Waiting for study results, physicians explore ways to optimize AMD treatment

Many physicians are awaiting the results of a trial comparing two leading anti-VEGF agents in the treatment of neovascular age-related macular degeneration. But because study results will not be known for several years, they continue to practice with varying therapies, regimens and doses, trying to find an ideal treatment for their patients.

The CATT is comparing Lucentis (ranibizumab, Genentech), which has been approved by the U.S. Food and Drug Administration to treat wet AMD, vs. Avastin (bevacizumab, Genentech), which is used off-label for this indication.

The large, multicenter trial is not scheduled to be completed until 2011, and in the meantime, physicians are also looking at other ways to optimize treatment.

Combining existing therapies and decreasing the number of re-treatments are of particular interest, and both are being done in clinical practice.

Subhransu K. Ray, MD, PhD, said he sees neovascular AMD as a heterogeneous disease process. Treatment of the disease should be more individualized, accounting for particular features of its presentation.

Subhransu K. Ray, MD, PhD, said that physicians should tailor the treatment to the specific clinical features of the disease in AMD patients. Image: Vaccaro B

“You really have to tailor your treatment to the specific clinical features of disease these patients have,” Dr. Ray said.

Varying presentations of AMD

AMD has a complex pathogenesis, involving vascular, nonvascular and inflammatory components.

Patients do not always present with a classic neovascular membrane, subretinal fluid and subretinal hemorrhage, Dr. Ray said. Pigment epithelial detachments, sub pigment epithelial hemorrhages, pigment epithelial rips and cystoid macular edema are all also varying presentations of the disease. These findings likely point to a multifactorial maintenance of the disease state.

“It’s hard to define one right treatment for a disease that is so heterogeneous in terms of its presentation and disease progression,” he said.

Dr. Ray said that VEGF is not the only biological factor at play in neovascular AMD, hence the focus on combined and tailored treatments.

“We know based on pathology samples that are taken from patients with wet AMD that there is a real presence of inflammatory mediators,” Dr. Ray said, citing expression of MHC class II molecules as well as an influx of microphages and leukocytes. “It’s clearly not just VEGF that is maintaining this neovascular complex. VEGF may be central to initiating and supporting the membrane as well as promoting vascular leakage, but other agents are also involved. Thus, even with chronic monthly suppression of VEGF over 12 or even 24 months, many of these membranes promptly leak after discontinuation of therapy.

“There isn’t just one grab bag diagnosis of ‘wet AMD.’ That was a classification we used when we didn’t have the variety of high-tech imaging tools, when we didn’t have all the collection of variable presentations, so we had to call it either ‘dry’ or ‘wet,’ and that simplistic division is not as valid anymore,” he said. “In fact, in the future, we would hope to use genetic markers, refined imaging tools, as well as direct measures of an individual’s biological markers, to better define optimal treatment protocols.”

Although AMD is non-neovascular in approximately 80% of cases, 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. According to the National Eye Institute, AMD is the leading cause of severe vision loss in people older than 65 years of age in the United States, and the advanced stage currently affects one or both eyes of 1.6 million Americans.

Combination therapies

At least 17 studies are under way to compare some form of combination treatment with ranibizumab therapy, according to the National Institutes of Health Clinical Trials Registry.

Dr. Ray is the lead investigator in the PDEX II trial, a prospective, randomized, multicenter study comparing ranibizumab, dexamethasone and Visudyne (verteporfin, Novartis/QLT) triple therapy with ranibizumab monotherapy.

In the PDEX II trial, as in many other studies, the visual acuity results achieved in the ANCHOR and MARINA trials are considered the gold standard for comparison.

“We decided to set a trial where we looked at triple therapy vs. the best defined form of monotherapy at the time, which was 12 straight months of ranibizumab,” Dr. Ray said.

All patients in the study received treatment on day 0. Afterward, patients in the ranibizumab group received monthly intravitreal injections for 12 months; patients in the triple therapy group received further treatment only when needed as determined by evidence of subretinal hemorrhage, subretinal fluid or cystoid edema seen on optical coherence tomography or clinical examination or by evidence of leakage on angiogram.

Dr. Ray reported at the American Society of Retina Specialists meeting that patients receiving the triple therapy needed fewer than four treatments per year, and 10% of patients in the triple therapy group did not require any subsequent treatment while achieving comparable vision to the monotherapy group. The study completed its last patient visit in December, and the final data are being prepared for a manuscript that is expected this quarter.

“We are still carefully analyzing the data, but the overall gist is that you may be able to achieve similar visual outcomes with reduced treatment numbers,” he said.

Dr. Ray is currently enrolling patients for the LuceDex trial, a combination therapy trial that will compare dexamethasone plus ranibizumab against ranibizumab alone.

The LuceDex trial will evaluate whether an added bolus of dexamethasone with each dose of ranibizumab will reduce the number of treatments over time or reap a better clinical response with respect to vision and lesion suppression and/or eradication.

So far, Dr. Ray said, “both groups, not surprisingly, do exceedingly well given the tremendous action of ranibizumab alone. … However, there may be certain subpopulations of patients who may respond even better with the added dexamethasone treatment, and that’s part of what we’re investigating.”

Combining therapies to treat AMD is becoming a common practice.

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

Ursula Schmidt-Erfurth

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,” according to Ursula Schmidt-Erfurth, MD.

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 photodynamic therapy and ranibizumab.

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

Tailoring monotherapy

The combined results of the MARINA and ANCHOR 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.

“Most people think there’s really nothing we’re doing right now that’s resulting in better vision outcomes than what MARINA and ANCHOR studies showed,” Carl D. Regillo, MD, OSN Retina/Vitreous Board Member, said. He said the two pivotal phase 3 studies established that the best visual acuity results to date are achieved with 12 monthly treatments with an anti-VEGF agent.

“Monotherapy is really the standard for most practitioners,” Dr. Regillo said.

However, the required number of initial treatments and re-treatments is under investigation, both in the research laboratory and in practice.

The CATT will examine whether a reduced dosing schedule based on clinical response is as effective as a fixed schedule of monthly injections. Monthly surveillance will include OCT to monitor changes in subretinal and intraretinal fluid as well as fluorescein angiography to measure changes in lesion size.

Dr. Regillo is an investigator in the PIER study, which is looking at a less frequent fixed-dosing regimen of ranibizumab for neovascular AMD. The dosing regimen was intravitreal injection of ranibizumab once monthly for 3 months and then once every 3 months. First-year results were published in the American Journal of Ophthalmology, and even though a statistically significant benefit in visual acuity was achieved, the amount of benefit did not match that in the MARINA and ANCHOR regimens.

“After the results of the first year, the protocol changed,” Dr. Regillo said. In results presented at the Macula Society meeting in 2008, he reported that intensified monthly treatment in patients who had been receiving injections only every 3 months resulted in some added visual acuity benefit. In patients who started treatment after being in the placebo group for a year or more, however, little benefit could be achieved with either quarterly or monthly treatment.

Investigators continue to look for the optimum number of treatments that will result in outcomes comparable to those achieved in the MARINA and ANCHOR studies.

Treat-and-extend approach

One strategy aimed at reducing the number of intravitreal injections is the treat-and-extend approach, which, Dr. Regillo said, may hold the promise of fewer treatments, fewer office visits and less testing.

“A lot of us, including myself, use this style of individualizing therapy,” he said.

In this strategy, patients are treated with injections monthly until all signs of wetness or exudation have resolved, as seen on OCT examination. Afterward, treatment visits are extended, usually by a week or two at a time.

“So you’re fine-tuning or trying to come up with the ideal treatment interval for a given patient,” Dr. Regillo said.

Carl D. Regillo

He said patients have a good understanding that with each visit they are getting an evaluation and a treatment. The only decision to make is whether to extend the treatment interval, keep it the same or cut it back.

By using the least number of treatments to achieve good vision outcome, “we’re minimizing the risks, minimizing the cost, minimizing the inconvenience of office visits, testing and so forth,” Dr. Regillo said.

Treatment in Europe

Responding to the results of several studies on AMD therapies, physicians in Europe are modifying their regimens 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,” Dr. Lanzetta said.

“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 have also been clarified. The type, stage and severity of the lesion should be evaluated on the basis of visual acuity, fundus biomicroscopy, fluorescein angiography and OCT.

Dr. Lanzetta’s clinical 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 studies such as PIER, EXCITE, PrONTO and SUSTAIN 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 the patient is monitored at regular monthly intervals, he said.

Dr. Schmidt-Erfurth said that by adopting this more flexible, individualized regimen, 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 monthly, 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.

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

Additional therapies evaluated

Researchers are 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. The phase 3 COBALT clinical trial will evaluate whether bevasiranib administered every 8 or 12 weeks is as effective as ranibizumab administered every 4 weeks for preventing vision loss. Its effectiveness in maintenance therapy after initiation with three doses of ranibizumab is also under investigation.

VEGF Trap-Eye (Bayer HealthCare 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. One arm of the phase 3 VIEW studies is enrolling a cohort to be treated with 2 mg of VEGF Trap-Eye every 8 weeks compared with every 4 weeks.

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.

Non-anti-VEGF agents

Anti-VEGF agents are efficacious in lessening neovascularization, but some patients may not improve with therapy because of factors such as scarring and atrophy, Jeffrey S. Heier, MD, said.

The hope in ophthalmology for developing non-anti-VEGF agents — with antifibrotic, anti-inflammatory or neuroprotective properties — is that they can be used either as monotherapy or in combination with anti-VEGF drugs to maximize outcomes, he said.

Dr. Heier delivered early results of a phase 1 study on the intravitreal use of alpha-5-beta-1 integrin antagonist JSM 6427 (Jerini) at the American Society of Retina Specialists meeting.

In eyes with long-standing disease that had undergone multiple therapies, JSM 6427 showed early biological activity, which is promising with regard to treatment response, Dr. Heier said.

Another investigational agent, volociximab (Ophthotech), is a chimeric monoclonal antibody that inhibits the functional activity of alpha-5 beta-1 integrin found on the endothelial cells involved in the formation of blood vessels.

These drugs are still in early development, and their use in future treatments is still unclear.

Nevertheless, Dr. Heier sees potential for synergy between the non-VEGF mechanisms of action in combination with the established anti-VEGF mechanisms.

According to Jordi Mones, MD, 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.

One such compound 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 address 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,” he explained.

“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 and Pat Nale

Of the ongoing studies regarding treatment for wet AMD, which results are you looking forward to the most?

References:

• 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.
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• 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.
• Opko Health completes enrollment of phase 3 trial of compound for AMD treatment. www.osnsupersite.com.
• Regillo CD, Brown DM, Abraham P, Yue H, Ianchulev T, Schneider S, et al, on behalf of the PIER Study Group: Randomized, double-masked, sham-controlled trial of ranibizumab for neovascular age-related macular degeneration: PIER study year 1. Am J Ophthalmol. 2008;145:239-248.
• Registry of clinical trials: www.ClinicalTrials.gov; accessed Jan. 19, 2009.
• 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.

• Jeffrey S. Heier, MD, can be reached at Ophthalmic Consultants of Boston, 50 Staniford St., Suite 600, Boston, MA 02114; 617-367-4800; fax: 617-723-7028; e-mail: jsheier@eyeboston.com. Dr. Heier is a scientific advisor for which he receives consulting fees for Alcon Laboratories, Allergan, Genentech, iScience, Ista Pharmaceuticals, Jerini Ophthalmics, NeoVista, Novartis, Oxigene, Paloma, Pfizer, Regeneron and VisionCare Ophthalmic Technologies. He is involved in clinical trials for Alcon Laboratories, Allergan, Genentech, iScience, Ista Pharmaceuticals, Jerini Ophthalmics, NeoVista, Novartis, Pfizer, Regeneron and VisionCare Ophthalmic Technologies. He has been a presenter for which he receives honoraria for Genentech, Jerini Ophthalmics, NeoVista and Regeneron.
• 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. Dr. Lanzetta is a consultant for NeoVista and Novartis Pharma. He has a patent with Iridex. He has received honoraria or travel reimbursement from Allergan, Novartis Pharma, QLT and OptiMedica.
• 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. Dr. Mones has received consultant fees from Novartis, Allergan, Alcon, Ophthotech, Notal Vision, Pfizer, Eyetech and Genaera.
• Subhransu K. Ray, MD, PhD, can be reached at Bay Area Retina Associates, 122 LaCasa Via, Suite 223, Walnut Creek, CA 94598; 925-943-6800; fax: 925-848-3977; e-mail: retina01@gmail.com. Dr. Ray has received unrestricted grants from QLT and Genentech for the PDEX II and LuceDex studies, respectively. He is a consultant for QLT, Novartis and Genentech.
• Carl D. Regillo, MD, can be reached at Wills Eye Institute, 840 Walnut St., Suite 1020, Philadelphia, PA 19107; 215-264-3159; fax: 610-856-7787; e-mail: cregillo@aol.com. Dr. Regillo has received research grant support from Genentech, Novartis, QLT, Regeneron, Alimera and Allergan. He is a consultant for Genentech, Alcon and Novartis.
• 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. Dr. Schmidt-Erfurth is a consultant for Carl Zeiss, Novartis, Heidelberg Engineering, Bayer Schering and Genentech.