COMANAGEMENT
Advances in AMD Care
Top specialists provided insight into the management and treatment of AMD during the second Retinal Physician Symposium.

The second annual Retinal Physician Symposium (RPS), held in early June, presented a comprehensive overview of the latest therapeutic approaches for the management of age-related macular degeneration. (Editor's note: RPS is produced by the Healthcare Conference Group of Lippincott Williams & Wilkins (LWW) VisionCare. LWW also publishes both Retinal Physician and Optometric Management.)

One of the key questions entering the meeting was: Are quarterly injections of Lucentis (ranibizumab, Genentech) as effective as monthly injections? Previous studies have concluded that monthly injections are safe and can improve the vision of patients with wet AMD. In presenting one-year data from the PIER trial, David Brown, M.D., explained that quarterly dosing was safe and initially provided patients with an average of 15- to 16-letter improvement in acuity over sham injections. Unfortunately, visual acuity, on average, returned to baseline by the 12th month.

As a result, Genentech recommends that patients receive monthly injections of Lucentis or have their treatment schedules determined based on individualized testing.

The role of Avastin

Of equal interest, Philip Rosenfeld, M.D., provided an update on the use ofAvastin (bevacizumab, Genentech), as an off-label therapy for the treatment of wet AMD. Avastin has been approved by the FDA for first- or second-line treatment of metastatic colorectal cancer.

Dr. Rosenfeld pioneered the use of Avastin in wet AMD patients. He recognized the molecular similarities between Lucentis and Avastin and began with intravenous delivery of Avastin to a few wet AMD patients.

Dr. Rosenfeld did not see the systemic side effects (diarrhea, nausea and vomiting, for example) in his patients that had been reported with some cancer patients treated with Avastin. However, to avoid the potential risk, he switched to intravitreal injection.

Dr. Rosenfeld reported on a patient who demonstrated significant and long-lasting visual improvement after just one injection of Avastin. He also noted that short-term data on 7,000 Avastin injections raised no major safety concerns.

Dr. Rosenfeld said that retina specialists should understand that using Avastin to treat wet AMD is legal and ethical "if you're using good clinical judgment."

Dr. Rosenfeld called for prospective clinical trials to study the safety and efficacy of bevacizumab. His answer may have come last month, when the National Institutes of Health reported it will fund a study to compare the two Genentech drugs (see sidebar, "NIH Funds AMD Therapies Study" on page 32).

The VEGF trap

Peter Kaiser, M.D., reported on other wet AMD therapies that are currently in clinical trials, including vascular endothelial growth factor (VEGF) Trap (Regeneron), RNA interference (Acuity Pharmaceuticals and Sirna Therapeutics), and squalamine (Evizon, Genaera).

Dr. Kaiser says he finds VEGF Trap particularly interesting. VEGF is a protein found in the bloodstream that is secreted by tumors to stimulate new blood vessels that support the tumor. VEGF Trap creates a decoy receptor for VEGF. It binds well to all forms of VEGF and remains effective at low concentrations, possibly offering a longer-lasting duration of action.

A six-week, 21-patient phase 1 trial of VEGF Trap showed a median improvement in visual acuity of 13 letters. Regeneron has initiated a larger phase 2 trial to determine safety and efficacy at doses up to 4mg.

RNA interference silences VEGF-producing genes through the injection of a double-stranded RNA. Sirna has completed a 26-patient, phase 1 trial that consisted of one injection. The study demonstrated improved or stabilized vision in 96% of the study population, with 23% of patients showing a three-line vision gain at eight weeks. Sirna is now forming a phase 2 trial.

Acuity has conducted a 15-patient, 2 injection phase 1 trial with its Cand5 compound. The compound attacks VEGF directly, and in the phase 1 study, 80% of patients demonstrated stable or improved vision. Dr. Kaiser said that in the trial, Cand5 demonstrated an excellent safety profile. A phase 2 trial is currently nearing completion.

Dr. Kaiser mentioned that squalamine, an antiangiogenic given intravenously, has shown some ability to stabilize vision in phase 2 trials. A new, dose-escalating trial of squalamine is underway.

Triple therapy

In another RPS session, Albert Augustin, M.D., reported on a combination called "triple therapy" (an anti-inflammatory steroid, Avastin, and modified PDT) to treat advanced AMD. In seven patients who received the therapy, all showed significant improvement in visual acuity in just one treatment cycle. A second bevacizumab injection was performed in only seven eyes. Dr. Augustin reported that the study did not detect "any steroid-related or other severe side effects of the treatment." He sees the treatment as "more a cure vs. a suppression of the disease process."

OCT and Lucentis

Dr. Rosenfeld reported on the "Prospective OCT Study With Lucentis for Neovascular AMD," or PrONTO study. The study was designed to evaluate the response of advanced AMD patients to intravitreal Lucentis using optical coherence tomography (OCT). OCT images would be used to determine the need for retreatment after patients received three injections of Lucentis, each one month apart.

Dr. Rosenfeld said that he had several patients who were treated with Lucentis and did not require additional retreatment for as long as 31 months. These patients' vision continued to improve without retreatment. He concluded that patients responded differently to this therapy and retreatment could be determined on an individual basis.

In addition, Dr. Rosenfeld reasoned that vision loss was gradual as the fluid accumulated and the OCT was reliable in detecting the fluid before it became symptomatic. After the initial three injections, patients received additional injections only whether the OCT measurements showed a need. The study would address the quickness with which the OCT images and vision improved, as well as if these improvements could be maintained for two years under a prn dosing regimen.

The criteria for retreatment were one or more of the following:

► loss of at least five letters of vision

► evidence of fluid, increased central retinal thickness

► new hemorrhage

► new evidence of classic choroidal neovascularization (CNV).

The mean number of injections per patient in the first year of the two-year study was 5.5, although at least one patient of the 40 received 13 injections. With the need for retreatment unpredictable and unique from patient to patient, the PrONTO study offers a way to determine individual retreatment schedules.

Quantitative vs. qualitative

Dr. Brown facilitated further discussion on imaging in his report on "quantitative vs. qualitative" OCT assessments of disease progression following treatment with Lucentis.

"A patient has anti-VEGF therapy and gets a nice response," noted Dr. Brown. "With time, after treatment, you get diffuse edema. In other words, there's a thickening but no bubbles. This will only be shown by quantitative OCT if it accurately measures the retinal boundaries." (Four types of edema routinely return following treatment with Lucentis: diffuse edema, intraretinal cysts, subretinal edema and subretinal pigment epithelium fluid.)

Dr. Brown said that quantitative OCT assessments (post anti-VEGF treatments) can yield error rates as high as 70% in identifying the need for retreatment because the computer is prone to fixation errors, has difficulty in finding retinal boundaries, and fails to note the presence of subretinal pigment epithelium fluid. However, fluid is visible and easy to detect with qualitative OCT assessments. When fluid is detected, it is recommended that the retina specialist initiate retreatment, agreed both Drs. Brown and Rosenfeld.

The next-generation OCT

Dr. Rosenfeld discussed the "next-generation" OCT technology, called spectral domain, which is being developed by several companies, including Carl Zeiss Meditec and Topcon. At least one of these systems will be commercially available within the next year, predicted Dr. Rosenfeld.

The advantages of the system include increased speed, better sensitivity, higher resolution, and 3-D imaging. In addition, the systems will offer a "huge database that can be manipulated any way you want," said Dr. Rosenfeld.

What about surgery?

Paul Tornambe, M.D., questioned the role of surgery for the treatment of AMD.

"Any disease where you treat the effect of the stimulus rather than treating the stimulus is not going to be successful," he said, adding that "until we are able to do something directly with the up-regulation of a VEGF gene, that as long as VEGF keeps getting produced, we're going to have to keep retreating these people."

Dr. Tornambe summarized that something has to occur further upstream to be effective for advanced AMD.

In addition, he said that choroidal neovascular membrane (CNVM) removal is "dead" and that the Submacular Surgery Trials (SST) showed no visual benefit. Dr. Tornambe expressed disappointment with the surgical results in dealing with large clots. He said he was excited by the prospects of the intravitreal injection of dexamethasone and Lucentis or Avastin as a therapy that may minimize damage.

He concluded that "94% of the macula operations we perform now will not be performed in five years."

Nutrition and AMD

In a presentation on nutrition, AREDS and AREDS 2, Darius Moshfeghi, M.D., said that the AREDS trial "has demonstrated the feasibility and efficacy of antioxidant plus zinc supplementation in preventing progression to advanced forms of AMD in patients with intermediate and advanced forms of AMD."

The AREDS formulation resulted in positive visual acuity outcomes relative to placebo, said Dr. Moshfeghi. He noted that the AREDS 2 trial is enrolling patients to determine the additional benefit, if any, of xanthophyll and/or omega-3 long-chain polyunsaturated fatty acid supplementation in prevention of progression of AMD. (For more information on the AREDS 2 study, see the September issue of Optometric Management, page 12, "AREDS 2 Continues the Study of AMD and Nutrition.")

Other research

Allen C. Ho, M.D., discussed prevention trials and the status of trials outside of AREDS. Dr. Ho is interested in the roles of docosahexaenoic acid (DHA), and eicosapentaenoic acid in preventing the progression to advanced AMD. He said that omega-3 fatty acids may protect against AMD progression.

Dr. Ho expressed interest in laser to drusen (using low-energy laser treatment for "soft" drusen). However, preliminary studies did not provide enough evidence to assess whether laser to drusen decreased incidence of advanced AMD, choroidal neovascularization or geographic atrophy.

He acknowledged that rheotherapy, a blood filtering procedure, is an interesting concept, but it did not meet the primary efficacy outcome in a recent phase 3 trial (another phase 3 trial is being planned).

In assessing the anecortave acetate study, a pharmacologic prevention trial, Dr. Ho said the drug may be most apt for prevention of CNV and may be a useful adjunct to Lucentis in the treatment of existing CNV.