On June 30, 2006, the Food and Drug Administration (FDA) approvedranibizumab — which is manufactured by Genentech and marketedas Lucentis — for the treatment of neovascular age-relatedmacular degeneration. Ranibizumab is a fragment of a recombinantmonoclonal antibody (see Figure 1) that binds to and inhibitsall the biologically active forms of vascular endothelial growthfactor A. Administered by injection into the vitreous cavity(see Figure 2), ranibizumab prevents vision loss and improvesvisual acuity, with few serious adverse effects (as indicatedin the reports by Rosenfeld et al. and Brown et al. in thisissue of the Journal, pages 1419–1431 and 1432–1444);it thus represents a substantial advance against a leading causeof blindness (discussed by de Jong in this issue of the Journal,pages 1474–1485). According to the prescribing information,it is recommended that ranibizumab be injected monthly, withtreatment likely to be required indefinitely, although lessfrequent administration is being evaluated. Ranibizumab is alsoexpensive. The wholesale acquisition cost of a vial containinga single dose of 0.5 mg (0.05 ml) is $1,950.
Figure 1. Relationship between Ranibizumab and Bevacizumab.
Ranibizumab is a recombinant humanized monoclonal IgG1 kappa-isotype antibody fragment (with a molecular weight of about 48 kD). It is produced in an Escherichia coli expression system (and thus is not glycosylated) and is designed for intraocular use. Bevacizumab is a recombinant humanized monoclonal IgG1 antibody (with a molecular weight of about 149 kD). It is produced in a Chinese-hamster-ovary mammalian-cell expression system (and thus is glycosylated) and is designed for intravenous infusion. Both the antibody fragment and the full-length antibody bind to and inhibit all the biologically active forms of vascular endothelial growth factor (VEGF) A and are derived from the same mouse monoclonal antibody. However, ranibizumab has been genetically engineered through a process of selective mutation to increase its affinity for binding and inhibiting the growth factor. The Fab domain of ranibizumab differs from the Fab domain of bevacizumab by six amino acids, five on the heavy chain (four of which are in the binding site) and one on the light chain. Not all the intermediate Fabs between the mouse monoclonal antibody and ranibizumab are shown.
Figure 2. Intravitreal Injection for the Treatment of Neovascular Age-Related Macular Degeneration.
Under topical anesthesia and sterile conditions, ranibizumab or bevacizumab is typically injected with a 30-gaugex0.5-in. needle inserted 3.5 to 4 mm posterior to the limbus through the sclera into the vitreous cavity behind the lens of the eye. In general, patients can return to their usual activities within 24 hours. Usually, one eye is treated; depending on the situation, treatment in both eyes may be required, but it is generally given on separate days. The cross-section shows the retina and choroid as they would appear in a patient, with the neovascularization and accumulation of subretinal fluid that are characteristic of the disease. For the drugs to be effective, the vascular endothelial growth factor in and beneath the retina has to be inhibited. The fovea is the area at the center of the macula and is responsible for the best visual acuity.
In the United States, about 155,000 cases of age-related maculardegeneration are diagnosed each year; typical patients are 65years of age or older. Although the neovascular form of maculardegeneration accounts for about 10% of cases, it is responsiblefor the vast majority of the associated vision loss. Beforethe FDA approved ranibizumab, some ophthalmologists began usinganother monoclonal antibody, bevacizumab, that is closely relatedto ranibizumab to treat patients who have neovascular maculardegeneration or other chorioretinal diseases mediated by vascularendothelial growth factor. Marketed as Avastin and also manufacturedby Genentech, bevacizumab is a full-length antibody that isderived from the same mouse monoclonal antibody precursor asranibizumab (see Figure 1), neutralizes vascular endothelialgrowth factor, and costs considerably less than ranibizumabwhen administered as an intraocular injection.1,2
In February 2004, the FDA approved bevacizumab for the treatmentof metastatic cancer of the colon or rectum. Although the typicalprice of bevacizumab as part of a chemotherapy regimen is $4,400a month, a 4-ml vial containing 100 mg has a wholesale acquisitioncost of $550. Thus, physicians and compounding pharmacies canprepare small aliquots in syringes for intraocular injectionat a cost to the physician of $17 to $50, depending on the doseand the efficiency of the process.2 In some instances, chargesto patients may be considerably higher. On a molar basis, thetypical dose — 1.25 mg (0.05 ml) — of bevacizumabis similar to the approved dose of ranibizumab.
Intraocular administration of bevacizumab is entirely off-label;the drug is formulated for intravenous infusion, not intravitrealinjection. Nonetheless, and though data from controlled trialsare lacking, bevacizumab appears to be safe and effective inthe short term.1,3 And ophthalmologists frequently use medicationsoff-label.
As of mid-September 2006, ranibizumab had been approved in theUnited States and Switzerland (where it is marketed by Novartis,which has commercialization rights outside the United States).Bevacizumab has already brought Genentech billons of dollarsin sales; ranibizumab will soon do so as well.
The good news for patients is that there are two new medicationsfor neovascular age-related macular degeneration, both of whichappear to work better than the alternatives. But since theyhave never been directly compared, physicians can only speculateabout which drug is superior with regard to safety, efficacy,and frequency of administration. The price difference is alsotoo big to ignore.
Philip Rosenfeld of the University of Miami School of Medicinehas studied both drugs and has pioneered the use of bevacizumabin the eye. (Rosenfeld has also has received consulting feesand grant support from Genentech and consulting fees, lecturefees, and grant support from other companies.) After bevacizumabbecame available, Rosenfeld and his colleagues administeredit intravenously to 18 patients with neovascular age-relatedmacular degeneration. Their preliminary findings suggested benefitsthat were similar to the initial findings with intravitrealranibizumab. Improvement occurred in both eyes of patients withbilateral disease and lasted 6 months or longer in 12 of thepatients.4 However, the treatment cost an average of $2,200per infusion, and the investigators and other retinal specialistswere concerned about the potential for life-threatening adversereactions, such as heart attack and stroke, which had previouslybeen identified in patients with cancer.2
In an interview, Rosenfeld said that in May 2005 he was drivinghome and thinking about how bevacizumab could be delivered moresafely into the eye. "The `eureka moment' was when I suddenlyrealized that an appropriate molar amount of Avastin could beinjected into the eye, using the same low volume as Lucentisbut at a small fraction of the cost." The next day he spoketo a pharmacy director at the University of Miami about preparingthe injections.
In July 2005, Rosenfeld's group published two case reports showingbenefit.1 The first patient had neovascular age-related maculardegeneration and was losing vision in her one good eye despitehaving received all the therapies that were approved at thetime. The second patient had central retinal vein occlusionand had exhausted other treatment options, according to Rosenfeld.Within 6 months, the intraocular use of bevacizumab had spreadaround the world. The Ophthalmic Mutual Insurance Company ofSan Francisco, which is affiliated with the American Academyof Ophthalmology, even provides risk-management recommendationsfor such use and an informed-consent form that physicians canmodify to fit their practice.5 Most regional Medicare carrierscover intravitreal injections of bevacizumab, although thereis no national policy.
In many parts of the world, a medication that costs $1,950 fora monthly injection is unaffordable. In the United States, underMedicare, ranibizumab is covered through Part B; patients areresponsible for a 20% copayment for each injection. In someinstances, supplemental insurance, Medicaid, or support programsfor the poor or uninsured that are funded by the manufactureror others cover most or all of the patients' costs. But regardlessof who pays the bill, sales of ranibizumab generate revenuefor Genentech, the drug's high price contributes to the overallcost of health care, and the drug may sometimes still be unaffordable.
It is possible that bevacizumab would prove to be superior forneovascular age-related macular degeneration. For example, themolecule is about three times as large as ranibizumab and mayremain in the eye longer, decreasing the frequency with whichinjections are required. At present, intraocular pharmacokineticdata are lacking. However, ranibizumab could also prove to bebetter. In addition to its smaller size, ranibizumab is geneticallyengineered to have greater affinity for vascular endothelialgrowth factor and is formulated for intraocular use; more ofthe drug may therefore penetrate all the layers of the retina.Moreover, ranibizumab that leaks out of the eye into the circulationhas a half-life of hours; the half-life of a full-length antibodysuch as bevacizumab is longer. For this reason, ranibizumabcould theoretically be associated with less systemic toxicitythan bevacizumab, but it is not known whether this is in factthe case. As an antibody fragment, ranibizumab lacks an Fc portion,so it may be less likely to induce inflammation within the eye.However, according to Rosenfeld, no apparent inflammation hasbeen seen with bevacizumab, even with the highest dose thathas been administered.3
Genentech specifically developed ranibizumab for the treatmentof neovascular age-related macular degeneration. In an interview,Hal Barron, a senior vice-president and chief medical officerof Genentech, explained the company's position on the use ofintraocular bevacizumab. "We have a huge database suggestingthat Lucentis is very effective and very safe, so we are justnot sure of the value of taking something that is not formulatedfor the eye and subjecting patients to a randomized trial whenthere is, in our opinion, a very low likelihood of its beingsuperior," he said. Nevertheless, Barron acknowledged, "If peoplehave a hypothesis that it would be better or safer, one couldcertainly test that."
Since late 2005, the National Eye Institute has been consideringa proposal for a prospective multicenter trial that would compareranibizumab directly with bevacizumab. Although the institutehas signed off on the need for a trial, as of mid-Septemberit was still considering the research design and how to payfor the study, which would probably cost tens of millions ofdollars. If the study is to go forward, the federal governmentwill probably have to buy both drugs from Genentech. And theinvestigators will probably have to submit to the FDA an investigationalnew drug application for intravitreal bevacizumab. Such a comparisonmight not ultimately affect the difference in price betweenthe drugs, but it is certainly the only way to determine whichdrug is better for patients.
Source Information
Dr. Steinbrook (rsteinbrook{at}attglobal.net) is a national correspondent for the Journal.
An interview with Dr. Frederick L. Ferris III, clinical director of the National Eye Institute, can be heard at www.nejm.org.
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Interview
