, both who are involved in the MONT BLANC study (the European companion of the DENALI study in the United States and Canada), the best combination is currently PDT and ranibizumab.

“PDT physically occludes CNV, and ranibizumab inhibits angiogenesis and vascular leakage,” Dr. Lanzetta explained.

Intravitreal steroids, on the other hand, may act as inhibitors of inflammatory mediators and reduce edema. They have also been tested in several studies in combination with PDT.

A triple approach, combining PDT, a VEGF inhibitor and a corticosteroid, is an even better approach according to Albert J. Augustin, MD, chairman of the department of ophthalmology at Karlsruhe University, Germany.

Albert J. Augustin, MD, of the department of ophthalmology at Karlsruhe University in Germany, is in favor of combination therapy. Image: Augustin AJ

“I am very much in favor of combination therapy because the pathophysiology, pathobiochemistry and molecular biology of AMD is not for monotherapy. Each component addresses a specific part of the CNV process. With this new regimen, I have found that fewer overall treatments may be needed to maintain retinal health, and many patients can regain some lost vision,” he said.

Because he developed the triple therapy approach before the official approval of ranibizumab in Europe, the drug he uses as an anti-VEGF agent is bevacizumab. As a corticosteroid, he uses dexamethasone, which avoids the sharp IOP spikes caused by triamcinolone.

“I think this triple approach is the best we can offer to AMD patients. I don’t use it routinely, simply because Lucentis monotherapy has now been approved and is reimbursed in Germany. Patients have the right to be offered the first-line approved treatment. I propose the triple approach as a possible experimental alternative and leave the choice to them,” Dr. Augustin said.

In the past, he used to perform core vitrectomy with the triple therapy to prevent the acute IOP rise due to the increased volume created by the injection.

“We no longer use core vitrectomy now. We just do a paracentesis, and results have not changed,” he said.

What is in the future?

Research is continuing to evaluate new pharmacotherapies for AMD that may have greater potential in terms of safety and efficacy and therefore less frequent administration compared with existing therapies.

Bevasiranib (Opko Health) is a first-in-class small interfering RNA drug designed to silence the genes that produce VEGF. Previously experimented as monotherapy, it is proving more effective when administered as maintenance therapy after initiation of anti-VEGF treatment with three doses of ranibizumab, such as in the COBALT and CARBON phase 3 studies, Dr. Lanzetta explained.

VEGF Trap-Eye (Bayer Health Care and Regeneron) is a human soluble VEGF receptor fusion protein that binds all types of VEGF-A as well as the related placental growth factor.

“The VIEW 2 study, which involves 200 centers in Europe, Asia and South America, has also reached phase 3,” Dr. Lanzetta noted.

Additional phase 3 clinical trials, such as the CABERNET and ROSE, evaluating the combination of anti-VEGF pharmacotherapy with radiotherapy (Epi-Rad, NeoVista) are in progress.

According to Dr. Mones, anti-VEGF therapy has reached its standard, and future developments are more likely to come from compounds that address other molecular events that contribute to the pathology of AMD. Some are currently undergoing pre-clinical or phase 1 investigation.

“One of them is E10030 (Ophthotech), an anti-platelet-derived growth factor (anti-PDGF-B) aptamer. PDGF-B plays a key role in recruiting the pericytes that envelop the new vessels and make them more resistant to the anti-VEGF attack. In combination with anti-VEGF, this new agent could represent a breakthrough therapy,” Dr. Mones said.

Other molecules addresses the inflammatory component of AMD.

“The ARC1905 aptamer (Ophthotech) and JPE 1375 (Jerini) inhibit C5, a central component of the complement cascade occurring in macular degeneration. POT 4 (Potentia Pharmaceutical) inhibits C3,” Dr. Mones explained.

Volociximab (Ophthotech), a chimeric monoclonal antibody, inhibits the functional activity of alpha-5 beta-1 integrin found on the endothelial cells involved in the formation of blood vessels, and JSM6427 (Jerini), another integrin antagonist.

“These new strategies hold great promise. Some of them might also be a breakthrough in the treatment of the dry form of AMD, for which nothing has been available up to now,” Dr. Mones said. – by Michela Cimberle

Since the European Medicines Agency approval of Lucentis, is the use of Avastin still justified and ethical?

References:

• Augustin AJ, Puls S, Offerman I. Triple therapy for choroidal neovascularization due to age-related macular degeneration: verteporfin PDT, bevacizumab, and dexamethasone. Retina. 2007;27(2):133-140.
• Bolz M, Schmidt-Erfurth U. Ranibizumab EXCITE study: Exploring the value of optical coherence tomography for the management of ranibizumab therapy in age-related macular degeneration. Presented at the 8th Euretina Congress; May 22, 2008; Vienna.
• Brown MD, Kaiser PK, Michels M, et al; ANCHOR Study Group. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med. 2006;355(14):1432-1444.
• Eter N. Ranibizumab in patients with subfoveal choroidal neovascularization secondary to age-related macular degeneration: 12-month interim safety results from the SUSTAIN trial. Presented at the 8th Euretina Congress; May 23, 2008; Vienna.
• Ferris FL 3rd, Fine SL, Hyman L. Age-related macular degeneration and blindness due to neovascular maculopathy. Arch Ophthalmol. 1984;102(11):1640-1642.
• Hughes MS, Sang DN. New combination approaches explored for AMD management. Retina Today. March-April 2007:14-18.
• Ip MS, Scott IU, Brown GC, et al; American Academy of Ophthalmology. Anti-vascular endothelial growth factor pharmacotherapy for age-related macular degeneration: a report by the American Academy of Ophthalmology. Ophthalmology. 2008;115(10):1837-1846.
• Kahn HA, Leibowitz HM, Ganley JP, et al. The Framingham Eye Study. I . Outline and major prevalence findings. Am J Epidemiol. 1977;106(1):17-32.
• Klein R, Klein BE, Linton KL. Prevalence of age-related maculopathy: The Beaver Dam Eye Study. Ophthalmology. 1992;99(6):933-943.
• Lanzetta P. Combination therapy in AMD. Presented at Symposium on AMD; Oct. 5, 2008; Warsaw.
• Ophthotech Web site: www.ophthotech.com.
• Regillo CD, Brown DM, Abraham P, et al. Randomized, double-masked, sham-controlled trial of ranibizumab for neovascular age-related macular degeneration: PIER Study year 1. Am J Ophthalmol. 2008;145(2):239-248.
• Registry of clinical trials: www.ClinicalTrials.gov.
• Rosenfeld PJ, Brown DM, Heier JS, et al; MARINA Study Group. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006; 355(14):1419-1431.
• Rosenfeld PJ, Fung AE, Lalwani GA, Michels S, Venkatraman AS, Puliafito CA. Visual acuity outcomes following a variable-dosing regimen for ranibizumab in neovascular AMD: the PrONTO Study. Presented at: Association for Research in Vision and Ophthalmology annual meeting; April 30-May 4, 2006; Fort Lauderdale, Fla. E-abstract 2958.

• Albert J. Augustin, MD, can be reached at Augenklinik, Moltkestrasse 90, 76133 Karlsruhe, Germany; +49-7219742001; fax: +49-7219742009; e-mail: albertjaugustin@googlemail.com.
• Paolo Lanzetta, MD, can 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; e-mail: paolo.lanzetta@uniud.it.
• Jordi Mones, MD, can be reached at the Institut de la Màcula I de la Retina, Centro Médico Teknon, Consultoris Vilana 116-117, Vilana 12, 08022 Barcelona, Spain; +34-93-3933117; fax: +34-93-3933017; e-mail: jmones@institutmacularetina.com.
• Ursula Schmidt-Erfurth, MD, can be reached at Medical University of Vienna, Department of Ophthalmology, Waehringer Guertel 18-20, A-1090 Vienna, Austria; +43-1-40400-7931; fax: +43-1-40400-7932; e-mail: ursula.schmidt-erfurth@meduniwien.ac.at.