Pharmacologic treatments for AMD bring rapid change to retina

In the 6 years since PDT was introduced, AMD treatment has evolved from slowing disease progression to improving vision.

Over the past 6 years, the introduction of pharmacologic treatments has revolutionized the treatment of age-related macular degeneration. Less than a decade ago, AMD could only be slowed by destructive laser treatments. Now, beginning with photodynamic therapy in 2000, several pharmacologic treatments have become available and more are on the way. With current treatments, AMD can be slowed, and, if interim results are borne out in the final follow-up of ongoing trials, some AMD patients’ lost vision may even be restored.

As AMD has shifted from a laser-treated to a pharmacologically treated disease, ophthalmologists have been bombarded with an alphabet soup of studies investigating the new treatment options. This article reviews some of those trials and their implications for AMD treatment.

PDT trials

Studies such as the VIP (Verteporfin in photodynamic therapy) and TAP (Treatment of age-related macular degeneration with photodynamic therapy) trials put the spotlight on photodynamic therapy, the first pharmacologic treatment for AMD, which received Food and Drug Administration approval in May 2000.

According to Ocular Surgery News Retina/Vitreous Section Member George A. Williams, MD, the results of these trials showed that PDT could prevent progression of lesions in patients with subfoveal choroidal neovascularization in AMD.

Anti-VEGF trials

George A. Williams

The next pharmacologic treatment to receive regulatory approval was Macugen (pegaptanib sodium injection, OSI/Pfizer) in December 2004. Dr. Williams said that results from the VISION (VEGF inhibition study in ocular neovascularization) trial established that the drug was effective in preventing vision loss in all subtypes of AMD lesions. But “no loss of vision” in that trial meant loss of less than three lines of visual acuity, he noted, and although this was an improvement over results with PDT, the drug rarely improved vision.

Now retinal specialists are awaiting the final results in two trials of Lucentis (ranibizumab, Novartis/Genentech) that have shown promising interim results. In both the MARINA (Minimally classic/occult trial of the anti-VEGF antibody RhuFab V2 in the treatment of neovascular AMD) and ANCHOR (Anti-VEGF antibody for the treatment of predominantly classic choroidal neovascularization in AMD) studies, at 1 year about 95% of patients experienced no vision loss and a third or more of patients had a gain of three lines of vision or more. Both trials have a 2-year endpoint, so final results are still to come.

While Lucentis is available to U.S. clinicians only under clinical trial protocols, a related drug that is marketed for colorectal cancer has been adopted by many retinal specialists with great excitement. That drug, Avastin (bevacizumab, Genentech), is being widely used as an intravitreal injection to treat AMD in an off-label fashion, even though only limited studies of its safety and efficacy in AMD have been published.

Dr. Williams said the advent of Lucentis and Avastin have suddenly shifted AMD treatment from stopping disease progression to reversing its course.

“We’ve just crossed the line into visual improvement, and the data are impressive compared to our previous experience with treatments,” he said in a telephone interview with Ocular Surgery News.

There are at least four studies under way to assess the safety and efficacy of Lucentis, but the two best known are the MARINA and ANCHOR trials.

Robert L. Avery, MD, of the California Retina Consultants, has been a participant in both of these trials. He noted that Lucentis has shown strong evidence of safety and efficacy so far in the trials.

“Lucentis will probably be the dominant player here in the United States because it will have a better track record of safety and efficacy [than Avastin] and it will be FDA-approved [specifically for AMD], so many of us will shift many of our patients to Lucentis when it’s approved,” he told Ocular Surgery News in an interview.

PDT plus anti-VEGF

The off-label intravitreal use of Avastin for AMD has not yet been the subject of large-scale clinical trials like ANCHOR and MARINA. A few case series have been published, such as the case report last year in Ophthalmic Surgery, Lasers and Imaging by Philip J. Rosenfeld, MD, PhD, and colleagues at Bascom Palmer, but formal studies of Avastin for AMD are lacking.

Such studies may never be conducted because the similar, specifically ophthalmic drug Lucentis is likely to be available before those studies could reach a conclusion.

Dr. Avery said he and colleagues are planning a prospective study of PDT combined with Avastin.

“We are waiting for the [investigational new drug designation] from the FDA to be able to go ahead with that study,” he said.

Lucentis has already been the subject of a similar study known as the FOCUS (RhuFab V2 ocular treatment combining the use of Verteporfin to evaluate safety) trial. Dr. Avery said interim 1-year results of that 2-year study suggested that combining PDT with an anti-VEGF drug may decrease the frequency of PDT treatments needed.

“The FOCUS trial allowed less frequent PDT treatments. Our study will see if adding PDT to Avastin allows less frequent intravitreal injections, so it is a little bit different,” Dr. Avery said.

Prevention vs. treatment

With pharmacologic agents increasing the ability of ophthalmologists to treat AMD, the next step is to prevent the disease before it starts. This is a goal that the AREDS (Age-Related Eye Disease Study) research group is shedding light on.

“I think the AREDS trials have been very important,” Dr. Williams said. “They have the potential to actually save more vision than all the other studies combined.”

Dr. Avery echoed that opinion. He said he gives handouts to all his patients describing the potential benefits of the AREDS nutritional supplement regimen.

“Every day we see patients with atrophic macular degeneration that we think will benefit from instituting the AREDS vitamin regimen,” he said.

Enrollment will begin soon for AREDS 2, Dr. Williams said, which will examine the effect of additional nutritional factors in prevention of eye disease.

Another study examining the possibility of AMD prevention, according to Dr. Williams, is the AART (Anecortave acetate risk reduction trial). This ongoing trial will examine whether disease can be prevented in the healthy fellow eyes of patients with exudative AMD in one eye.

Dr. Williams said that he is eager to see the data from this trial.

“If that were to show that you could significantly decrease the development of neovascularization, and therefore visual loss, by treating the uninvolved eye, that would be a huge breakthrough,” he said.

A note from the editors

In this issue, we introduce OSN Trial Scorecards, compact summaries of important ongoing and completed clinical trials that will accompany future articles in OSN to remind our busy clinician-readers of the highlights and findings of each trial.

For more information:

• George A. Williams, MD, can be reached at 3535 West 13 Mile Road, Suite 555, Royal Oak, MI 48073; 248-551-2175; fax: 248-551-4362; e-mail: gwilliams@beaumont.edu. Dr. Williams is or has been an investigator for verteporfin, pegaptanib, ranibizumab and anecortave acetate; he is a paid consultant for Alcon.
• Robert L. Avery, MD, can be reached at California Retina Consultants, 515 East Micheltorena St., Suite C, Santa Barbara, CA 93103; 805-963-1648; fax: 805-965-5214; e-mail: avery1@jhu.edu. Dr Avery has received consulting fees from Alcon, Genentech, (OSI) Eyetech, Pfizer and QLT.

• Jared Schultz is an OSN Staff Writer who covers all aspects of ophthalmology. He focuses geographically on Europe and the Asia-Pacific region.