December 01, 2006
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Overview of the changing environment of AMD

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Treatment expectations for age-related macular degeneration have been revolutionized, particularly with the introduction of anti-vascular endothelial growth factor (VEGF) agents. Historically, the wet AMD disease process was arrested with laser photocoagulation; however, poor visual outcomes were usually the result. An important advance was brought forth with photodynamic therapy, which allowed more tissue-specific targeting. However, few patients experienced visual improvement with PDT monotherapy. In an attempt to improve vision, adjuvant therapy with intravitreal steroids was introduced. While providing a more durable treatment effect for many patients, the commonly used steroid, triamcinolone acetonide (Kenalog-4, Bristol Myers Squibb), has well-recognized attendant safety issues. These include IOP elevations often requiring medical or even surgical intervention and the development of cataract.

The introduction of anti-VEGF agents represents a major step forward in the treatment of neovascular AMD as they directly target the disease process. The approval of the first anti-VEGF agent, pegaptanib sodium (Macugen, [OSI] Eyetech), in late 2004 led to the rapid adoption of drug monotherapy for the treatment of wet AMD. The 2-year VISION study (VEGF Inhibition Study in Ocular Neovascularization) confirmed the safety and long-term efficacy of pegaptanib in stabilizing vision; however, visual acuity was improved in only a small percentage of patients originally enrolled.1-2 Ranibizumab (Lucentis, Genentech), the relatively less selective anti-VEGF-A agent compared with pegaptanib sodium, received FDA approval for intravitreal use in mid 2006. Clinical trials using ranibizumab for wet AMD demonstrated that treatment resulted in visual improvement in 30% to 40% of eyes,3-4, which in turn changed both ophthalmologists’ and patients’ expectations.

The FDA approval of both pegaptanib and ranibizumab was a time-consuming process. Before ranibizumab was brought to market, ophthalmologists began using intravitreal bevacizumab (Avastin, Genentech) off-label for AMD. Although such treatment led to decreased leakage of lesions and improved visual acuity in many treated eyes, no compelling randomized clinical trials have been organized to firmly establish the efficacy and safety of this agent. Nevertheless, many clinicians are convinced that it provides superior and cost-effective results. However, some clinicians are concerned about the theoretical and practical safety aspects of VEGF-A inhibitors, particularly when used intravitreally for months or years. For instance, intravitreal bevacizumab enters the bloodstream and most likely depletes native VEGF to low levels for weeks compared with the more transitory effects of pegaptanib and ranibizumab, which have half-lives in serum measured in days. Although relatively few cases of systemic toxicity have been reported with intravitreal bevacizumab usage, safety data are lacking and reporting of such events is neither incentivized nor required outside of most clinical trials. The potential adverse events that occur at low frequencies can only be learned about through large well-monitored clinical trials or via post-marketing data acquisition.

In an attempt to minimize potential systemic toxicities of chronic therapy, modified dosing regimens have been designed. For example, the induction/maintenance strategy is one already implemented by our oncologist peers. Agents that are powerful and have less favorable safety profiles are used to initiate improvement and then maintenance of the favorable biological effect is accomplished with a safer but less potent drug. With respect to wet AMD, ranibizumab or bevacizumab has been used by some to induce regression of the neovascular complex and to improve visual acuity and then pegaptanib sodium is dosed every 6 weeks to maintain these improvements.

References
  1. Gragoudas ES, Adamis AP, Cunningham ET Jr, et al. Pegaptanib for neovascular age-related macular degeneration. N Engl J Med. 2004;341:2805-2816.
  2. D’Amico DJ, VISION Clinical Trial Group, Patel M, et al. Pegaptanib sodium for neovascular age-related macular degeneration: Two-year safety results of the two prospective, multicenter, controlled clinical trials. Ophthalmology. 2006;113:992-1001.
  3. Rosenfeld PJ, Brown DM, Heier JS. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006;355(15):1419-1431.
  4. Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med. 2006;355(14):1432-1444.