The NEW ENGLAND JOURNAL of MEDICINE
`
`Perspective
`
`october 5, 2006
`
`The Price of Sight — Ranibizumab, Bevacizumab,
`and the Treatment of Macular Degeneration
`Robert Steinbrook, M.D.
`
`Related articles, pp. 1419, 1432, 1474, and 1493
`
`On June 30, 2006, the Food and Drug Adminis-
`
`tration (FDA) approved ranibizumab — which
`is manufactured by Genentech and marketed as
`Lucentis — for the treatment of neovascular age-
`
`related macular degeneration. Ra-
`nibizumab is a fragment of a re-
`combinant monoclonal antibody
`(see Figure 1) that binds to and
`inhibits all the biologically ac-
`tive forms of vascular endothe-
`lial growth factor A. Administered
`by injection into the vitreous cav-
`ity (see Figure 2), ranibizumab
`prevents vision loss and improves
`visual acuity, with few serious ad-
`verse effects (as indicated in the
`reports by Rosenfeld et al. and
`Brown et al. in this issue of the
`Journal, pages 1419–1431 and
`1432–1444); it thus represents a
`substantial advance against a lead-
`ing cause of blindness (discussed
`by de Jong in this issue of the Jour-
`
`nal, pages 1474–1485). According
`to the prescribing information, it
`is recommended that ranibizum-
`ab be injected monthly, with treat-
`ment likely to be required indef-
`initely, although less frequent
`administration is being evaluated.
`Ranibizumab is also expensive.
`The wholesale acquisition cost of
`a vial containing a single dose of
`0.5 mg (0.05 ml) is $1,950.
`In the United States, about
`155,000 cases of age-related mac-
`ular degeneration are diagnosed
`each year; typical patients are 65
`years of age or older. Although the
`neovascular form of macular de-
`generation accounts for about 10%
`of cases, it is responsible for the
`
`vast majority of the associated vi-
`sion loss. Before the FDA approved
`ranibizumab, some ophthalmolo-
`gists began using another mono-
`clonal antibody, bevacizumab, that
`is closely related to ranibizumab
`to treat patients who have neo-
`vascular macular degeneration or
`other chorioretinal diseases me-
`diated by vascular endothelial
`growth factor. Marketed as Avas-
`tin and also manufactured by
`Genentech, bevacizumab is a full-
`length antibody that is derived
`from the same mouse monoclo-
`nal antibody precursor as ranibi-
`zumab (see Figure 1), neutralizes
`vascular endothelial growth fac-
`tor, and costs considerably less
`than ranibizumab when adminis-
`tered as an intraocular injection.1,2
`In February 2004, the FDA ap-
`proved bevacizumab for the treat-
`ment of metastatic cancer of the
`colon or rectum. Although the typ-
`
`n engl j med 355;14 www.nejm.org october 5, 2006
`
`1409
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on December 4, 2018. For personal use only. No other uses without permission.
`
` Copyright © 2006 Massachusetts Medical Society. All rights reserved.
`
`CELLTRION - EXHIBIT 1037
`
`

`

`PERSPECTIVE
`
`The Price of Sight — Ranibizumab, Bevacizumab, and the Treatment of Macular Degeneration
`
`Humanized
`Fab
`
`Affinity
`maturation
`
`(Selective
`mutation)
`
`Heavy
`chain
`
`Light
`chain
`
` Fc
`
`Ranibizumab
`(Lucentis)
`
`Construction
`of humanized
`antibody
`
`Mouse anti-VEGF
`monoclonal antibody,
`approximately 150 kD
`
`Fc
`
`Humanized
`Fab
`
`Bevacizumab
`(Avastin)
`
`Humanized
`antibody
` fragment,
`approximately
`48 kD
`
`Complete
`humanized
`antibody,
`approximately
`149 kD
`
`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 molecu-
`lar 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.
`
`ical price of bevacizumab as part
`of a chemotherapy regimen is
`$4,400 a month, a 4-ml vial con-
`taining 100 mg has a wholesale
`acquisition cost of $550. Thus,
`physicians and compounding
`pharmacies can prepare small ali-
`quots in syringes for intraocular
`injection at a cost to the physician
`of $17 to $50, depending on the
`dose and the efficiency of the pro-
`cess.2 In some instances, charges
`to patients may be considerably
`higher. On a molar basis, the typ-
`ical dose — 1.25 mg (0.05 ml) —
`of bevacizumab is similar to the
`approved dose of ranibizumab.
`Intraocular administration of
`bevacizumab is entirely off-label;
`
`the drug is formulated for intra-
`venous infusion, not intravitreal
`injection. Nonetheless, and though
`data from controlled trials are
`lacking, bevacizumab appears to
`be safe and effective in the short
`term.1,3 And ophthalmologists fre-
`quently use medications off-label.
`As of mid-September 2006,
`ranibizumab had been approved
`in the United States and Switzer-
`land (where it is marketed by No-
`vartis, which has commercializa-
`tion rights outside the United
`States). Bevacizumab has already
`brought Genentech billons of dol-
`lars in sales; ranibizumab will
`soon do so as well.
`The good news for patients is
`
`that there are two new medica-
`tions for neovascular age-related
`macular degeneration, both of
`which appear to work better than
`the alternatives. But since they
`have never been directly compared,
`physicians can only speculate
`about which drug is superior with
`regard to safety, efficacy, and fre-
`quency of administration. The
`price difference is also too big to
`ignore.
`Philip Rosenfeld of the Uni-
`versity of Miami School of Medi-
`cine has studied both drugs and
`has pioneered the use of bevaci-
`zumab in the eye. (Rosenfeld has
`also has received consulting fees
`and grant support from Genen-
`tech and consulting fees, lecture
`fees, and grant support from oth-
`er companies.) After bevacizumab
`became available, Rosenfeld and
`his colleagues administered it in-
`travenously to 18 patients with
`neovascular age-related macular
`degeneration. Their preliminary
`findings suggested benefits that
`were similar to the initial findings
`with intravitreal ranibizumab. Im-
`provement occurred in both eyes
`of patients with bilateral disease
`and lasted 6 months or longer in
`12 of the patients.4 However, the
`treatment cost an average of
`$2,200 per infusion, and the in-
`vestigators and other retinal spe-
`cialists were concerned about the
`potential for life-threatening ad-
`verse reactions, such as heart at-
`tack and stroke, which had pre-
`viously been identified in patients
`with cancer.2
`In an interview, Rosenfeld said
`that in May 2005 he was driving
`home and thinking about how
`bevacizumab could be delivered
`more safely into the eye. “The
`‘eureka moment’ was when I
`suddenly realized that an appro-
`priate molar amount of Avastin
`
`1410
`
`n engl j med 355;14 www.nejm.org october 5, 2006
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on December 4, 2018. For personal use only. No other uses without permission.
`
` Copyright © 2006 Massachusetts Medical Society. All rights reserved.
`
`

`

`PERSPECTIVE
`
`The Price of Sight — Ranibizumab, Bevacizumab, and the Treatment of Macular Degeneration
`
`Fovea
`
`Retina
`
`Choroid
`
`Sclera
`
`3.5 to 4 mm
`
`Neovascularization
`
`Fovea
`
`Intraretinal fluid
`
`Subretinal fluid
`
`Drusen
`
`Bruch’s
`membrane
`
`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-gauge × 0.5-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 sub-
`retinal fluid that are characteristic of the disease. For the drugs to be effective, the vascular endo-
`thelial 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.
`
`could be injected into the eye,
`using the same low volume as
`Lucentis but at a small fraction of
`the cost.” The next day he spoke
`to a pharmacy director at the Uni-
`versity of Miami about preparing
`the injections.
`In July 2005, Rosenfeld’s group
`published two case reports show-
`ing benefit.1 The first patient had
`neovascular age-related macular
`degeneration and was losing vi-
`sion in her one good eye despite
`
`having received all the therapies
`that were approved at the time.
`The second patient had central
`retinal vein occlusion and had ex-
`hausted other treatment options,
`according to Rosenfeld. Within
`6 months, the intraocular use of
`bevacizumab had spread around
`the world. The Ophthalmic Mutual
`Insurance Company of San Fran-
`cisco, which is affiliated with the
`American Academy of Ophthal-
`mology, even provides risk-man-
`
`agement recommendations for
`such use and an informed-con-
`sent form that physicians can
`modify to fit their practice.5 Most
`regional Medicare carriers cover
`intravitreal injections of bevaci-
`zumab, although there is no na-
`tional policy.
`In many parts of the world, a
`medication that costs $1,950 for
`a monthly injection is unafford-
`able. In the United States, under
`Medicare, ranibizumab is covered
`through Part B; patients are re-
`sponsible for a 20% copayment
`for each injection. In some in-
`stances, supplemental insurance,
`Medicaid, or support programs for
`the poor or uninsured that are
`funded by the manufacturer or
`others cover most or all of the
`patients’ costs. But regardless of
`who pays the bill, sales of ranibi-
`zumab generate revenue for Gen-
`entech, the drug’s high price
`contributes to the overall cost of
`health care, and the drug may
`sometimes still be unaffordable.
`It is possible that bevacizu-
`mab would prove to be superior
`for neovascular age-related mac-
`ular degeneration. For example,
`the molecule is about three times
`as large as ranibizumab and may
`remain in the eye long er, decreas-
`ing the frequency with which in-
`jections are required. At present,
`intraocular pharmacokinetic data
`are lacking. However, ranibizu-
`mab could also prove to be better.
`In addition to its smaller size,
`ranibizumab is genetically engi-
`neered to have greater affinity for
`vascular endothelial growth fac-
`tor and is formulated for intra-
`ocular use; more of the drug may
`therefore penetrate all the layers
`of the retina. Moreover, ranibi-
`zumab that leaks out of the eye
`into the circulation has a half-life
`of hours; the half-life of a full-
`
`n engl j med 355;14 www.nejm.org october 5, 2006
`
`1411
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on December 4, 2018. For personal use only. No other uses without permission.
`
` Copyright © 2006 Massachusetts Medical Society. All rights reserved.
`
`

`

`PERSPECTIVE
`
`The Price of Sight — Ranibizumab, Bevacizumab, and the Treatment of Macular Degeneration
`
`length antibody such as bevaci-
`zumab is longer. For this reason,
`ranibizumab could theoretically
`be associated with less systemic
`toxicity than bevacizumab, but it
`is not known whether this is in
`fact the case. As an antibody frag-
`ment, ranibizumab lacks an Fc
`portion, so it may be less likely to
`induce inflammation within the
`eye. However, according to Rosen-
`feld, no apparent inflammation
`has been seen with bevacizumab,
`even with the highest dose that
`has been administered.3
`Genentech specifically devel-
`oped ranibizumab for the treat-
`ment of neovascular age-related
`macular degeneration. In an in-
`terview, Hal Barron, a senior vice-
`president and chief medical of-
`ficer of Genentech, explained the
`company’s position on the use of
`intraocular bevacizumab. “We have
`a huge database suggesting that
`Lucentis is very effective and very
`safe, so we are just not sure of the
`value of taking something that
`
`is not formulated for the eye and
`subjecting patients to a random-
`ized trial when there is, in our
`opinion, a very low likelihood of
`its being superior,” he said. Nev-
`ertheless, Barron acknowledged,
`“If people have a hypothesis that
`it would be better or safer, one
`could certainly test that.”
`Since late 2005, the National
`Eye Institute has been consider-
`ing a proposal for a prospective
`multicenter trial that would com-
`pare ranibizumab directly with
`bevacizumab. Although the insti-
`tute has signed off on the need
`for a trial, as of mid-September it
`was still considering the research
`design and how to pay for the
`study, which would probably cost
`tens of millions of dollars. If the
`study is to go forward, the federal
`government will probably have to
`buy both drugs from Genentech.
`And the investigators will prob-
`ably have to submit to the FDA
`an investigational new drug ap-
`plication for intravitreal bevaci-
`
`zumab. Such a comparison might
`not ultimately affect the differ-
`ence in price between the drugs,
`but it is certainly the only way to
`determine which drug is better
`for patients.
`
`Dr. Steinbrook (rsteinbrook@attglobal.net)
`is a national correspondent for the Journal.
`
`Rosenfeld PJ. Intravitreal Avastin: the low
`1.
`cost alternative to Lucentis? Am J Ophthal-
`mol 2006;142:141-3.
`Idem. Avastin in ophthalmology: a global
`2.
`phenomenon. Current Insights. Vol. 1. No.
`2. Spring 2006. (San Francisco: American
`Academy of Ophthalmology.)
`Bashshur ZF, Bazarbachi A, Schakal A,
`3.
`Haddad ZA, El Haibi CP, Noureddin BN. In-
`travitreal bevacizumab for the management
`of choroidal neovascularization in age-relat-
`ed macular degeneration. Am J Ophthalmol
`2006;142:1-9.
`Moshfeghi AA, Rosenfeld PJ, Puliafito
`4.
`CA, et al. Systemic bevacizumab (Avastin)
`therapy for neo-vascular age-related macular
`degeneration: twenty-four-week results of an
`uncontrolled open-label study. Ophthalmol-
`ogy (in press).
`Ophthalmic Mutual Insurance Company.
`5.
`Risk management recommendations for off-
`label, intravitreal use of Avastin. August 2,
`2006. (Accessed September 19, 2006, at
`http://www.omic.com/resources/risk_man/
`forms/consent/Avastin%20080206.rtf.)
`
`Tracing Atrial Fibrillation — 100 Years
`W. Bruce Fye, M.D.
`
`Today, there is talk about an
`
`epidemic of atrial fibrillation,
`and physicians caring for patients
`with this common arrhythmia
`face a bewildering array of treat-
`ment options. Contrast this situ-
`ation with that of 1900, when no
`one understood the arrhythmia’s
`mechanism or realized that it
`occurred in humans. One hun-
`dred years ago, in 1906, two pub-
`lications — one from the Neth-
`erlands and the other from the
`United States — revealed that the
`
`arrhythmia, then called “auricu-
`lar fibrillation,” did indeed affect
`humans, that it was in fact com-
`mon in patients with heart dis-
`ease, and that it could be identi-
`fied by means of a new instrument,
`the electrocardiograph. These two
`articles marked a turning point
`in the history of atrial fibrillation.
`Their publication, along with
`subsequent reports and the de-
`velopment of electrocardiography,
`helped clinical investigators be-
`gin to solve a perplexing problem
`
`that physicians soon came to rec-
`ognize as a common one.1,2
`Around 1900, a few clinical
`investigators, notably James Mack-
`enzie in Scotland and Karel
`Wenckebach in Holland, were
`studying cardiac arrhythmias with
`the use of arterial and venous
`pulse tracings. Pulse tracings re-
`flect the consequences of cardiac
`contractions; they do not docu-
`ment the actual electrical im-
`pulses that stimulate the atria
`and ventricles to contract in the
`
`1412
`
`n engl j med 355;14 www.nejm.org october 5, 2006
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on December 4, 2018. For personal use only. No other uses without permission.
`
` Copyright © 2006 Massachusetts Medical Society. All rights reserved.
`
`