Bevacizumab versus ranibizumab — the verdict

T h e n e w e ng l a n d j o u r na l o f m e dic i n e Bevacizumab versus Ranibizumab — The Verdict
For 5 years, patients and clinicians have wrestled In this issue of the Journal, Martin and col- with the choice between two drugs for the treat- leagues7 provide such evidence in their findings ment of neovascular age-related macular degen- from the first year of the Comparison of AMD eration (AMD), a common cause of irreversible Treatment Trials (CATT), a large, prospective, blindness among the elderly worldwide. Vision loss multicenter, randomized clinical trial comparing results from the abnormal growth and leakage of bevacizumab and ranibizumab. Despite formida- blood vessels in the macula, a specialized por- ble obstacles,8 the investigators successfully com- tion of the retina responsible for the best visual pared the two drugs and two different dosing acuity. Without this macular vision, patients be- regimens: a monthly regimen versus an as-needed come legally blind. Vascular endothelial growth regimen (i.e., drug administration only when signs factor (VEGF), the cytokine primarily responsible of exudation are present). A monthly regimen is for blood-vessel growth, is inhibited when anti- considered the standard for treatment.1,2 An as- VEGF drugs are injected repeatedly into the eye, needed regimen is used less frequently and relies and blindness is prevented in most patients. The on clinical judgment and imaging techniques to majority of treated patients go on to have some determine when to reinject the drug.9 The most common imaging method that is used is optical The two anti-VEGF drugs most commonly coherence tomography (OCT), a noninvasive tech- used are bevacizumab (Avastin) and ranibizu- nique that identifies fluid leakage from blood mab (Lucentis), both developed by Genentech.4 vessels. This VEGF-mediated exudate resolves after Bevacizumab, a full-length humanized monoclo- the injection of ranibizumab or bevacizumab. An nal antibody, has been approved by the Food and OCT-guided as-needed regimen has been shown Drug Administration (FDA) for the systemic treat- to result in improved visual acuity,9 but CATT is ment of certain cancers. Ranibizumab, an antigen- the first prospective approach to directly compare binding fragment, is a smaller molecule that was a monthly regimen with an as-needed regimen.
specifically developed and approved to treat eye Martin et al. found that the monthly use of diseases and is derived from the same anti-VEGF either bevacizumab or ranibizumab results in the mouse monoclonal antibody as bevacizumab. same visual acuity outcome. This finding holds Both ranibizumab and bevacizumab bind VEGF at true for the mean visual acuity and the propor- the same position; however, they differ in size, tion of patients who gain 15 letters (which repre- affinity for VEGF, speed of clearance from the eye, sents a doubling of the visual acuity), lose 15 let- and cost.5 Ranibizumab, the FDA-approved treat- ters, or remain stable. Critics will argue that the ment for neovascular AMD, costs approximately OCT outcomes suggest differences between these $2,000 per dose, whereas beva cizumab, the off- two drugs. Although the OCT retinal thickness label treatment, costs approximately $50. This cost measurements favor ranibizumab, this difference difference, along with the perceived clinical simi- is not reflected in any of the visual-acuity or larities between these two drugs, has led to the angio graphic outcomes. Whether this difference widespread use of bevacizumab in the absence of is associated with changes in vision should be- come clear during the second year of follow-up.
Downloaded from nejm.org at UNIVERSITEIT VAN AMSTERDAM on April 30, 2011. For personal use only. No other uses without permission. Copyright 2011 Massachusetts Medical Society. All rights reserved. In addition, Martin et al. observed equivalent The CATT results, together with the totality of visual-acuity outcomes with both the monthly and global experience, support the use of either be- the as-needed regimens of ranibizumab. This re- vacizumab or ranibizumab for the treatment of sult is particularly good news for patients. The neovascular AMD. An as-needed regimen is an success of the as-needed regimen in a multi- acceptable alternative to a monthly regimen, but center clinical trial cannot be overstated, given the strict compliance on the part of both the clinician intrinsic difficulties associated with the training and the patient is required. Health care providers of investigators to agree on OCT interpretation and payers worldwide will now have to justify the and retreatment guidelines. Given deficiencies cost of using ranibizumab. Regulators in certain that were reported by the reading center, it is countries will be forced to reconsider their policies likely that visual acuity and anatomic outcomes that make it illegal to use drugs off-label, particu- would have been even better with improved in- larly when so many of their citizens cannot afford vestigator compliance. Other strategies to im- ranibizumab. The CATT data support the contin- prove overall treatment outcomes might include ued global use of intravitreal bevacizu mab as an the use of newer OCT techniques with improved effective, low-cost alternative to ranibizumab.
image resolution to help with retreatment deci- Disclosure forms provided by the author are available with the sions and the use of three mandated monthly full text of this article at NEJM.org.
Although the as-needed regimen with bevaci- From the Bascom Palmer Eye Institute, University of Miami zumab appeared similar to the as-needed regimen with ranibizumab, the as-needed bevacizumab This article (10.1056/NEJMe1103334) was published on April 28, regimen compared less favorably with monthly 2011, at NEJM.org.
regimens for either bevacizumab or ranibizumab. 1. Rosenfeld PJ, Brown DM, Heier JS, et al. Ranibizumab for
One possibility may be that bevacizumab has a neovascular age-related macular degeneration. N Engl J Med less durable treatment effect in a subgroup of pa- 2006;355:1419-31.
tients and thus more frequent administration may 2. Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus
verteporfin for neovascular age-related macular degeneration. be required. If the frequency of administration N Engl J Med 2006;355:1432-44.
were increased, then the outcomes in such pa- 3. Fong DS, Custis P, Howes J, Hsu JW. Intravitreal bevacizu-
tients should approach the outcomes observed mab and ranibizumab for age-related macular degeneration: a multicenter, retrospective study. Ophthalmology 2010;117:298- Although CATT addresses the question of ef- 4. Steinbrook R. The price of sight — ranibizumab, bevacizu-
ficacy, the study was insufficiently powered to mab, and the treatment of macular degeneration. N Engl J Med identify differences in drug-related adverse events.7 5. Stewart MW. Predicted biologic activity of intravitreal beva-
Although bevacizumab persists longer than ra- cizumab. Retina 2007;27:1196-200.
nibizumab in the systemic circulation after an 6. Brechner RJ, Rosenfeld PJ, Babish JD, Caplan S. Pharmaco-
therapy for neovascular age-related macular degeneration: an intravitreal injection,10 Martin et al. observed none analysis of the 100% Medicare fee-for-service Part B claims file. of the expected adverse events associated with sys- Am J Ophthalmol 2011 February 8 (Epub ahead of print).
temic anti-VEGF therapy. Although more patients 7. The CATT Research Group. Ranibizumab and bevacizumab
for neovascular age-related macular degeneration. N Engl J Med receiving bevacizumab had multiple systemic se- 2011. DOI: 10.1056/NEJMoa1102673.
rious adverse events and hospitalizations than 8. Martin DF, Maguire MG, Fine SL. Identifying and eliminat-
those receiving ranibizumab, these events were ing the roadblocks to comparative-effectiveness research. not associated with organ systems typically iden- 9. Lalwani GA, Rosenfeld PJ, Fung AE, et al. A variable-dosing
tified with systemic anti-VEGF therapy. The results regimen with intravitreal ranibizumab for neovascular age- from the second year of CATT and from five oth- related macular degeneration: year 2 of the PrONTO Study. Am J Ophthalmol 2009;148(1):43.e1-58.e1.
er large, ongoing, multicenter comparative clinical 10. Csaky K, Do DV. Safety implications of vascular endothelial
trials in Europe should help to clarify whether growth factor blockade for subjects receiving intravitreal anti- these adverse events are related to intravitreal anti- vascular endothelial growth factor therapies. Am J Ophthalmol Copyright 2011 Massachusetts Medical Society. Downloaded from nejm.org at UNIVERSITEIT VAN AMSTERDAM on April 30, 2011. For personal use only. No other uses without permission. Copyright 2011 Massachusetts Medical Society. All rights reserved.

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