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Volume 15, No. 10Supplement 7October 2006
Supplement to
Based on the proceedings of an expert advisory panel,
Miami, March 10, 2006
Targeted Therapy For the Treatment of
Macular Degeneration
• Overview of Age-Related Macular Degeneration
• Treatments for Age-Related Macular Degeneration
• PANEL DISCUSSION: Ranibizumab Therapy in the ManagedCare Market
• Considerations for Managed Care Decision Makers
HIGHLIGHTS
Sponsored by Genentech Inc.
CareM A N A G E D
CareS U P P L E M E N T T O
October 2006
This supplement is sponsored by Genentech Inc. The material in this supplement has been independentlypeer reviewed. The grantor played no role in reviewer selection.
Opinions are those of the authors and do not necessarily reflect those of the institutions that employ them,or of Genentech Inc., MediMedia USA, or the publisher, editor, or editorial board of MANAGED CARE.
Clinical judgment must guide each clinician in weighing the benefits of treatment against the risk of toxic-ity. Dosages, indications, and methods of use for products referred to in this supplement may reflect the clini-cal experience of the authors or may reflect the professional literature or other clinical sources and may not bethe same as indicated on the approved package insert. Please consult the complete prescribing informationon any products mentioned in this publication. MediMedia USA assumes no liability for the information pub-lished herein.
Targeted Therapy for the Treatment Of Macular Degeneration
Based on the proceedings of an expert advisory panel, Miami, March 10, 2006
FACULTY PRESENTATIONS
Overview of Age-Related Macular Degeneration ........................................3PRAVIN U. DUGEL, MDRetinal Consultants of Arizona
Treatments for Age-Related Macular Degeneration ....................................7PRAVIN U. DUGEL, MD
PANEL DISCUSSION
Ranibizumab Therapy in the Managed Care Market ................................16PRAVIN U. DUGEL, MDGARY L. JOHNSON, MD, MBA, Group Health CooperativeROBERT LONIGRO, MD, Tufts Health PlanGLENDA S. OWENS, RPH, MHA, Arcadian Health PlanBALAKRISHNA R. PAI, MD, Health Alliance PlanSHERMAN PODOLSKY, MD, Vista HealthplanALBERT J. RIZZOLI, MD, Presbyterian Health PlanCHARLES A. STEMPLE, DO, MBA, HumanaBRET S. YARCZOWER MD, Geisinger Health Plan
MANAGED CARE CONSIDERATIONSPoints To Ponder ...........................................................................................20
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MANAGED CARE (ISSN 1062-3388) is published monthly by MediMedia USA Inc., 780 Township Line Road, Yardley, PA 19067.This is Supplement 7 to Volume 15, No. 10. Periodicals postage paid at Morrisville, Pa., and at additional mailing offices. POSTMASTER: Send address changes to MANAGED CARE, 780 Township Line Road, Yardley, PA 19067. Price: $10 per copy,$100 per year in the United States; $120 per year elsewhere. E-mail: [email protected]: (267) 685-2788; fax (267) 685-2966; circulation inquiries (267) 685-2789. Copyright ©2006 MediMedia USA Inc.
2 SUPPLEMENT
TREATMENT OF MACULAR DEGENERATION 3
The National Health Interview Survey found thatabout 3 percent of Americans 50 years of age or older re-ported having been told by a doctor that they have AMD,with the prevalence ranging from 1 percent in people ages50–64 to nearly 5 percent in the 65-or-older age group(Saaddine 2004). Another recent study has estimated
that advanced AMD affects about1.75 million Americans (Friedman2004). This number includes peo-ple with either neovascular AMD(the focus of this supplement) orgeographic atrophy (a well-definedround or oval area of retinal de-pigmentation). In a population-based study, the incidence of ad-vanced AMD in patients age 65 was5.5 percent (Klein 2002). Owing tothe aging of the population in the
United States, the number of people with advanced AMDis expected to increase to nearly 3 million by 2020 (Fried-man 2004). In the absence of an effective means of treat-ing or preventing AMD, this disease will present an ever-larger economic and social burden as the populationages.
Neovascular AMD is commonly called wet AMD be-cause it is associated with leakage of blood or serumfrom new blood vessels that develop in the choroid, thevessel-rich tissue between the retina and sclera. No suchleakage occurs in atrophic (avascular) AMD, which istherefore known as dry AMD. Both wet and dry AMD canresult in loss of vision. Wet AMD is much less commonthan dry AMD, but the wet form accounts for about 75to 90 percent of the severe vision loss associated withAMD (Ferris 1984, Klein 1997).
AMD rarely results in complete loss of vision becauseit does not spread beyond the macula; hence, most pa-tients retain peripheral vision sufficient for walking.Nevertheless, visual loss from AMD greatly reduces pa-tients’ self-sufficiency, increasing their dependence onfamily members and caregivers. When only the extra-foveal portion of the macula is involved, a person withAMD still can have 20/20 vision, but once neovascular-ization occurs under the fovea, central vision is severelycompromised. With neovascular AMD, the loss of cen-tral vision that precludes driving or reading fine print canoccur rapidly — seemingly, overnight. Visual acuity canchange from normal to 20/200 or worse in a matter of
Age-related macular degeneration (AMD) is the lead-ing cause of blindness among older people in the UnitedStates (Congdon 2004). The macula is a circular area,about 5–6 mm in diameter, in the central portion of theretina and is centered on a much smaller area, the fovea.Populated with the highest concentration of photo-receptors in the retina, the macula is responsible for thehigh-resolution visual acuity that enables people to rec-ognize faces, read small print, and drive — which is whythe loss of central vision adversely affects patients’ qual-ity of life. Clinical depression has been found in onethird of patients with AMD and about 60 percent of pa-tients with AMD-related vision loss report significant re-duction in their ability to participate in activities theyvalue (Brody 2001, Rovner 2002b, Rovner 2002a).
Overview of Age-Related Macular DegenerationPRAVIN U. DUGEL, MD
Retinal Consultants of Arizona, Phoenix
Pravin U. Dugel,MD
Pravin U. Dugel, MD, is an ophthalmologist at the RetinalConsultants of Arizona and Clinical Instructor of Vitreo-retinal Diseases and Surgery in the department of oph-thalmology at the University of Arizona. He graduatedfrom University of California–Los Angeles School of Medi-cine in 1988, completed his residency at the Doheny Eye In-stitute of the University of Southern California School ofMedicine, then completed fellowships in VitreoretinalSurgery at the Doheny Eye Institute and in VitreoretinalDiseases at the Bascom Palmer Eye Institute, University ofMiami. He has been a co-investigator in National Eye In-stitute research studies and in several Multicenter Studies,including the MARINA and ANCHOR trials described inthis supplement. Dugel has authored more than 30 papersand chapters, and is the first person to receive both theHeed Foundation Fellowship Award and the Ronald G.Michels Vitreoretinal Surgery Fellowship Award.
Age-related macular degeneration (AMD) exists in two forms, commonly known as dryand wet. Though much less common, the wet(neovascular) form is responsible for the major-ity of severe central vision loss associated withadvanced AMD. A secreted glycoprotein, vascu-lar endothelial growth factor (VEGF), has beenimplicated in the development of neovascularAMD and is an attractive therapeutic target.
SUMMARY
4 SUPPLEMENT
weeks, but the more frequent path is for visual acuity todeteriorate slowly and to stabilize within 3 years, usuallyto between 20/250 and 20/400 (Fine 2000).
The appearance of drusen — tiny packets of extra-cellular debris that slowly accumulate between the reti-nal pigment epithelium (RPE) and Bruch’s membrane —is a sign of early AMD. (The RPE is a layer of cells thatmaintains the adjacent photoreceptors, or rods andcones; Bruch’s membrane is a thin collagenous structurethat separates the RPE from the choroid.) Based on thepresence of drusen, nearly every person over the age of50 can be said to have some amount of macular degen-eration. Progression of drusen tends to be very slow, butthe more drusen a patient has, the higher the risk for neo-vascular bleeding.
Having at least one druse with a diameter ≥125 µm isa risk factor for progressing to neovascular AMD. An es-timated 7 million Americans over age 40 have at least onedruse of this size, and this number is predicted to increaseby an additional 6.4 million by 2020 (Friedman 2004).For patients with at least one large druse, there is an es-timated 6 percent risk of progressing to neovascularAMD within 5 years. With 10 or more such drusen, the5-year risk increases to 14 percent. The prevalence ofneovascular AMD remains low until people reach their70s, but prevalence increases sharply after the age of 80.After age 80, the prevalence of neovascular AMD inwomen is more than triple that of men.
Various risk factors for neovascular AMD haveemerged (Table 1). However, the etiology is poorly un-derstood. Oxidative stress, trauma to Bruch’s membrane,inflammation, hypoxia, and nutrient deprivation are
among the factors implicated as initiating events (Roth2004, Zarbin 2004).
Role of VEGF in neovascular AMDThe existence of some Factor X was once thought to
be responsible for the stimulation of neovascularizationin AMD. The identity of Factor X appears to have beendiscovered — a secreted glycoprotein known as vascularendothelial growth factor-A (VEGF-A). VEGF-A is animportant mediator of angiogenesis, the process bywhich both physiologic vascularization and pathologicneovascularization occur (Figure 1).
VEGF-A is a member of the VEGF gene family.Amongthe other members of this family, which are involved inlymphangiogenesis and inflammation, are VEGF-B, -C,-D, and -E, along with placental growth factor (Ferrara2003). For the remainder of this article and in the fol-
TABLE 1 Emerging risk factors for neovascular AMD
Risk factor Reference
Advanced age Friedman 2004
Smoking Khan 2006, Klein 1993
Alcohol consumption Buch 2005
Family history Buch 2005
Variation in gene for complement factor H
Haines 2005, Klein 2005, Li 2006, Maller 2006, Sepp 2006
Variation in other genes Haines 2006
FIGURE 1
VEGF-A promotes vascular leakage and angiogenesis
Injection of VEGF-A
stimulates vascular leakage
Injection of VEGF-A stimulates new vessel growth
Guinea pig skin
VEGF-A=vascular endothelial growth factor-A.
SOURCE: MUROHARA 1998Rabbit cornea
8 16 32 64 128 Saline
VEGF-A (ng)
TREATMENT OF MACULAR DEGENERATION 5
lowing article, “VEGF” will be used to refer to VEGF-Aonly.
In addition to promoting angiogenesis, VEGF is a po-tent enhancer of vascular permeability. It was initiallycalled “vascular permeability factor,” but it was renamedupon being purified and cloned by Ferrara (Senger 1983,Ferrara 1989,Leung 1989).As an enhancer of vascular per-meability effect, VEGF is 50,000 times more potent thanhistamine. In fact, VEGF is more powerful as a perme-ability factor than as an angiogenesis factor, but the twoconcepts are interrelated. If angiogenesis is likened to a newbranch growing from a tree, some kind of breakage mustoccur in the trunk to permit the new branch to emerge.Without an increase in vascular permeability, whetherphysiologic or pathologic, angiogenesis cannot occur.
VEGF is secreted by a variety of cells in response tolocal tissue stress, most commonly hypoxia/ischemia, aswell as changes in pH (Ferrara 2003). VEGF is upregu-lated by other growth factors and hormones, includingepidermal growth factor, transforming growth factors αand β‚ basic fibroblast growth factor, platelet-derivedgrowth factor, keratinocyte growth factor, insulin-likegrowth factor-1, interleukins 1α and -6, and estrogen.
VEGF exists in at least six isoforms, all arising from al-ternative splicing of mRNA transcribed from a singlegene (Gaudreault 2005). These variations encode proteinmolecules consisting of 121, 145, 165, 183, 189, or 206amino acids. In addition, any of these six isoforms canbe cleaved by plasmin into an isoform of 110 aminoacids. VEGF165 is the predominant isoform and is foundin normal eyes of rats, monkeys, and humans, alongwith VEGF121. However, the precise role of each isoformin AMD has not been determined.
VEGF binds to a VEGF receptor, of which there are twosubtypes — VEGFR1 and VEGFR2 — both found on thesurface of endothelial cells. The angiogenic, mitogenic,and permeability-enhancing properties of VEGF are me-diated by VEGFR2.
To establish that VEGF drives retinal neovasculariza-tion,VEGF was injected into the eyes of healthy monkeys(Figure 2) (Tolentino 2002). The injections were con-tinued every 3 days for up to 78 days. Neovascular glau-coma developed by day 19, and at the time of vitrectomyat day 80, intraretinal neovascularization was noted.VEGF alone was sufficient to induce vascular dilation andtortuosity, microaneurysm formation, intraretinal hem-orrhages, and intraretinal vascular proliferation.
TABLE 2 Ocular neovascular diseases associated
with increased levels of VEGF
Disease Reference
AMD Otani 2002
Proliferative diabeticretinopathy
Wilkinson-Berka 2004
Diabetic macular edema Funatsu 2003
Retinopathy of prematurity Cooke 2004
Iris neovascularization Pe’er 1997
Central and branch retinal-vein occlusion
Pe’er 1998
von Hippel-Lindau syndrome
Harris 2000
Intraocular melanomas and retinoblastomas
Stitt 1998
FIGURE 2
Intravitreal injection of VEGF-A promotes leakage and neovascularization
Before VEGF-A injection After VEGF-A injection
VEGF-A=vascular endothelial growth factor-A.
SOURCE: TOLENTINO 2002
In addition to neovascular AMD, VEGF has been im-plicated in many other neovascular diseases of the eye(Table 2, page 5). Therefore, it has become an attractivetherapeutic target. In the following article, I will reviewthe treatments for neovascular AMD — notably, thoseaimed at blocking the effects of VEGF.
ReferencesBrody BL, Gamst AC, Williams RA, et al. Depression, visual acu-
ity, comorbidity, and disability associated with age-relatedmacular degeneration. Ophthalmology. 2001;108:1893–1900.
Buch H, Vinding T, la Cour M, et al. Risk factors for age-relatedmaculopathy in a 14-year follow-up study: the CopenhagenCity Eye Study. Acta Ophthalmol Scand. 2005;83:409–418.
Congdon N, O’Colmain B, Klaver CC, et al. Eye Diseases Preva-lence Research Group. Causes and prevalence of visual im-pairment among adults in the United States. Arch Ophthal-mol. 2004;122:477–485.
Cooke RW, Drury JA, Mountford R, Clark D. Genetic polymor-phisms and retinopathy of prematurity. Invest OphthalmolVis Sci. 2004;45:1712–1715.
Edwards AO, Ritter R 3rd, Abel KJ, et al. Complement factor Hpolymorphism and age-related macular degenration. Sci-ence. 2005;308:362–364.
Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and itsreceptors. Nat Med. 2003;9:669–676.
Ferrara N, Henzel WJ. Pituitary follicular cells secrete a novelheparin-binding growth factor specific for vascular endo-thelial cells. Biochem Biophys Res Commun. 1989;161:851–858.
Ferris FL 3rd, Fine SL, Hyman L. Age-related macular degenera-tion and blindness due to neovascular maculopathy. ArchOphthalmol. 1984;102:1640–1642.
Fine SL, Berger JW, Maguire MG, Ho AC. Age-related maculardegeneration. N Engl J Med. 2000;342:483–492.
Friedman DS, O’Colmain BJ, Munoz B, et al.; Eye DiseasesPrevalence Research Group. Prevalence of age-related mac-ular degeneration in the United States. Arch Ophthalmol.2004;122:564–572.
Funatsu H, Yamashita H, Ikeda T, et al. Vitreous levels of inter-leukin-6 and vascular endothelial growth factor are relatedto diabetic macular edema. Ophthalmology. 2003;110:1690–1696.
Gaudreault J, Fei D, Rusit J, et al. Preclinical pharmacokinetics ofranibizumab (rhuFabV2) after a single intravitreal admini-stration. Invest Ophthalmol Vis Sci. 2005;46:726–733.
Haines JL, Schnetz-Boutaud N, Schmidt S, et al. Functional can-didate genes in age-related macular degeneration: signifi-cant association with VEGF, VLDLR, and LRP6. Invest Oph-thalmol Vis Sci. 2006;47:329–335.
Haines JL, Hauser MA, Schmidt S, et al. Complement factor Hvariant increases the risk of age-related macular degenera-tion. Science. 2005;308:419–421.
Harris AL. von Hippel-Lindau syndrome: target for anti-vascular endothelial growth factor (VEGF) receptor ther-apy. Oncologist. 2000;5(suppl 1):32–36.
Khan JC, Thurlby DA, Shahid H, et al.; Genetic Factors in AMDStudy. Smoking and age related macular degeneration: thenumber of pack years of cigarette smoking is a major deter-minant of risk for both geographic atrophy and choroidalneovascularisation. Br J Ophthalmol. 2006;90:75–80.
Klein R, Klein BE, Linton KL, DeMets DL. The Beaver Dam eyestudy: the relation of age-related maculopathy to smoking.Am J Epidemiol. 1993;137:190–200.
Klein R, Klein BE, Tomany SC, et al. Ten-year incidence and pro-gression of age-related maculopathy: The Beaver Dam eyestudy. Ophthalmology. 2002;109:1767–1779.
Klein RJ, Zeiss C, Chew EY, et al. Complement factor H poly-morphism in age-related macular degeneration. Science.2005;308:385–389.
Leung DW, Cachianes G, Kuang WJ, et al. Vascular endothelialgrowth factor is a secreted angiogenic mitogen. Science.1989;246:1306–1309.
Li M, Atmaca-Sonmez P, Othman M, et al. CFH haplotypeswithout the Y402H coding variant show strong associationwith susceptibilitiy to age-related macular degenration. NatGenet. 2006;38:1049–1054.
Maller J, George S, Purcell S, et al. Common variation in threegenes, including a noncoding variant in CFH, strongly in-fluences risk of age-related macular degeneration. NatGenet. 2006;38:1055–1059.
Murohara T, Horowitz JR, Silver M, et al. Vascular endothelialgrowth factor/vascular permeability factor enhances vascu-lar permeability via nitric oxide and prostacyclin. Circula-tion. 1998;97:99–107.
Otani A, Takagi H, Oh H, et al. Vascular endothelial growth fac-tor family and receptor expression in human choroidalneovascular membranes. Microvasc Res. 2002;64:162–169.
Pe’er J, Neufeld M, Baras M, et al. Rubeosis iridis in retino-blastoma. Histologic findings and the possible role of vas-cular endothelial growth factor in its induction. Ophthal-mology. 1997;104:1251–1258.
Pe’er J, Folberg R, Itin A, et al. Vascular endothelial growth factorupregulation in human central retinal vein occlusion. Oph-thalmology. 1998;105:412–416.
Roth F, Bindewald A, Holz FG. Key pathophysiologic pathwaysin age-related macular disease. Graefes Arch Clin Exp Oph-thalmol. 2004;242:710–716.
Rovner BW, Casten RJ. Activity loss and depression in age-related macular degeneration. Am J Geriatr Psychiatry.2002a;10:305–310.
Rovner BW, Casten RJ, Tasman WS. Effect of depression on vi-sion function in age-related macular degeneration. ArchOphthalmol. 2002b;120:1041–1044.
Saaddine J, Benjamin S, Pan L, et al. Prevalence of visual impair-ment and selected eye diseases among persons aged ≥50years with and without diabetes — United States, 2002.MMWR. 2004;53:1069–1071.
Senger DR, Galli SJ, Dvorak AM, et al. Tumor cells secrete a vas-cular permeability factor that promotes accumulation ofascites fluid. Science. 1983;219:983–985.
Sepp T, Khan JC, Thurlby DA, et al. Complement factor H vari-ant Y402H is a major risk determinant for geographic atro-phy and choroidal neovascularization in smokers and non-smokers. Invest Ophthalmol Vis Sci. 2006;47:536–540.
Stitt AW, Simpson DA, Boocock C, et al. Expression of vascularendothelial growth factor (VEGF) and its receptors is regu-lated in eyes with intra-ocular tumours. J Pathol.1998;186:306–312.
Tolentino MJ, McLeod DS, Taomoto M, et al. Pathologic featuresof vascular endothelial growth factor-induced retinopathyin the nonhuman primate. Am J Ophthalmol. 2002;133:373–385.
Wilkinson-Berka JL. Vasoactive factors and diabetic retinopathy:vascular endothelial growth factor, cycoloxygenase-2 andnitric oxide. Curr Pharm Des. 2004;10:3331–3348.
Zarbin MA. Current concepts in the pathogenesis of age-relatedmacular degeneration. Arch Ophthalmol. 2004;122:598–614.
6 SUPPLEMENT
TREATMENT OF MACULAR DEGENERATION 7
As of early 2006, the treatments available for AMDwere limited in their ability to improve visual acuity.These treatments included laser photocoagulation,photodynamic therapy (PDT) with verteporfin (Visu-dyne), combination therapy with PDT and steroids, andpegaptanib (Macugen), an aptamer against vascularendothelial growth factor. Vascular endothelial growthfactor A (hereafter referred to as VEGF) has been impli-cated in neovascular AMD. This article will discuss thecurrent therapies and then examine the evidence sup-porting a novel treatment for neovascular AMD, rani-bizumab (Lucentis), a humanized monoclonal antibodyfragment against VEGF.
Some treatments are appropriate only for patientswith certain kinds of choroidal neovascularization(CNV). On the basis of its appearance in fluoresceinangiography, CNV can be grouped into three categories:predominantly classic, minimally classic, and occult. In apredominantly classic, or well-defined CNV, more thanhalf of the area of the choroidal neovascular lesion hasdistinct borders. A minimally classic lesion has somedistinct borders but less than half of the area of the le-sion is well defined. An occult lesion completely lackswell-defined borders.
Assessments of visual acuity are the primary tool fordetermining the efficacy of treatments for neovascularAMD. The familiar chart used for assessing visual acu-
ity is the Snellen chart, named for the 19th century Dutchophthalmologist who created it. On the Snellen scale,20/20 represents normal visual acuity and 20/200 repre-sents legal blindness. In modern research, the most com-monly used tool for assessing visual acuity is the ETDRSeye chart, which was first used in the Early Treatment ofDiabetic Retinopathy Study. The ETDRS chart consistsof rows, or lines of letters, five letters to a line, with eachline of type smaller than the one above it. The patientreads down the chart until he or she reaches a row wherea minimum of three letters on a line cannot be read.Upon retesting, the loss of 15 letters (three lines of let-ters) is clinically considered a moderate loss of visual acu-ity; the loss of 30 letters (six lines) or more is considereda severe loss. The number of ETDRS letters a person cansee is approximately equivalent to the following Snellenranges: >73 letters, 20/40; 73–54 letters, 20/40 to 20/80;53–34 letters, 20/100 to 20/200;≤33 letters, <20/200 (Fer-ris 1982).
Laser photocoagulationIntroduced in the early 1990s, laser photocoagulation
was the first treatment used to treat neovascular AMD.Despite its high-tech name, it proved to be a rather crudetool — the clinical equivalent of a hand grenade. Whenlaser photocoagulation achieves its intended result —burning new blood vessels — it also causes indiscrimi-nate collateral damage to overlying photoreceptors,which results in significant and permanent vision losswherever the laser is applied. Laser photocoagulation ofan extrafoveal blood vessel creates a blind spot on thatpart of the retina, but the patient may be willing to ac-cept that loss in the hope of preserving central vision. Onthe other hand, laser photocoagulation of a subfovealblood vessel destroys central vision.
Strict criteria, therefore, are needed to minimize un-wanted damage. Eligibility criteria used by the MacularPhotocoagulation Study Group (MPS) have beenadopted as guidelines for determining which kinds ofCNV are suitable for treatment (MPS 1991). These guide-lines recommend that only symptomatic, well-demarcated extrafoveal and juxtafoveal lesions be treated.Occult lesions are not suitable for treatment as no treat-ment benefit for occult lesions has been shown.
In a small study, MPS criteria were applied to patients
Treatments for Age-Related Macular DegenerationPRAVIN U. DUGEL, MD
Retinal Consultants of Arizona, Phoenix
Until now, treatments for neovascular age-related macular degeneration (AMD) have beenknown for their ability to reduce the rate of dis-ease progression. A new treatment for neo-vascular AMD, ranibizumab (a humanizedmonoclonal antibody fragment against vascu-lar endothelial growth factor), is the first treat-ment that has been shown to maintain visualacuity in nearly all patients with any subtype oflesion associated with neovascular AMD. Inphase 3 trials, visual acuity improved in aboutone third of patients after 1 and 2 years oftreatment.
SUMMARY
8 SUPPLEMENT
who were newly diagnosed with neovascular AMD,and only 13 percent (9/67) were eligible for lasercoagulation (Freund 1993). Moreover, recurrencerates after laser photocoagulation are high — abouthalf within 3 years (MPS 1994) — and the recur-rences tend to be subfoveal. Because of the limit-ations of thermal laser photocoagulation, only asmall percentage of people with neovascular AMDare likely to benefit from it.
The need for a new approach led to testing of anindirect laser treatment, or scatter photocoagula-tion, for occult lesions. In pilot trials of this tech-nique, the treatment was not found to be benefi-cial (Arnold 1997, Bressler 1996, Cardillo Piccolino1993).
Photodynamic therapy with verteporfinPhotodynamic therapy (PDT) with verteporfin,
a light-activated drug, emerged in 2000 as a meansof selectively ablating neovascular AMD lesionswhile minimizing thermal damage to overlyingand underlying structures.Verteporfin is indicatedfor treatment of patients with predominantly clas-sic subfoveal CNV; evidence is insufficient to in-dicate verteporfin for treatment of predominantlyoccult subfoveal CNV (verteporfin 2004).
Verteporfin therapy comprises two steps: a 10-minuteintravenous infusion of verteporfin, which accumulatessomewhat preferentially in the neovasculature, includingCNV, followed by activation of the drug with a non-thermal red laser (689 nm wavelength) 15 minutes afterthe beginning of the infusion. In the presence of oxygen,activated verteporfin generates reactive oxygen speciesthat cause local damage to the neovascular endothelium,resulting in occlusion of the vessel.
PDT with verteporfin has been found to be most bene-ficial in patients with predominantly classic CNV at base-line. Two clinical trials of PDT showed that in this sub-group, 68 percent of verteporfin-treated patients lost <3lines on the ETDRS chart, compared with 40 percent ofthe patients who received a placebo; after two years, 59percent of the patients in the verteporfin group lost <3lines versus 31 percent in the placebo group (verteporfin2004). Severe vision loss (≥6 lines of visual acuity) oc-curred in 12 and 15 percent of verteporfin-treated pa-tients at years 1 and 2, respectively, compared with 34 and36 percent of placebo-treated patients. PDT is increas-ingly used in conjunction with intravitreal triam-cinolone, but that combination increases the risk of glau-coma and cataracts (Gillies 2004).
Pegaptanib anti-VEGF treatmentIn December 2004, pegaptanib became the first anti-
VEGF therapy approved by the U.S. Food and Drug Ad-ministration for the treatment of neovascular AMD. Pe-
gaptanib is an aptamer, a short strand (28 bases) of syn-thetic RNA that binds to and inhibits the VEGF165 iso-form. Pegaptanib is delivered as an intravitreal injectioncontaining 0.3 mg of drug every 6 weeks. In clinical tri-als, injections were given over a period of 48 weeks (nineinjections).
Two concurrent phase 3 clinical trials of pegaptanibwere conducted: one trial enrolled 586 patients in theUnited States and Canada and the other enrolled 622 pa-tients in Europe, Israel, Australia, and South America(Gragoudas 2004). The study population ranged in agefrom 52 to 92 years (mean, 77) and included patients withall angiographic subtypes of CNV (predominantly clas-sic, minimally classic, and occult with no classic CNV)in roughly equal proportions (Table 1). Patients were ex-cluded if they had a history or evidence of severe cardiacdisease (myocardial infarction within 6 months, ventri-cular tachyarrythmias, or unstable angina); history or ev-idence of peripheral vascular disease; clinically significantimpaired renal or hepatic function; stroke within 12months of study entry; or previous therapeutic radiationto the eye, head, or neck.
In both trials, pegaptanib treatment was compared tosham treatment. To maintain patient masking, a syringelacking a needle was pressed against the anesthetizedeyeball.
Patients with a history of PDT with verteporfin wereallowed in the study; 8 percent of the pegaptanib 0.3 mggroup and 6 percent of the sham group reported such a
TABLE 1 Demographics and baseline characteristics of
subjects in pegaptanib phase 3 trials
Sham
(n=298)
Pegaptanib
0.3 mg*
(n=295)
Gender (% female) 60 55
Race (% white) 95 96
Age, mean (years) 75.7 76.4
Mean VA (ETDRS letter score) 52.7 52.8
Mean lesion size (DA) 4.2 3.7
CNV classification (% of subjects)
Occult with no classic 40 38
Minimally classic 34 38
Predominantly classic 26 24
CNV=choroidal neovascularization, DA=optic-disk area (equal to 2.54 mm2),ETDRS=Early Treatment of Diabetic Retinopathy Study, VA=visual acuity.*These phase 3 trials also included arms for pegaptanib 1.0 and 3.0 arms, but they areexcluded because results were similar to those for pegaptanib 0.3 mg, the FDA-approved dose. No benefit was associated with the higher doses.SOURCES: GRAGOUDAS 2004, PEGAPTANIB 2004
TREATMENT OF MACULAR DEGENERATION 9
history at baseline.At the discretion of the physician, whowas masked to treatment assignment, PDT was permit-ted in patients with predominantly classic lesions as perthe verteporfin label. The incidence of prior PDT use wasslightly greater in the North American trial (13 percent)than in the other (predominantly European) trial (3 per-cent), possibly reflecting variations in clinical practice(pegaptanib 2004). The percentage of patients receivingPDT from study investigators at baseline (5–10 days be-fore the study began) was similar in the pegaptanib 0.3mg group (12 percent) and sham group (13 percent).After baseline, however, slightly more sham-treated pa-tients received PDT than patients who were treated with0.3 mg of pegaptanib (21 versus 17 percent, respectively).Overall, the percentage of subjects who received PDT washigher in the sham group (25 percent, or 75/296) thanin the pegaptanib 0.3 mg group (20 percent, 58/294)(pegaptanib 2005).
In a recent report of these combined phase 3 registrydata, 70 percent of patients who received pegaptanib 0.3mg lost <15 letters of visual acuity at 54 weeks, comparedwith 55 percent who received the sham injection (Table2). Thirty-three percent of the pegaptanib group and 23percent of the sham group reported maintenance or gainof visual acuity. During the second year of treatment, pe-gaptanib was less effective than during the first year. Inthe predominantly European study, 57 percent of patientsin the pegaptanib 0.3 mg group and 57 percent in thesham group lost <15 letters from baseline to week 102;in the North American study, 61 percent of patientstreated with pegaptanib 0.3 mg and 34 percent of sham-treated patients lost <15 letters in the same time period.
Phase 3 trials of ranibizumabRanibizumab is a humanized monoclonal antibody
fragment engineered to have high binding affinity for all
isoforms of VEGF, thereby blocking the ability of VEGFto promote vessel permeability and angiogenesis. Inhuman trials, administration of ranibizumab via intra-vitreal injection has been selected to maximize localVEGF inhibition in the retina while minimizing VEGFinhibition systemically. Results from two phase 3, 2-year trials of ranibizumab were recently reported: MA-RINA1 and ANCHOR2. MARINA was a sham-controlledtrial of patients with minimally classic or occult CNV;ANCHOR was an active-controlled trial (PDT withverteporfin) enrolling patients with predominantly clas-sic subfoveal lesions. Two-year data are available forMARINA, while 1-year data have been reported forANCHOR.
MARINAMARINA was a phase 3, randomized, multicenter,
double-masked, sham-controlled study to evaluate theefficacy and safety of ranibizumab in subjects withminimally classic CNV or occult with no classic sub-foveal CNV secondary to AMD (Rosenfeld 2006).MARINA enrolled a population that was not eligible forPDT.
The eligibility criteria were age ≥50 years; minimallyclassic or occult with no classic CNV; Snellen-equivalentvisual acuity ranging from 20/40 to 20/320; evidence ofpresumed recent disease progression (blood or recentgrowth shown by fluorescein angiography or recent lossin visual acuity); and lesion size ≤12 disk areas. Patientswere well-matched across all study groups in terms ofdemographics and ocular characteristics at baseline(Table 3, page 10). Exclusion criteria included prior sub-
1 Minimally classic/occult trial of the Anti-VEGF antibodyRanibizumab In the treatment of Neovascular AMD.
2 ANti-VEGF antibody for the treatment of predominantly classic CHORoidal neovascularization in AMD.
TABLE 2 Selected endpoints at week 54 in phase 3 trials of pegaptanib
Sham
(n=296)
Pegaptanib 0.3
mg (n=294)
P value
vs. sham
Losing <15 letters from baseline (primary endpoint) 55% 70% <.001
Letter gain or loss from baseline (% of subjects)
Gain ≥0 letters 23 33 .003
Gain ≥15 letters 2 6 .04
Loss ≥30 letters (severe loss) 22 10 <.001
VA ≤20/200 (legal blindness) 56 38 <.001
Mean area of leakage, number of DAs (baseline) 5.2 (3.6) 4.3(3.3)
DA=optic-disk area (equal to 2.54 mm2), VA=visual acuity.SOURCE: GRAGOUDAS 2004
10 SUPPLEMENT
foveal laser treatment, PDT with verteporfin, and ex-perimental treatments for wet AMD.
The primary endpoint was the current FDA standardin AMD trials: the proportion of subjects who lost <15ETDRS letters of visual acuity at 12 months, comparedto baseline, in the best corrected visual acuity score. Im-portant secondary endpoints included the mean changein vision from baseline, the proportion of patients whogained 15 letters or more at month 12, and the mean areaof leakage. Exploratory endpoints included the propor-tion of patients whose vision was 20/40 or better atmonth 12, the proportion of patients gaining zero or anyletters, the proportion of patients gaining 30 or more let-ters, and the proportion of patients with severe vision loss(losing more than 30 letters).
Patients were randomized in a 1:1:1 fashion amongthree arms: sham, ranibizumab 0.3 mg, and ranibizumab0.5 mg. Beginning at month 0, and once a month there-after, patients received either an injection of active medi-cation or a sham injection through the 12-month time-frame for the primary endpoint, and continued up to 2years. Approximately 80–90 percent of the patients re-mained in the study for the full 24 months. At the dis-cretion of the investigator, patients could receive PDT ifthere was a conversion to predominantly classic CNV orif there was a loss of >20 letters on two consecutive vis-its, and small lesions <2 DAs in size. Patients in the shamgroup were allowed to cross over to the ranibizumab 0.5mg group at unmasking in October 2005, and 12 patientsin the sham group chose to do so in the final 2 monthsof the study.
At month 12, 95 percent of patients in both rani-bizumab arms maintained or improved vision, defined
as the loss of <15 letters, comparedwith 62 percent of patients in the shamgroup. By month 24, 92 percent of pa-tients in the ranibizumab 0.3 mg groupand 90 percent of patients in the 0.5mg group had lost <15 letters frombaseline, while 53 percent of patients inthe sham group met this endpoint(Table 4). By the end of the study, be-tween 26 and 33 percent of patientstreated with ranibizumab had gained≥15 letters, compared with 4 percent orfewer of the sham-treated patients.
At baseline, between 11 and 15 per-cent of all study patients had 20/40 vi-sion or better. After 2 years, 42 percentand 35 percent of patients in theranibizumab 0.5 mg and 0.3 mggroups, respectively, had 20/40 visionor better. The percentage of patientswho had 20/200 vision or worse in-creased from 13 to 48 percent in the
sham group by the end of the study, but decreased bymonth 12 for both ranibizumab groups. The percentageof patients with 20/200 vision or worse at 24 months wasthe same as at baseline for the ranibizumab 0.3 mg groupand increased about 2 percentage points for the rani-bizumab 0.5 mg group (Table 4).
Patients in both ranibizumab groups gained aboutseven letters from baseline by month 12, for an overalldifference of 17 letters between sham and ranibizumab-treated groups halfway through the study; by month 24,the difference between the ranibizumab groups and thesham group had grown to 20–21 letters (Figure 1). Themean area of leakage due to CNV increased in the shamgroup, but decreased in both the 0.3 mg and 0.5 mggroups.
Ranibizumab vs. PDT in ANCHORLike MARINA, ANCHOR was a randomized, multi-
center, double-masked study. It was designed to comparethe efficacy and safety of ranibizumab with verteporfinPDT in subjects with predominantly classic subfovealCNV. The primary endpoint was the same as inMARINA: the proportion of subjects losing <15 letters.Key secondary endpoints were the proportion of subjectswho gained ≥15 letters and the mean change in visualacuity from baseline to month 12 (Brown 2006).
The principal eligibility criteria included age ≥50 years,visual acuity between 20/40 and 20/320, with primary orrecurrent subfoveal CNV due to AMD. The lesion had tomeet the criteria for PDT treatment. Exclusion criteria in-cluded prior subfoveal laser treatment, PDT, or experi-mental treatments for wet AMD. Following fluoresceinangiography to confirm the lesion subtype, patients
TABLE 3 Demographics and baseline characteristics
of subjects in MARINA
Sham
(n=238)
Ranibizumab
0.3 mg
(n=238)
Ranibizumab
0.5 mg
(n=240)
Gender (% female) 66.8 64.3 63.3
Race (% white) 97.1 96.2 96.7
Age, mean (years) 77.0 77.4 76.8
Mean VA (ETDRS letter score) 53.6 53.1 53.7
Mean lesion size (DA) 4.4 4.3 4.5
CNV classification (% of subjects)
Occult with no classic 63.4 63.4 62.1
Minimally classic 36.6 36.1 37.9
Predominantly classic 0 0.4 0
CNV=choroidal neovascularization, DA=optic-disk area (equal to 2.54 mm2), ETDRS=Early Treatment of Diabetic Retinopathy Study, VA=visual acuity.SOURCE: ROSENFELD 2006
TREATMENT OF MACULAR DEGENERATION 11
TABLE 4 Selected endpoints in MARINA at months 12 and 24
Month 12 Month 24
Sham
(n=238)
Ranibizumab
0.3 mg
(n=238)
Ranibizumab
0.5 mg
(n=240) Sham
Ranibizumab
0.3 mg
Ranibizumab
0.5 mg
Primary endpoint (% of subjects)
Losing <15 letters from baseline (%)
62.2 94.5 94.6 52.9 92.0 90.0
Secondary endpoints (% of subjects)
Letter gain or loss from baseline
Gain ≥15 letters 5.0 24.8* 33.8* 3.8 26.1* 33.3*
Loss ≥30 letters(severe loss)
14.3 0.8* 1.2* 22.7 3.4* 2.5*
Visual acuity
VA ≥20/40 (baseline)
10.9 (15.1)
38.7* (11.3)
40.0* (15.0)
5.9 (15.1)
34.5* (11.3)
42.1* (15.0)
VA ≤20/200 (baseline)
42.9 (13.4)
12.2* (14.7)
11.7* (12.9)
47.9 (13.4)
14.7* (14.7)
15.0* (12.9)
VA=visual acuity.*P <.001 vs. sham.SOURCE: ROSENFELD 2006
FIGURE 1 Number of letters gained or lost, MARINAMean change from baseline at month 24 (secondary endpoint)
SOURCE: ROSENFELD 2006
Baseline
(Day 7)
6 12 18 24
–15
–10
–5
0
5
10
2.6 2.3
0.6
6.55.6
–6.6
7.26.5
–10.4
6.86.1
–13.6
6.65.4
–14.9
Month
Ranibizumab 0.5 mg (n=240) Ranibizumab 0.3 mg (n=238) Sham (n=238)
Month P <.001
Baseline (Day 7)Ranibizumab 0.5 mg
P =.003Ranibizumab 0.3 mg
P =.006
12 SUPPLEMENT
(N=423) were randomized to PDT with sham rani-bizumab injection, sham PDT with ranibizumab 0.3 mg,or sham PDT with ranibizumab 0.5 mg. The arms werewell-matched with respect to demographics and baselineocular characteristics (Table 5).
Subjects who were randomized to the ranibizumab 0.3or 0.5 mg groups received monthly intravitreal injectionsstarting at month 0, while the subjectsrandomized to receive verteporfinPDT received monthly sham injec-tions.All subjects received either activeverteporfin PDT or sham PDT on thefirst visit. On subsequent visits, the ne-cessity for repeat verteporfin versussham PDT was determined based onangiographic evidence of retinal leak-age. Thus, all subjects had the potentialto have PDT or sham PDT every 3months, and all subjects received eitheran actual ranibizumab injection or asham injection monthly.
Consistent with the results achievedin the previously mentioned trials ofPDT, 64 percent of the PDT group inANCHOR met the primary endpoint,compared with 94 and 96 percent ofthe ranibizumab 0.3 and 0.5 mggroups, respectively (Table 6). Atmonth 12, a gain of 8.5 and 11.3 letterswas observed in the ranibizumab 0.3and 0.5 mg groups, respectively, which
equals differences of 18 and 21 letters,respectively, compared with PDT (Fig-ure 2).
A gain of ≥15 letters was observed in36 and 40 percent in the ranibizumab-treated subjects, as opposed to only in5.6 percent in the PDT arm. Whilenone of the ranibizumab-treated pa-tients experienced severe loss in visualacuity (losing ≥30 letters from baselineto month 12), 13 percent of the PDTgroup experienced such a loss. In ad-dition, marked differences in visualacuity (20/40 or better and 20/200 orworse) were observed at month 12 be-tween the ranibizumab groups andPDT-treated patients (Table 6).
Safety analysis of ranibizumabIn analyzing the combined safety
data from MARINA and ANCHOR,ocular and systemic serious adverseevents that have been observed in pre-vious anti-VEGF studies were consid-
ered. The ocular events include endophthalmitis, uveitis,retinal detachment, retinal tear, vitreous hemorrhage,and lens damage.
Generally, ocular adverse events were minimal (Table7). Rates of endophthalmitis were low, with no positivecultures in MARINA and one in ANCHOR. The inci-dence of inflammatory, non-infectious uveitis amounted
TABLE 5 Demographics and baseline characteristics
of subjects in ANCHOR
PDT (n=143)
Ranibizumab
0.3 mg
(n=140)
Ranibizumab
0.5 mg
(n=140)
Gender (% female) 55.2 47.9 46.4
Race (% white) 97.9 97.9 97.1
Age (mean years) 77.7 77.4 76.0
Mean VA (ETDRS letter score) 45.5 47.0 47.1
CNV classification (% of subjects)
Occult 0 0.7 0
Minimally classic 1.4 3.6 3.6
Predominantly classic 98.6 95.7 96.4
Mean lesion size (number of DAs)
1.88 1.89 1.79
CNV=choroidal neovascularization, DA=optic-disk area (equal to 2.54 mm2), ETDRS=Early Treatmentof Diabetic Retinopathy Study, VA=visual acuity.SOURCE: BROWN 2006
TABLE 6 Selected endpoints in ANCHOR at month 12
Verteporfin
PDT
(n=143)
Ranibizumab
0.3 mg
(n=140)
Ranibizumab
0.5 mg
(n=140)
Primary endpoint (% of subjects)
Losing <15 letters from baseline
64.3 94.3* 96.4*
Secondary endpoints (% of subjects)
Letter gain or loss from baseline
Gain ≥15 letters 5.6 35.7* 40.3*
Loss ≥30 letters (severe loss) 13.3 0* 0*
Visual acuity
VA ≥20/40 (baseline) 2.8 (0) 31.4* (1.4) 38.6* (4.3)
VA ≤20/200 (baseline) 60.1 (32.2) 22.1* (25.0) 16.4* (23.0)
PDT=photodynamic therapy, ETDRS=Early Treatment of Diabetic Retinopathy Study, VA=visual acuity.*P <.001 vs. PDT.SOURCE: BROWN 2006
TREATMENT OF MACULAR DEGENERATION 13
TABLE 7 Combined safety data for 2 years of MARINA and 1 of ANCHOR: key ocular serious AEs
MARINA
24 months
ANCHOR
12 months
Sham
(n=236)
Ranibizumab
0.3 mg
(n=238)
Ranibizumab
0.5 mg
(n=239)
PDT
(n=143)
Ranibizumab
0.3 mg
(n=137)
Ranibizumab
0.5 mg
(n=140)
Number of events
Presumed endophthalmitis
Culture positive 0 0 0 0 0 1
Culture negative 0 1 3* 0 0 0
Culture not done 0 1 0 0 0 1†
Uveitis 0 3 3‡ 0 0 1†
Rhegmatogenous retinal detachment
1 0 0 1‡ 1 0
Retinal tear 0 1 1 0 0 0
Vitreous hemorrhage 2 1 1 0 1 0
Lens damage 0 0 1 0 0 0
AE=adverse event.*One case reported as uveitis by investigator.†Same subject had 2 episodes each reported as uveitis, received systemic antibiotics once.‡Same subject had 2 episodes.
SOURCES: BROWN 2006, ROSENFELD 2006
FIGURE 2 Number of letters gained or lost, ANCHOR
Mean change from baseline at month 12 (secondary endpoint)
Baseline
(Day 7)Month
3 6 9 12
–10
–5
0
5
10
15
4.6
2.93.9
10
6.8
–2.5
10.6
7.9
–5.6
11.4
8.1
–7.1
11.3
8.5
–9.5
Ranibizumab 0.5 mg (n=139) Ranibizumab 0.3 mg (n=140) PDT (n=143)
PDT=verteporfin photodynamic therapy.SOURCE: BROWN 2006
10.0
Month P <.001
14 SUPPLEMENT
to six in MARINA and one in ANCHOR. Only one caseof retinal detachment occurred in MARINA, in the shamgroup, and two in ANCHOR, including one in the shamgroup. Incidences of retinal tearing and vitreous hemor-rhage were low. Only one patient from MARINA expe-rienced lens damage.
While some systemic adverse events might be expectedto arise from anti-VEGF therapy, the apparent systemicsafety risks are minimal. The incidence of hypertensionwas similar across populations in each study, with verylittle change in blood pressure (Table 8). Key arterialthromboembolic events occurred in similar rates acrossall groups in both studies. Greater immunoreactivity toranibizumab was found in MARINA, but patients withmore immunoreactivity did not differ from those withless immunoreactivity in terms of outcomes. Immuno-reactivity to antigen-binding fragment is found in healthypatients. Slightly more nonocular hemorrhages occurredin the ranibizumab groups (21–22 percent in theranibizumab groups versus 13 percent in the shamgroup) in the second year of MARINA, but the study wasnot powered to determine if this was due to chance orranibizumab.
Because of the relatively small number of patients en-rolled in MARINA and ANCHOR, a larger study(N=5,000) began enrolling patients in November 2005in a phase 3b study to assess further the safety and tol- 3 Safety Assessment of Intravitreal Lucentis fOR AMD.
erability of ranibizumab. This study is known asSAILOR.3 Patients with all subtypes of new or recurrentactive subfoveal neovascular AMD are being enrolled inthis 1-year study to evaluate the safety of ranibizumab 0.3mg and 0.5 mg administered once monthly for 3 monthsand thereafter on an as-needed basis.
ConclusionThe FDA granted a biologics license application for
ranibizumab on June 30, 2006. Approval of ranibizumabmeans that, for the first time, patients with neovascularAMD can be treated with a biologic therapy that hasdemonstrated the ability to maintain vision in 95 percentof patients, regardless of lesion subtype, and to improvevisual acuity in a substantial number of patients.
References
Arnold J, Algan M, Soubrane G, et al. Indirect scatter laserphotocoagulation to subfoveal choroidal neovasculariza-tion in age-related macular degeneration. Graefes Arch ClinExp Ophthalmol. 1997;235:208–216.
Bressler NM, Maguire MG, Murphy PL, et al. Macular scatter(‘grid’) laser treatment of poorly demarcated subfovealchoroidal neovascularization in age-related macular degen-eration. Results of a randomized pilot trial. Arch Ophthal-mol. 1996;114:1456–1464.
TABLE 8 Combined safety data for 2 years of MARINA and 1 year of ANCHOR: key systemic AEs
MARINA
24 months
ANCHOR
12 months
Sham
(n=236)
Ranibizumab
0.3 mg
(n=238)
Ranibizumab
0.5 mg
(n=239) PDT (n=143)
Ranibizumab
0.3 mg
(n=140)
Ranibizumab
0.5 mg
(n=140)
Number of events (% of group)
Hypertension 38 (16.1) 41 (17.2) 39 (16.3) 12 (8.4) 3 (2.2) 9 (6.4)
Mean change in BP (mm Hg)
–3.3/–3.5 –2.6/–2.5 –4.4/–1.1 0.1/0.3 –2.0/–2.0 –2.0/1.0
Key arterial thromboembolic events
Myocardial infarction 4 (1.7) 6* (2.5) 3 (1.3) 1 (0.7) 1 (0.7) 3 (2.1)
Cerebrovascular accident
2 (0.8) 3 (1.3) 6 (2.5) 1 (0.7) 1 (0.7) 1 (0.7)
Death
Vascular (APTC criteria) 4 (1.7) 3 (1.3) 3 (1.3) 1 (0.7) 1 (0.7) 2 (1.4)
Nonvascular 2 (0.8) 2 (0.8) 3 (1.3) 1 (0.7) 2 (1.5) 0 (0.0)
AE=adverse event, APTC=Antiplatelet Trialists’ Collaboration, BP=blood pressure.*Same subject had 2 episodes.SOURCES: BROWN 2006, ROSENFELD 2006
TREATMENT OF MACULAR DEGENERATION 15
Brown DM, Kaiser PK, Michaels M, et al, for the ANCHORStudy Group. Ranibizumab versus verteporfin for neo-vascular age-related macular degeneration. N Engl J Med.2006:355:1432–1444.
Cardillo Piccolino F, Ghiglione D, Allegri P. Grid laser treatmentof occult choroidal neovascularization in age related macu-lar degeneration. Int Ophthalmol. 1993;17:77–83.
Ferris FL 3rd, Kassoff A, Bresnick GH, Bailey I. New visual acuitycharts for clinical research. Am J Ophthalmol. 1982;94:91–96.
Freund KB, Yannuzzi LA, Sorenson JA. Age-related macular de-generation and choroidal neovascularization. Am J Oph-thalmol. 1993;115:786–791.
Gillies MC, Simpson JM, Billson FA, et al. Safety of an intra-vitreal injection of triamcinolone: results from a random-ized clinical trial. Arch Ophthalmol. 2004;122:336–340.
Gragoudas ES, Adamis AP, Cunningham ET Jr, et al.; VEGF Inhi-bition Study in Ocular Neovascularization Clinical TrialGroup. Pegaptanib for neovascular age-related macular de-generation. N Engl J Med. 2004;351:2805–2816.
MPS (Macular Photocoagulation Study) Group. Subfoveal neo-vascular lesions in age-related macular degeneration.
Guidelines for evaluation and treatment in the macularphotocoagulation study. Group. Arch Ophthalmol.1991;109:1242–1257.
MPS. Persistent and recurrent neovascularization after laserphotocoagulation for subfoveal choroidal neovasculariza-tion of age-related macular degeneration. Arch Ophthalmol.1994;112:489–499.
Pegaptanib (Macugen) prescribing information. New York: Eye-tech Pharmaceuticals/Pfizer. March 2006.
Pegaptanib Sodium Injection in the Treatment of Neovascular Age-Related Macular Degeneration: Briefing Document for theDermatologic and Ophthalmic Drugs Advisory Committee.New York/New London, Conn.: Eyetech Pharmaceuticals/Pfizer Global Research and Development. August 2004.Available online: «http://www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4053B1_01_Eyetech-Briefing-Doc.pdf».Accessed Sept. 25, 2006.
Rosenfeld PJ, Brown DM, Heier JS, et al, for the MARINA StudyGroup. Ranibizumab for neovascular age-related maculardegeneration. N Engl J Med. 2006;355:1419–1431.
Verteporfin (Visudyne) prescribing information. East Hanover,N.J.: Novartis Pharmaceuticals Corp. Oct. 2005.
PANEL DISCUSSION
16 SUPPLEMENT
LEE TERMINI: What are your initial impressions of whatDr. Dugel presented today?
SHERMAN PODOLSKY, MD: Dr. Dugel, when patientscome to you, what are their two or three most impor-tant concerns with respect to their daily lives?
PRAVIN U. DUGEL, MD: Their most important concern,bar none, is their ability to live independently. As soonas patients hear “macular degeneration,” they thinkthey are going to go blind. The first thing I tell themis that they will never go blind — they will be able tolive independently. The next thing that concerns themis driving, which is related to their independence.Afterthat is paying bills. That is the order of business: blind-ness, driving, paying bills.
ALBERT J. RIZZOLI, MD: What do you actually tell the pa-tient?
DUGEL: You can’t set expectations that are too high. Iwould tell them we have a drug that I think works bet-ter than anything we have had before. I would tell themthat the chances of being able to maintain their visionare excellent, perhaps as high as 90 percent. There is alsoa chance that they might gain some vision.
GARY L. JOHNSON, MD, MBA: Could you explain thephysiology of how vision improves after treatment?
DUGEL: It is believed to be similar to what happens whenyou have a cut in your skin: first you get bright redblood, and then a clot, eventually followed by a scar.Around that scar, the skin is stretched because thescar contracts. The same thing happens under theretina, and it happens fairly quickly. When it con-tracts, photoreceptors are sheared away; they die andnever come back. Clearly, as soon as there is blood,some photoreceptor cells will never regain function.But there is less and less damage as you go out. It ap-
Ranibizumab Therapy In the Managed Care Market
PANELISTS
Pravin U. Dugel, MD
Ophthalmologist, Retinal Consultants of ArizonaPhoenix, Ariz.
Gary L. Johnson, MD, MBA
Director of Care Management, Group Health CooperativeMadison, Wisc.
Robert LoNigro, MD, MS
Medical Director, Tufts Health PlanBoston, Mass.
Glenda S. Owens, RPh, MHA
Vice President, Arcadian Health PlanRedondo Beach, Calif.
Balakrishna R. Pai, MD
Senior Associate Medical Director, Health Alliance PlanDetroit, Mich.
Sherman Podolsky, MD
Chief Medical Officer, Vista HealthplanSunrise, Fla.
Albert J. Rizzoli, MD
Medical Director, Presbyterian Health PlanAlbuquerque, N.M.
Charles A. Stemple, DO, MBA
Regional Medical Director, HumanaLoveland, Ohio
Bret S. Yarczower, MD
Medical Director, Geisinger Health PlanDanville, Pa.
After Pravin Dugel, MD’s presentations onmacular degeneration and its treatment,medical and pharmacy decision makers fromthird-party payers discussed the implicationsof the data he presented. Lee Termini, of MediMedia USA, moderated the discussion,which focused largely on how payers wouldapproach ranibizumab (Lucentis).
SUMMARY
TREATMENT OF MACULAR DEGENERATION 17
We can do an optical coherence tomography, orOCT, which essentially shows a cross-section of thelayers of the retina. It’s a simple test with no side ef-fects; no dye is involved. It’s a fairly accurate measureof the thickness and fluid consistency of the retina. Ifthe clot has already set and produced a scar, the dam-age is done. It would not be a good idea to have thispatient go through a series of injections. On the otherhand, if OCT shows thickening because of fluid, youcan tell the patient that if we can get rid of that fluid,perhaps some cells will be recovered.
CHARLES A. STEMPLE, DO, MBA: Will vessels hyper-proliferate if you stop treatment?
DUGEL: The crux of your question is, “When doyou stop?” I don’t know. I would treat for a yearand then use OCT to guide me from that point on.If OCT showed fluid, I would continue treating. Ifthe fluid were gone, I might watch it a little moreclosely, and if the fluid recurred I would treat. Wewill adjust our protocol according to the differ-ences among patients [Editor’s note: See “Howmuch is enough?” at left].YARCZOWER: The measure we’re seeing in thesetrials seems like kind of a crude measure of im-provement — letters that you can or can’t see. Iwould like a better perspective of what a loss of 15or 30 letters means in terms of vision.GLENDA S. OWENS, RPh, MHA: Yes. I was fasci-nated by the research, but this is new lingo for us— the letters and lines. I still don’t know how I canexplain to somebody from a managed care per-spective what kind of outcome this really is. Itwould be more intuitive to say,“Now these patientscan drive when, before treatment, they couldn’t,”or “They have improved their vision from 20/125to 20/40” [Editor’s note: see “Translating lines toquality of life,” page 18].ROBERT LoNIGRO, MD, MS: This is a revolutionin the treatment of macular degeneration. Thingswill not be the same from now on. I suspect that,as with other biologics, this will be a fairly expen-sive intervention; pegaptanib (Macugen) is alreadyon the market, but the potential population forranibizumab is much larger.
Potential other uses for this agent or agents likeit make me very concerned that the financial flood-gate is opening. I have yet to understand what thereal benefit is, in terms of vision improvement, andthat is what will persuade my health plan to invest.How do we figure out whether we are going tocover it for everybody or whether we are going torequire prior authorization for it? I don’t know.TERMINI: If you start out by saying ranibizumabis revolutionary, how could you not make it avail-able?
pears that photoreceptors that are slightly peripheralcan be rescued to a certain extent, and that is the basisfor visual-acuity improvement.
BRET S. YARCZOWER, MD: Does the velocity of macu-lar degeneration, the change over time, play any rolein the choice of therapy?
DUGEL: The sooner we detect it, the more vision we cansave. But you’re touching on the issue of use: Wheredo you draw the line? If you see a patient whose arti-ficial vision is 20/200, do you tell that patient there isnothing more we can do, or do you tell them we cancontinue injecting you for 6 months or a year, andthere is a chance we might improve your vision?
How much is enough?
Shortly after the U.S. Food and Drug Administration ap-proved ranibizumab (Lucentis), questions arose as to howoften patients who are considered appropriate for the
therapy should receive it. Although patients could receive up to12 injections over the course of a year, the manufacturer,Genentech, has estimated that “The average patient will betreated approximately 5 to 7 times per year” (MCW 2006).
During the panel discussion last March captured within thissection, Pravin Dugel, MD, was asked about frequency of useand whether ranibizumab would be administered by retinalspecialists or ophthalmologists.
“In the short-term, only retinal specialists [would administerthe treatment],” Dugel replied. “In the long-term, I don’t know.If I were in [the managed care medical or pharmacy director’s]situation, I would make every attempt to make sure ranibizu-mab is used only by retinal specialists, because they will use thismedication appropriately. I think you will find less abuse there.”
Dugel recommended that payers identify specialists theytrust to guide them on appropriate use of ranibizumab.
“I think the way to do this is to distinguish providers in yourcommunity with a track record, whom you know are involved inclinical trials like these and are able to do more than just gleaninformation from the Internet,” he told the panel. “Anything canbe abused, but if a request comes to you for a person to getranibizumab after 6 months, then you might say, ‘Well, what didthe OCT [optimal coherence tomography] show?’ Then youwould know [whether the request is appropriate] after speak-ing with someone you trust.”
Several managed care medical and pharmacy directors whoparticipated in the discussion felt that the denial rate forranibizumab would be extraordinarily low, in light of the manu-facturer’s strategy of building a sales force for retinal specialistsonly. “You have to look at it in terms of what the cost per reviewis,” said one medical director. “The denial rate is going to below, and considering the incidence of the use of this drug willbe low, there are far bigger fish to fry.”
References
MCW (Managed Care Week). Anonymous. Payers have new optionsfor vision-loss drugs, additional costs. 2006 Aug 21;16(32):7.
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RIZZOLI: What we didn’t hear is when to start this. Dr.Dugel, you said everybody starting at age 50 begins todevelop macular degeneration, so there’s your group.Are you going to treat all of those patients?
DUGEL: No. Only a minority of that group — 10 percentof people who have macular degeneration — havewet, or exudative, macular degeneration. Of those pa-tients, the majority already have subfoveal neo-vascularization when they come to see me, and that’sthe group that I would treat.
PODOLSKY: Realistically, how many patients would be
LoNIGRO: It’s an interesting conundrum. Rani-bizumab sounds like it is better than currenttreatment, so we probably will pay for it. At thesame time, we have a lot of data in front of us,and I’m still trying to internalize it to figure outwhat we’re really going to be paying for. Thismay be the best treatment we have for this dis-order, but what is the marginal benefit versus themarginal cost? We’re facing the people who arepaying for health care, there are 800 differentbiologic agents coming to the market, and all ofa sudden the cost of health care is doubling.That is part of the picture.
STEMPLE: If ranibizumab is priced premium topegaptanib and verteporfin (Visudyne), thequestion is whether there is a population sub-set that should use verteporfin or pegaptanibfirst in step therapy. So, first off, you have toshow across the entire patient population thatranibizumab is clearly superior — that there isno subset that health plans could designate forverteporfin or pegaptanib first — because that’swhat health plans are going to look for.
The products on the marketplace today havedefined populations for which they may be ef-fective, but even if you take those subsets,ranibizumab is clearly superior for all patientsand all disease states. There isn’t any subset forwhich ranibizumab would not be a preferredagent. From what we have seen today, rani-bizumab totally displaces the other two agents.There is no reason to keep the other two in anypreferred positioning.
[Editor’s note: At this point, several participantsdiscussed the importance of the manufacturer’s ef-fort to identify populations for which ranibizumabis appropriate. Some likened it to a similar effortwith omalizumab [Xolair]. “Genentech was suc-cessful because it established specific criteria for theuse of omalizumab,” said one medical director. “Itdidn’t break the bank. For the most part, I’vestopped reviewing omalizumab because it is notworth reviewing anymore. I have not seen any-body use it inappropriately.”]
RIZZOLI: One thing I can see happening is that plansmight shut it off at 24 months until studies show usthere is a benefit beyond that time.
PODOLSKY: I would like a synopsis of the literature andthe experience showing how patients should be moni-tored — what should be done, at what stage. I’ve hearddifferent things: I’ve heard it should be given for a yearand then OCT should be used and I’ve heard that weshould look for patient response and use OCT.
Translating lines to quality of life
To get a better idea of what changes in visual acuity (VA)mean for patients in their daily lives, investigators rely onpatient-reported outcomes.
A primary source for this information is the National Eye Insti-tute Visual Function Questionnaire (NEI VFQ-25), a survey thatasks patients about their quality of life as it is affected by theireveryday vision. Patients are asked about their ability to readthe newspaper, cook, sew, fix things around the house, usehand tools, and find objects on a crowded shelf. They are alsoasked questions about their ability to read street signs, negoti-ate stairs and curbs in dim light, and watch movies. The surveygives investigators a clearer picture of patients’ dependence onothers, social function, and mental health.
A 10 percent decrease in the NEI VFQ-25 is the equivalent of aloss of three lines (15 letters) on the Early Treatment of DiabeticRetinopathy Study (ETDRS) chart (Miskala 2004, Lindblad 2005).In patients with age-related macular degeneration (AMD), achange of ≥10 percent is clinically significant and marks theprogression from intermediate to advanced AMD. In late 2005,a Medicare advisory board agreed that a change of 5 to 10 per-cent represents a significant change.
Rosenfeld (2006) gives a real-world perspective on the gainsin lines presented previously in this supplement by Dugel. Asignificant number of patients who entered the ranibizumabtrials unable to qualify for a driver’s license finished their treat-ment with 20/40 vision — the threshold for achieving a driver’slicense in most states. Formal quality-of-life studies among pa-tients who enrolled in the trials are under way.
References
Dugel PU. Treatments for age-related macular degeneration.Manag Care. 2006;15(10 suppl 7):7–15.
Lindblad AS, Clemons TE. Responsiveness of the National Eye Insti-tute Visual Function Questionnaire to progression to advancedage-related macular degeneration, vision loss, and lens opac-ity: AREDS Report no. 14. Arch Ophthalmol. 2005;123:1207–1214.
Miskala PH, Bressler NM, Meinert CL. Relative contributions of re-duced vision and general health to NEI-VFQ scores in patientswith neovascular age-related macular degeneration. Arch Oph-thalmol. 2004;122:758–766.
Rosenfeld PJ, Brown DM, Heier JS, et al, for the MARINA StudyGroup. Ranibizumab for neovascular age-related macular de-generation. N Engl J Med. 2006;355:1419–1431.
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TERMINI: Anyone else?BALAKRISHNA R. PAI, MD: The complication and side-
effect profiles are very impressive. I feel very comfort-able using this medication.
JOHNSON: It sounds like a revolutionary, efficaciousproduct that may supplant other forms of therapy, butthe key is patient selection. What are the alternatives,how long do you monitor patients, and how long doyou keep them on therapy?
DUGEL: It is my firm belief that once this goes on themarket, every other therapy I’ve talked about today isgoing to be of historic significance only. This is far su-perior to everything across the board. There is nocomparison.
So, all the money that is spent now on PDT, onpegaptanib, and on thermal laser photocoagulationare going to go out the door, except for the 5 percentor so of patients who may show up with an ex-trafoveal, well-defined neovascular membrane. Thosepeople will still need thermal laser photocoagulation.
treated? Many plans do preauthorization, but if thetherapy in question is an accepted therapy, then pre-authorization is a waste of time and money. I wonderif the number of people who will be treated is such thatthe dollar average would be too low to even comeclose to the radar screen.
[Editor’s note: Here, a Genentech representative presentedan estimate that about 1.3 people per 1,000 in theMedicare population would be appropriate candidatesfor ranibizumab.]
PODOLSKY [to LoNigro]: Bob, you have 10,000 Medicarepatients in your membership?
LoNIGRO: Right.PODOLSKY: Out of 710,000 people. So for him, it’s
going to end up being 10 people who need this. Mypoint is, in a major plan, 10 people will get it [a few]times a year for 1 year, maybe 2. In terms of preau-thorization, that’s a lot of work — and for what? If theretinal specialists want to do it, they should just goahead and do it.
MANAGED CARE CONSIDERATIONS
Points To Ponder
On the basis of the clinical trial data presented in this supplement, the arrival ofranibizumab (Lucentis) promises to change the way MCOs think about treatmentfor their members with neovascular age-related macular degeneration (AMD).Data from the pivotal phase 3 MARINA and ANCHOR trials show that ranibizumab
is more efficacious than sham or photodynamic therapy (PDT) with verteporfin (Visudyne)in maintaining visual acuity. In upwards of 90 percent of patients, ranibizumab has been shownto maintain visual acuity, and in a substantial proportion, to even improve visual acuity.
The benefits of ranibizumab have been observed in patients with each of the three subtypesof choroidal neovascular lesion (occult, minimally classic, and predominantly classic). Addi-tionally, in MARINA, ranibizumab was more efficacious than sham in improving patients’vision-related quality of life.
Discussions by the managed care medical and pharmacy directors who attended this advi-sory board meeting suggested that ranibizumab raises numerous important questions forMCOs, such as:
Patient population. What criteria make patients eligible or ineligible for therapy?Age. Can a patient be too old for ranibizumab therapy?Comorbidities. Do certain comorbidities preclude ranibizumab therapy? Or would
ranibizumab therapy be especially desirable in the context of some comorbidities as ameans of preserving some quality of life even as the patient’s overall health declines?
Length of therapy. How long should ranibizumab treatment be used? One year? Two years?Indefinitely? How to know when to stop therapy? How to know when to resume ther-apy, assuming there is a benefit from resumption of therapy?
Monitoring therapy. By what means, and how often, should response to ranibizumab ther-apy be monitored? What is the best outcome for assessing response to therapy? Changein visual acuity? Change in quality of life? Some combination of both?
Safety of therapy. Clinical trial data are reassuring but ultimately inconclusive because of thesmall numbers of subjects. What will postmarketing data show?
Prior authorization. Should prior authorization be required for ranibizumab? If so, what arethe criteria for approving or denying the treatment?
Step therapy. Is step therapy ever appropriate for treatment of age-related macular degenera-tion? If so, how should ranibizumab be used? As the first step? Last step?
Preferred therapy. Are the benefits of ranibizumab such that it should be regarded as the pre-ferred therapy for neovascular AMD?
Current products. What does the availability of ranibizumab mean for the use of other treat-ments for neovascular AMD? How should ranibizumab be used with respect to pegap-tanib and verteporfin?
Formulary placement. In a tiered formulary, where should ranibizumab be placed? Whatkind of copayment should be required for ranibizumab? A fixed amount or a percent-age?
Cost-effectiveness. Is ranibizumab cost-effective? If so, by what measures?Cost savings. Does ranibizumab therapy result in cost savings for a health plan, such as by
reducing treatment for AMD-related depression or hospitalization for fractures owingto vision-related falls, or are the benefits of ranibizumab therapy expressed primarilyin terms of maintained or improved quality of life?
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