AMD Treatment UPDATE
Along with Visudyne and TTT, injectable anti-angiogenesis agents are on the forefront of current research.
BY RON GALLEMORE, M.D., PH.D., AND DAVID S. BOYER, M.D.

Despite the advent of new treatments such as photodynamic therapy (PDT) and increasing use of antioxidant supplements, age-related macular degeneration (AMD) remains the leading cause of blindness in the Western world. The therapies currently under investigation could markedly change the way we manage our patients and our practices. Here, we provide an update.

Anti-angiogenesis agents block blood vessel growth and reduce vascular permeability; they show promise as a potential new approach to treating wet AMD. Here is a brief review of the latest clinical studies and off-label uses of the anti-angiogenesis drugs that are currently available. (Unless otherwise specified, all studies represent randomized, controlled multi-center trials.)

Anecortave acetate. This is a new angiostatic steroid developed by Alcon for the inhibition of ocular neovascularization. It's administered via a juxtascleral injection behind the macula using a special cannula. It has no glucocortecoid activity, so it doesn't induce secondary glaucoma or cataract formation. In addition, it has a long half-life and can be injected at 6-month intervals.

Clinical trial results to date include:

• A Phase II study of anecortave acetate as monotherapy for predominantly classic CNV found that, at 1 year, the drug was superior to placebo at maintaining and improving vision, with 80% of patients losing less than three lines compared with 50% of patients in the placebo group.
• Another Phase II study demonstrated that anecortave combined with Visudyne was only slightly better than Visudyne alone at maintaining or improving vision at 6 months of follow-up.

A Phase III study is now comparing anecortave acetate with photodynamic therapy.

Off-label use of steroids. Steroids are also being tested "off-label" as a way to manage wet AMD. A pilot study demonstrated that a periocular injection of triamcinolone, combined with PDT, reduced the need for re-treatments. Intravitreal Kenalog injections may also result in fewer re-treatments. Oral steroids have been used in a similar capacity, but no controlled studies have been done.

The evidence suggests that after conventional laser treatment, using intraocular steroids as a primary treatment for recurrent CNV may be as effective as repeated laser treatment. Despite this encouraging data, we recommend waiting for the results of formal studies before initiating off-label use of steroids for adjunctive or primary management of wet AMD.

Macugen (pegaptanib sodium). This is an anti-vasoactive endothelial growth factor (VEG-F) aptamer developed by Eyetech, delivered by intravitreal injection. Upcoming Phase II/III studies, which have now completed enrollment, will make two comparisons:

• Macugen alone vs. placebo for wet AMD with occult CNV (with or without a minimally classic component)
• Macugen alone for wet AMD with predominantly classic CNV, after failing to respond to PDT with Visudyne.

An open label study involving select patients may soon be underway as the FDA considers approval of this agent. (Macugen is also under evaluation for the treatment of diabetic macular edema because anti-VEGF strategies appear to be effective in the management of diabetic retinopathy.)

Ranibizumab. This antibody fragment, rhuFab V2, was developed by Genentech; like pegaptanib sodium, it's designed to block VEG-F activity and is delivered by intravitreal injection.

Results from the Phase Ib/II study of this drug were significant at 98 days. Ninety-four percent of patients receiving rhuFab had stabilization of, or improvement of, vision. (Twenty-six percent showed improved vision -- 15 letters on the ETDRS chart -- while 68% were stabilized.) On average, patients receiving rhuFab V2 gained 9.0 letters, compared to patients treated with standard of care, who lost 4.9 letters.

The most common side effect following injection was mild, transient, reversible inflammation.

A Phase II/III study comparing Visudyne with a combination of Visudyne and rhuFab is now underway. Upcoming studies will also gauge the effectiveness of rhuFab for treatment of minimally classic and occult CNV.

Diclofenac. Diclofenac is a non-steroidal anti-inflammatory drug, delivered as an eye drop, that's being tested as an adjunct to PDT (used before and after treatment). The study hopes to determine whether diclofenac can reduce the need for re-treatments and/or improve visual outcomes in patients with wet AMD and predominantly classic CNV.

Tryptophanyl-tRNA synthetase (TrpRs). This is a relatively new anti-angiogenesis agent that has been reported to have greater efficacy in a model of retinal angiogenesis than any previously known agent. Most inhib-itors block 20% to 40% of new vessel growth; a recent study found that TrpRs blocked 100% of new vessel growth in 70% of the studied cases.

Because TrpRs is a naturally occurring human protein, it may reduce the toxic side effect of inflammation (a common immune system response to foreign substances). The drug could also be delivered via "gene therapy," in which cell-based vectors that produce the substance continuously, or in a regulated manner, are placed inside the eye.

Transpupillary Thermotherapy (TTT)

Preliminary studies of TTT have demonstrated stabilization of vision in 70% of patients and reduction of subretinal fluid in 90% of eyes. This treatment is currently under evaluation in a randomized, controlled clinical trial for the treatment of primarily occult wet AMD.

We inform patients whom we consider to be good candidates for this therapy that TTT is under study in a clinical trial; they can participate (if eligible), or be treated outside of the study. Some carriers will now reimburse for TTT, but we have patients sign a release indicating that Medicare or their current provider may not cover the service and that they may be responsible for the cost of treatment.

The Right Treatment for the Right Patient

With so many options -- and a number of other new drugs on the horizon -- managing patients with wet macular degeneration may require a multi-pronged approach. In our practice, we apply flow diagrams to the management of our patients; we determine the optimal clinical study, given a patient's specific form of AMD, or try different treatments as, for example, a lesion converts from occult to classic. Unfortunately, there is a significant downside; each new treatment means new costs for the patient and the practice, as well as the re-negotiation of contracts with healthcare providers.

Today, retina surgeons need to develop a systematic approach for the integration of new therapies. Likewise, general eye doctors need to focus on rapid detection and referral of patients who may be candidates for these new therapies. Hopefully, the proliferation of new options will soon lead to drugs and treatment strategies that bring even greater improvement in vision -- and more hope -- to these patients.

Drs. Gallemore and Boyer are in private practice with the Retina-Vitreous Associates Medical Group in Los Angeles, and are part of the clinical faculties at the Jules Stein Eye Institute, UCLA School of Medicine, and Doheny Eye Institute, USC School of Medicine, respectively. You can reach Dr. Gallemore at (213) 483-8810 or via e-mail at Retina2000@Yahoo.com; you can reach Dr. Boyer at vitdoc@aol.com.