New treatments, combinations promising for AMD

New, highly promising treatment approaches for age-related macular degeneration (AMD) address the disease through pharmacologic and surgical avenues. Combinations of therapeutic approaches are also showing efficacy in clinical trials, and researchers are continually working on new therapies to manage this sight-threatening disease.

“Many drugs are currently in trials,” said Jeffry D. Gerson, OD, FAAO, a fellow of the Optometric Retina Society who practices in Kansas City, Mo. “Most clinicians’ knowledge is limited to the more common drugs, but a host of drugs are in trials and may become more popular in a year or two.”

Anti-VEGF drugs: Lucentis

Anti-vascular endothelial growth factor (VEGF) medications show a great deal of promise in treating the wet form of AMD. The mechanism of action of these drugs is to inhibit blood vessel growth, thereby preventing scar tissue development and protecting vision.

Lucentis (ranibizumab, Novartis/Genentech) was approved June 30 by the Food and Drug Administration (FDA) for treatment of wet AMD, following a 6-month priority review.

According to Genentech in a press release announcing the drug’s approval, 95% of patients treated with the drug maintained vision in phase 3 clinical trials. About 40% of patients had vision improvement by at least three lines at 1 year, and up to 40% of patients achieved vision of 20/40 or better, the release said.

The FDA approval was based on data collected from two large phase 3 clinical trials, the MARINA and ANCHOR studies, the release stated. In the MARINA study (Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab In the Treatment of Neovascular AMD), patients experienced an average improvement of 6.6 letters from baseline at 2 years, compared to a loss of 14.9 letters in the sham group.

In the ANCHOR study (Anti-VEGF Antibody for Treatment of Predominantly Classic Choroidal Neovascularization in AMD), patients on average experienced an 11.3-letter gain from baseline at 1 year, compared to a loss of 9.5 letters in patients treated with photodynamic therapy, the release stated.

The most common adverse reactions in the trials included conjunctival hemorrhage, eye pain, vitreous floaters, increased IOP and intraocular inflammation. Serious adverse events, including endophthalmitis, retinal detachments and traumatic cataracts, occurred in less than 0.1% of patients who received the injections, according to the release. The drug is contraindicated in patients with hypersensitivity to the components of the medication and ocular or periocular infections, the release stated.

Brett J. King, OD, FAAO, a lecturer and author on retinal topics based in Kansas City, Mo., discussed the mechanism of action of Lucentis in treating AMD. “This monoclonal antibody penetrates all layers of the retina and works on all forms of VEGF,” he told Primary Care Optometry News. “It has not been shown to be effective against other factors, such as bFgF, and because it is a humanized product, there was initially concern about the host developing antibodies against the active agent, but this has not proven to be true.”

Anti-VEGF drugs: Macugen

Another FDA-approved anti-VEGF agent is Macugen (pegaptanib sodium injection, OSI Pharmaceuticals/Pfizer), a pegylated aptameter that specifically targets and inactivates VEGFs, according to Dr. King.

“Macugen is a chemically synthesized strand of RNA,” Dr. King said. “By being manufactured instead of naturally occurring, it has tremendous sensitivity and specificity to a single isoform of VEGF only.”

OSI Pharmaceuticals and Pfizer announced in late June that they will begin a phase 4 trial on Macugen to determine the safety and efficacy of the drug as a maintenance therapy for patients who have received prior neovascular AMD treatment and experienced improvement in macular disease. The new trial is expected to last 54 weeks and will include 1,000 patients at 100 sites nationwide.

According to OSI, enrollment criteria includes subjects that have had at least one, but no more than three, treatments for neovascular AMD within 30 to 120 days before study entry leading to an improvement in macular disease. Macugen will be administered once every 6 weeks for 48 weeks.

The primary endpoint is the percentage of subjects who remain at baseline vision or gain vision from baseline to 54 weeks. Secondary endpoints include the percentage of subjects maintaining or gaining 1, 2 or 3 lines of visual acuity at week 54 compared to baseline vision at the beginning of the trial. Additional secondary endpoints include the mean change of VA from baseline to week 54; the percentage of subjects losing fewer than 3 lines at 54 weeks; and anatomical outcomes on fluorescein angiography and optical coherence tomography.

Anti-VEGF drugs: Avastin

Another drug, Avastin (bevacizumab), also manufactured by Genentech, may show promise as an off-label treatment for AMD, Dr. Gerson told Primary Care Optometry News. This drug is currently approved for metastatic colorectal cancer.

“This anti-VEGF was first administered intravenously and then intravitreally,” he said. “So far, only small case reports have been done, but they’ve been very positive.”

To date, the off-label intravitreal use of Avastin for AMD has not yet been assessed in large-scale clinical trials. A few case series have been published, including one last year in Ophthalmic Surgery, Lasers and Imaging by Philip J. Rosenfeld, MD, PhD, and colleagues at Bascom Palmer Eye Institute.

Dr. Gerson said larger studies should be conducted to fully explore the efficacy of this drug. “There really needs to be a controlled trial to find out if it is as effective as people think and to establish its effects over the long-term,” he said. “Many specialists feel that Avastin may prove to be superior to Lucentis.”

He added, however, that the FDA approval of Lucentis may result in a decreased use of Avastin, partly because Avastin’s off-label use is not reimbursed. “People are split 50/50 on this,” he said.

Dr. Gerson maintained that Avastin, which is manufactured by the same company as Lucentis, might also be significantly less expensive than Lucentis. “They haven’t yet published a price for Lucentis, but Macugen costs quite a bit more than Avastin,” he said. “So if Lucentis is priced within the same range as Macugen, it will be more expensive than Avastin.”

He said many practitioners do feel confident about the efficacy of Avastin as an off-label AMD treatment. “A lot of people think it will be just as effective as Lucentis,” he said.

Intravitreal triamcinolone

The use of intravitreal triamcinolone, in several different combinations, has shown benefit in treating AMD. “In my practice, we have not done any combinations of anti-VEGFs and steroids, and I don’t know many people who have,” Dr. Gerson said. “Practitioners are using triamcinolone in combination with photodynamic therapy (PDT). There have been multiple reports of that combination being successful.”

In a May 2005 study presented at the Association for Research in Vision and Ophthalmology meeting (Franklin and Easterling), the adjunctive use of intravitreal triamcinolone with PDT was found to result in substantial visual improvements in AMD patients who had never been treated with PDT before.

The retrospective chart review, conducted at the University of Tennessee, Chattanooga, looked at 32 patients who had triamcinolone injections immediately before receiving the standard PDT.

Of the subjects, six had had prior PDT therapy, and the remainder had received no treatment. In the treatment group who had never had previous PDT, four patients gained more than three lines of visual acuity, four gained two lines, and one gained three lines.

Dr. Gerson said PDT with triamcinolone is “very mainstream” at this point. He said triamcinolone has not been often combined with anti-VEGFs because steroids have some anti-VEGF activity.

Surgical approaches

The treatment of AMD is also being approached surgically, although some of these procedures are not widely performed at this time. Based on research by former Duke University Eye Center Chairman Robert Machemer, MD, and further developed by Cynthia Toth, MD, macular translocation is designed for patients who are losing the last of their central vision to AMD, according to the Duke Eye Center Web site.

The objective of this procedure, according to the Web site, is to lift the macula away from underlying blood vessels and move it to a new, healthier location to restore central vision.

Submacular surgery is another surgical modality for the treatment of AMD. In this approach, abnormal blood vessels are surgically removed from beneath the macula. The macula is not relocated.

Dr. King said focal destructive laser, which was once the only option for these patients, is still used today, although rarely. “The best solution to date for these patients will be combination therapy,” he said.

Dr. Gerson reiterated this sentiment. “The roles of these treatments are evolving. Five years ago, people were doing PDT as a standalone treatment, whereas now they are using PDT with steroids and anti-VEGFs,” he said. “With anti-VEGFs, it will be a similar story. Right now, it is the best thing available, but when newer therapies emerge, it will become additive to those new therapies.”

For more information:

• Jeffry D. Gerson, OD, FAAO, is a member of the Optometric Retina Society and practices in Kansas City, Mo. He can be reached at Mid America Retina Consultants, 4321 Washington Blvd., Kansas City, MO 64111; (816) 756-5900; fax: (816) 756-5457; e-mail: jgerson@hotmail.com.
• Brett J. King, OD, FAAO, is a lecturer and author. He can be reached at 1010 Corondelet Dr., Kansas City, MO 64114; (816) 942-1113; fax: (816) 942-5181; e-mail: bking@stilesglaucoma.com. Drs. Gerson and King have no direct financial interest in the products mentioned in this article, nor are they paid consultants for any companies mentioned.

References:

• Franklin AJ, Easterling AR. Combined photodynamic therapy and intravitreal triamcinolone acetonide in the treatment of neovascular age-related macular degeneration. Presented at the Association for Research in Vision and Ophthalmology; May 1, 2005. Ft. Lauderdale, FL.
• Rosenfeld PJ, Fung AE, Puliafito CA. Optical coherence tomography findings after an intravitreal injection of bevacizumab (Avastin) for macular edema from central retinal vein occlusion. Ophthalmic Surg Lasers Imaging. 2005;36(4):336-339.