The rapid growth of the elderly population in the United States coupled with the known epidemiology of AMD will result in millions more patients afflicted with AMD in the near future. At present, the prevalence of AMD is 15 million with nearly 2 million suffering from advanced disease.1 Fortunately, our treatment armamentarium now has effective therapies to combat neovascular AMD, which is responsible for the bulk of patient morbidity. Lucentis has been shown in clinical trials to stabilize visual acuity in over 95% of patients and to improve visual acuity in 35-40% of patients at 1 and 2 years.2-4 No other ocular pharmaceutical has so radically changed the expectations regarding the treatment of AMD.
So why has Lucentis not gained universal usage in the treatment of neovascular AMD? The story is well known. Avastin, an anti-VEGF compound initially developed for the treatment of certain types of tumors, existed prior to the development of Lucentis and was anecdotally found to have an effect in the treatment of neovascular AMD. Large-scale phase III clinical trials are lacking, but there is level 2 evidence of effect.5-9 Perhaps most of the controversy surrounding Lucentis and Avastin is less about rigorous clinical trials, potential side effect differences and pharmacodynamics and more about financial considerations. The cost of Lucentis, a drug specifically formulated for the eye, is approximately $2,000 per intravitreal dose, while Avastin, formulated for intravenous use and available in larger quantities that can be compounded into smaller units, costs approximately $60 per intravitreal dose.
The most obvious way to compare the two treatments is a large scale clinical trial. Such a clinical trial is being planned, the Comparison of AMD Treatment Trial (CATT) with funding from the National Eye Institute. If the CATT shows Avastin and Lucentis are equivalent, from a financial standpoint, the answer of which is most cost effective is Avastin. In fact, cost-effectiveness models have shown that Lucentis would have to be 2.5 more effective compared to Avastin in order to be cost effective.10 However, if Lucentis is then abandoned in favor of Avastin, there will obviously be a significant financial loss for Genentech. Are there potential, less quantifiable losses for the ophthalmology community?
Industry-spent research and development money in the United States was estimated at 55 billion dollars for 2007.11 Genentech alone spent nearly two billion dollars in research and development in 2006. Hundreds of millions of dollars have already been spent in clinical trials for Lucentis, where per patient costs are in the tens of thousands of dollars. Avastin was also not without significant costs; it underwent substantial research and development as well as costly clinical trials. The financial considerations for the use of Avastin in cancer treatment are substantial. Although there will be short term financial advantages if Avastin gains a greater market share, there may significant losses for all involved in the future with regards to funding of research studies and drug development. With a relatively inexpensive medication like Avastin available, what will be the incentive for pharmaceutical companies to strive to develop more efficacious treatments?
Photodynamic therapy and Macugen represented early but less successful attempts at AMD treatment. The evolution of current anti-VEGF treatments stemmed from an unmet need for AMD treatment. Although Lucentis and Avastin represent the first treatments to show significant improvement in vision with neovascular AMD, they are by no means a panacea. More research is needed to raise the “therapeutic bar”. There is a cost for this research and development and many risks involved.
In addition to future drug development, what will be the impact on smaller investigator initiated studies and research into further applications for anti-VEGF compounds? Genentech continues to fund investigator initiated studies looking at other potential applications for Lucentis. The more immediate impact of a substantial switch from Lucentis may be the dramatic reduction in grant support for independent clinical research.
The economic burden associated with Lucentis treatment, especially in developing countries,12 may dictate the widespread usage of Avastin regardless of the impact on future research and development. However, the situation highlights the often complex relationship between the pharmaceutical industry and physicians. Clearly, pharmaceutical companies have financial interests in the development of new medications. Physicians carry with them the primary interest in patient care and affordable access. In order to meet both these demands there must be a balance between reasonable drug costs which continue to propagate substantial investment into research and less expensive pharmaceutical alternatives that allow for widespread usage but fail to provide incentives for future investment into more efficacious treatments.
Friedman DS, O’Colmain BJ, Munoz B, et.al. Prevalence of age-related macular degeneration in the United States. Arch Ophthalmol 2004; 122:564-72.
Rosenfeld PJ, Brown DM, Heier J. et.al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006; 355:1419-31.
Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J med 2006; 355:1432-44.
Regillo CD, Brown DM, Abraham H, Kaiser PK, Mieler WF. Randomized, double-masked, sham-controlled trial of ranibizumab for neovascular age-related macular degeneration: PIER study year 1. Am J Ophthalmol 2007 (in press).
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Rosenfeld PJ, Moshfegi AA, Puliafito CA. Optical coherence tomography findings after an intravitreal injection of bevacizumab (Avastin) for neovascular age-related macular degeneration. Ophthalmic Surg Lasers Imaging 2005; 36: 331-5.
Rich RM, Rosenfeld PJ, Puliafito CA, et.al. Short-term safety and efficacy of intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration. Retina 2006; 26: 495-511.
Moshfegi AA, Rosenfeld PJ, Puliafito CA, et al. Systemic bevacizumab (Avastin) therapy for neovascular age-related macular degeneration: twenty-four-week results of an uncontrolled open-label clinical study. Ophthalmology 2006; 113: 2002-11.
Ferrera N, Hillan KJ, Novotny W. Bevacizumab (Avastin), a humanized anti-VEGF monoclonal antibody for cancer therapy. Biochem Biophys Res Commun 2005; 333:328-35.
Raftery J, Clegg A, Jones J, Tan SC, Lotery A. Ranibizumab (Lucentis) versus bevacizumab (Avastin): modelling cost effectiveness. Br J Ophthalmol. 2007; 91:1244-6.
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About our author(s):
John Galasso, MD, Vitreoretinal Fellow
University of Illinois at Chicago, Department of Ophthalmology
Illinois Eye and Ear Infirmary
Jennifer I. Lim, MD, Professor of Ophthalmology, Director of the Retina Service
University of Illinois Department of Ophthalmology,
Illinois Eye and Ear Infirmary