Lucentis and Avastin for Wet AMD Lucentis and Avastin for Wet AMD and Retina Vascular Diseaseand Retina Vascular Disease
Henry L Hudson M.D. F.A.C.S.Henry L Hudson M.D. F.A.C.S.Retina Centers P.C.Retina Centers P.C.
Tucson AZTucson AZ
Financial DisclosureFinancial Disclosure
Henry L Hudson MD, FACS serves as a paid Henry L Hudson MD, FACS serves as a paid lecturer/consultant for:lecturer/consultant for:
Genentech, Novartis, Bausch and Lomb, QLTGenentech, Novartis, Bausch and Lomb, QLT
Retina Centers PC and Dr. Hudson receive Retina Centers PC and Dr. Hudson receive research funding fromresearch funding from
Genentech, Novartis, QLT, Opthotech, Opko, GSK, Genentech, Novartis, QLT, Opthotech, Opko, GSK, VisionCare, EpiRad, Regeneron and many othersVisionCare, EpiRad, Regeneron and many others
No financial interest in todayNo financial interest in today’’s presentation s presentation however!!however!!
Prevalence of Advanced* AMD in Prevalence of Advanced* AMD in the United Statesthe United States
*Defined as neovascular AMD and/or geographic atrophy in at least one eye.Prevalence figures were calculated using 2000 US census data.Friedman et al. Arch Ophthalmol. 2004;122:564.
0
200
400
600
800
1000
1200
60-64 65-69 70-75 75-79 ≥80
Num
ber o
f cas
es (t
hous
ands
)
Men
Women
Overall
Age (years)
Projected Prevalence of Projected Prevalence of Advanced* AMD in the United Advanced* AMD in the United
StatesStatesN
umbe
r of c
ases
(mill
ions
)
Year*Defined as neovascular AMD and/or geographic atrophy in at least one eye. Prevalence figures were calculated using 2000 US census data.Friedman et al. Arch Ophthalmol. 2004;122:564.
0
1
2
3
2000 2020
1.75
2.95
Neovascular AMD: Risk FactorsNeovascular AMD: Risk Factors
Emerging risk factorsEmerging risk factorsAgeAge11
RaceRace11
SmokingSmoking22
Family historyFamily history33
Variation in the Variation in the complement factor H complement factor H genegene44--66 and other and other genesgenes77
1. Friedman et al. Arch Ophthalmol. 2004;122:564; 2. Kahn et al. Br J Ophthalmol. 2006;90:75; 3. Buch et al. Acta Ophthalmol Scand. 2005;83:409; 4. Klein et al. Science. 2005;308:385; 5. Haines et al. Science.2005;208:419; 6. Sepp et al. Invest Ophthalmol Vis Sci. 2006;47:536; 7. Haines et al. Invest Ophthalmol Vis Sci. 2006;47:329.
Neovascular AMD: EtiologyNeovascular AMD: Etiology
Possible initiating eventsPossible initiating eventsHypoxiaHypoxiaNutrient deprivationNutrient deprivationTrauma to BruchTrauma to Bruch’’s membranes membraneInfection, inflammatory responseInfection, inflammatory responseOxidative stress to the retina and retinal Oxidative stress to the retina and retinal pigment epithelium (RPE)pigment epithelium (RPE)
Roth et al. Graefes Arch Clin Exp Ophthalmol. 2004;242:710.
Discovery of VEGFDiscovery of VEGF--A* Spans Over 4 A* Spans Over 4 DecadesDecades
1948: First hypothesized as 1948: First hypothesized as ““Factor XFactor X”” associated associated with specific retinopathies by Michaelsonwith specific retinopathies by Michaelson11
1971: 1971: ““Angiogenic factorAngiogenic factor”” produced in tumors produced in tumors proposed by Folkmanproposed by Folkman22
1983: First described as a 1983: First described as a ““vascular permeability vascular permeability factorfactor”” by Dvorakby Dvorak33
1989: VEGF1989: VEGF--A protein purified, cloned, and named A protein purified, cloned, and named at at GenentechGenentech by Napoleone Ferraraby Napoleone Ferrara4,54,5
*VEGF-A is commonly referred to as VEGF.1. Michaelson. Trans Ophthalmol Soc U K. 1948;68:137; 2. Folkman. N Engl J Med. 1971;285:1182;3. Senger et al. Science. 1983;219:983; 4. Ferrara et al. Biochem Biophys Res Commun. 1989;161:851; 5. Leung et al. Science. 1989; 246:1306.
VEGFVEGF--A Is a Member of a Family of A Is a Member of a Family of Angiogenic Growth FactorsAngiogenic Growth Factors
Other VEGF family Other VEGF family members include: members include:
VEGFVEGF--B, VEGFB, VEGF--C,C,VEGFVEGF--D, VEGFD, VEGF--E,E,and PlGFand PlGF**
Homodimeric Homodimeric glycoproteinglycoprotein
Secreted by a variety Secreted by a variety of cellsof cells
Receptorbinding site
Receptorbinding site
VEGF-A165
*Placental growth factor.Ferrara et al. Nat Med. 2003;9:669.
Angiogenesis Plays Multiple Roles in Vascular Angiogenesis Plays Multiple Roles in Vascular DevelopmentDevelopment
Angiogenesis plays a role in normal development and Angiogenesis plays a role in normal development and maintenance of vasculature maintenance of vasculature
Angiogenesis occurs in a variety of diseases:Angiogenesis occurs in a variety of diseases:Cancer/tumorsCancer/tumorsRheumatoid arthritisRheumatoid arthritisPsoriasis Psoriasis Proliferative retinopathiesProliferative retinopathies
Angiogenesis is the growth of new blood vesselsAngiogenesis is the growth of new blood vessels
Neovascular AMDNeovascular AMD
The Angiogenic Cascade is a The Angiogenic Cascade is a Complex ProcessComplex Process
Endothelial cell activation
Basementmembranedegradation
Endothelial cell proliferation,
migration
Tubeformation
Griffioen and Molema. Pharmacol Rev. 2000;52:237; Das et al. Prog Retin Eye Res. 2003;22:721;Davis and Senger. Circ Res. 2005;97:1093.
Tubeelongation,remodeling
VEGFVEGF--A Is a Key Mediator of Angiogenesis A Is a Key Mediator of Angiogenesis and Vascular Leakageand Vascular Leakage
Receptoractivation
Signaltransduction
Gene expressionGene expression
ANGIOGENESIS VASCULAR LEAKAGE
Nucleus
VEGF-A bindingto VEGFRVEGFR-2
VEGFVEGF--A Promotes Vascular LeakageA Promotes Vascular Leakageand Vessel Growthand Vessel Growth
Injection of VEGFInjection of VEGF--A stimulatesA stimulatesnew vessel growthnew vessel growth
Murohara et al. Circulation. 1998;97:99.
Rabbit CorneaMiles Assay
8 16 32 64 128 Saline
VEGF-A (ng)
Injection of VEGFInjection of VEGF--A stimulatesA stimulatesvascular leakagevascular leakage
VEGFVEGF--A Plays a Key Role in AngiogenesisA Plays a Key Role in Angiogenesis
VEGFVEGF--A is a member of the VEGF familyA is a member of the VEGF familyof growth factorsof growth factors
Multiple biologically active VEGFMultiple biologically active VEGF--A isoforms and A isoforms and cleavage products existcleavage products exist
VEGFVEGF--A is a powerful stimulator of angiogenesis A is a powerful stimulator of angiogenesis
Angiogenesis can lead to the overgrowth of Angiogenesis can lead to the overgrowth of highly permeable blood vessels (eg, CNV)highly permeable blood vessels (eg, CNV)
LUCENTIS LUCENTIS and Avastinand Avastin®®
Developed for Distinct DiseasesDeveloped for Distinct DiseasesLUCENTIS
(ranibizumab)48 kDa
Affinitymaturation
(140×)
Humanization
Humanization
(rhu Fab v1)
Presta. Cancer Res. 1997;57:4593; Chen. J Mol Biol. 1999;293:865; Baca. Proc Natl Acad Sci USA. 1997;94:10063; Muller. Structure. 1998;6:1153.
MouseAnti-VEGF-A mAb
(~150 kDa)
(Fab-12)
Constructionof full length
antibodyAvastin
(bevacizumab)149 kDa
LUCENTIS: Pivotal Trials LUCENTIS: Pivotal Trials Exploring Efficacy and Exploring Efficacy and
Safety in Neovascular AMDSafety in Neovascular AMD
A Phase III Study of LUCENTIS A Phase III Study of LUCENTIS (ranibizumab injection) in (ranibizumab injection) in
Subfoveal Neovascular AMDSubfoveal Neovascular AMD—— 22--Year Results Year Results ——
01020304050
60708090
100
<15<15--Letter Loss From BaselineLetter Loss From Baselineat Month 12 and 24at Month 12 and 24
*P<0.0001 vs sham.94.6%*
% o
f sub
ject
s
62.2%
90.0%*
52.9%
Month 12 Month 24
Sham(n=238)
LUCENTIS0.5 mg (n=240)
Sham(n=238)
LUCENTIS0.5 mg (n=240)
Mean Change in Visual Acuity Over Mean Change in Visual Acuity Over Time Through Month 24Time Through Month 24
Sham (n=238)
Month
ETD
RS
lette
rs
-14.9
-10.4
2 4 6 8 10 12 14 16 18 20 22 24
-15
-10
-5
0
5
10
Mean Change in Visual Acuity Over Mean Change in Visual Acuity Over Time Through Month 24Time Through Month 24
21.4-letter differenceP<0.0001
Month
ETD
RS
lette
rs
-14.9
+6.6+7.2
-10.4
2 4 6 8 10 12 14 16 18 20 22 24
-15
-10
-5
0
5
10
Sham (n=238) LUCENTIS 0.5 mg (n=240)
0102030405060708090
100
≥≥1515--Letter Gain From BaselineLetter Gain From Baselineat Month 12 and 24at Month 12 and 24
33.8%*
% o
f sub
ject
s
*P<0.0001 vs sham.
4.6% 3.8%
33.3%*
Month 12 Month 24
Sham (n=238)LUCENTIS 0.5 mg (n=240)
Phase III Study of LUCENTIS Phase III Study of LUCENTIS (ranibizumab injection) vs (ranibizumab injection) vs
VisudyneVisudyne®® (verteporfin) PDT in (verteporfin) PDT in Predominantly Classic Subfoveal Predominantly Classic Subfoveal
Neovascular AMDNeovascular AMD—— Year 1 Results Year 1 Results ——
0102030405060708090
100
*P<0.0001 vs PDT.
PDT(n=143)
LUCENTIS 0.5 mg(n=139)
96.4%*
% o
f sub
ject
s
64.3%
<<1515--Letter Loss From BaselineLetter Loss From Baselineat Month 12at Month 12
Note: Vertical bars are ± 1 standard error of the mean.
Mean Change in Visual Acuity Over Mean Change in Visual Acuity Over Time Through Month 12Time Through Month 12
ETD
RS
lette
rs
Month-15
-10
-5
0
5
10
15
1 2 3 4 5 6 7 8 9 10 11 12
–9.5
PDT (n=143)
P<0.0001
+11.3
–9.5
20.8-letterdifference
PDT (n=143) LUCENTIS 0.5 mg (n=139)
ETD
RS
lette
rs
Month-15
-10
-5
0
5
10
15
1 2 3 4 5 6 7 8 9 10 11 12
Mean Change in Visual Acuity Over Mean Change in Visual Acuity Over Time Through Month 12Time Through Month 12
Note: Vertical bars are ± 1 standard error of the mean.
0102030405060708090
100
≥≥1515--Letter Gain From Baseline Letter Gain From Baseline at Month 12at Month 12
40.3%*
% o
f sub
ject
s
*P<0.0001 vs PDT.
5.6%
PDT(n=143)
LUCENTIS 0.5 mg(n=139)
Conclusions*Conclusions*LUCENTIS maintains or improves VA in all lesion typesLUCENTIS maintains or improves VA in all lesion types
≥≥90% lost <15 letters in MARINA and ANCHOR90% lost <15 letters in MARINA and ANCHOR34% (MARINA) to 40% (ANCHOR) improved 34% (MARINA) to 40% (ANCHOR) improved ≥≥1515--lettersletters6.6 (MARINA) to 11.36.6 (MARINA) to 11.3--letter (ANCHOR) mean improvement in VAletter (ANCHOR) mean improvement in VA
All anatomic outcomes favored LUCENTIS vs controlsAll anatomic outcomes favored LUCENTIS vs controls
Ocular serious adverse events occurred in <0.1% of intravitreal Ocular serious adverse events occurred in <0.1% of intravitreal injectionsinjections
No imbalance in nonocular adverse events overallNo imbalance in nonocular adverse events overall
*Data from MARINA through month 24 and from ANCHOR through month 12.
AvastinAvastin
Similar to Lucentis ,as it is potent VeGF inhibitorSimilar to Lucentis ,as it is potent VeGF inhibitorWhole antibody not a Fab, therefore longer half life in the eye Whole antibody not a Fab, therefore longer half life in the eye and and serum, penetrates the retina, but not as well as Lucentis (Averyserum, penetrates the retina, but not as well as Lucentis (Avery))First used intravitreally by Phil Rosenfeld MD from BPEIFirst used intravitreally by Phil Rosenfeld MD from BPEINot commercially available from the company for intraocular use,Not commercially available from the company for intraocular use,compounded at local pharmaciescompounded at local pharmaciesNot FDA approved for AMD indicationNot FDA approved for AMD indicationMultiple case series, without controls demonstrate efficacy of Multiple case series, without controls demonstrate efficacy of intravitreal Avastin in wet AMDintravitreal Avastin in wet AMDCATT (NEI) trial enrolling to compare Lucentis and Avastin head CATT (NEI) trial enrolling to compare Lucentis and Avastin head to to headhead
Avastin Case Series in AMDAvastin Case Series in AMD
AveryAvery-- Ophthalmology Mar 2006Ophthalmology Mar 200679 patients, mean Va gain from 20/200 to 20/8079 patients, mean Va gain from 20/200 to 20/80
Spaide et al Spaide et al –– Retina Apr 2006Retina Apr 2006266 eyes, Va improved from 20/184 to 20/102 average Oct 266 eyes, Va improved from 20/184 to 20/102 average Oct decreased 93 microns from 340 to 247decreased 93 microns from 340 to 247
BashshurBashshur-- (Lebanon) AJO Jul 2006 17 eyes(Lebanon) AJO Jul 2006 17 eyesVa increased from 20/250 to 20/76Va increased from 20/250 to 20/76
Costa (Brazil) IOVS Oct 2006 45 eyesCosta (Brazil) IOVS Oct 2006 45 eyesVa increased from baseline by 1 lineVa increased from baseline by 1 line
20 + other case series20 + other case series
CATT TrialCATT Trial
1200 Patients desired1200 Patients desired4 arms4 arms
1) Lucentis every 4 weeks for one year1) Lucentis every 4 weeks for one year2)Avastin every 4 weeks for one year2)Avastin every 4 weeks for one year3)Lucentis monthly prn3)Lucentis monthly prn4)Avastin monthly prn4)Avastin monthly prn
57 Centers in US57 Centers in USTarget completion by Feb 2010Target completion by Feb 2010
Anti VegF Therapy in Diabetic RetinopathyAnti VegF Therapy in Diabetic Retinopathy
Lucentis in DME ( Diabetic Macular Edema)Lucentis in DME ( Diabetic Macular Edema)READ1 ( phase 1 safety and efficacy study) led toREAD1 ( phase 1 safety and efficacy study) led toREAD2 (126 patients fully recruited, comparing READ2 (126 patients fully recruited, comparing Lucentis to focal laser to focal laser plus lucentis) led Lucentis to focal laser to focal laser plus lucentis) led totoRISE and RIDE ( phase 3 parallel pivotal studies in US RISE and RIDE ( phase 3 parallel pivotal studies in US and exand ex--US)US)
RISE 366 patients fully recruited comparing Lucentis 0.5mg RISE 366 patients fully recruited comparing Lucentis 0.5mg vs ranibizumab 0.3mg vs sham in DME 66 study sites in US vs ranibizumab 0.3mg vs sham in DME 66 study sites in US primary outcome percent of patients that gain 3 lines of VA, primary outcome percent of patients that gain 3 lines of VA, secondary outcomessecondary outcomes--mean gain and OCT improvementmean gain and OCT improvementRIDE 366 patients at 50 US and exRIDE 366 patients at 50 US and ex--US sites same outcomesUS sites same outcomes
Avastin in Diabetic Macular EdemaAvastin in Diabetic Macular Edema
Multiple Single site studies done and one Multiple Single site studies done and one large short term trial by the DRCR.Netlarge short term trial by the DRCR.NetOphthalmology Oct 2007Ophthalmology Oct 2007
120 eyes randomized to laser/ 1.25 mg 120 eyes randomized to laser/ 1.25 mg Avastin x2/2.5mg Avastinx2/ 1.25mg Avastin Avastin x2/2.5mg Avastinx2/ 1.25mg Avastin then sham at 6 weeks/1.25 mg Avastin/laser at then sham at 6 weeks/1.25 mg Avastin/laser at 3 weeks/Avastin at 6 weeks3 weeks/Avastin at 6 weeks
Not powered for efficacy but OCT improved Not powered for efficacy but OCT improved more in the Avastin treated armsmore in the Avastin treated arms
Avastin and Lucentis in DMEAvastin and Lucentis in DME
Currently no prospective randomized clinical trial Currently no prospective randomized clinical trial data available for either drugdata available for either drugNo head to head comparison plannedNo head to head comparison plannedNot covered by the vast majority of insurance Not covered by the vast majority of insurance companiescompaniesUsed as salvage for patients in whom laser has Used as salvage for patients in whom laser has failed or cant be done ( mostly Avastin due to failed or cant be done ( mostly Avastin due to cost)cost)Pilot study in Brazil show IV Kenalog works Pilot study in Brazil show IV Kenalog works better and is cheaperbetter and is cheaper
Lucentis Therapy in Branch Retinal Vein OcclusionLucentis Therapy in Branch Retinal Vein Occlusion
BRAVO ( BRVO with macular edema)BRAVO ( BRVO with macular edema)Prospective randomized double masked trial Prospective randomized double masked trial
390 patients recruitment completed390 patients recruitment completed3 arms Lucentis 0.5mg vs ranibizumab 0.3 mg vs sham 3 arms Lucentis 0.5mg vs ranibizumab 0.3 mg vs sham Primary outcome mean change in visual acuity at 6 Primary outcome mean change in visual acuity at 6 months secondary outcomes gainers/losers/ OCT months secondary outcomes gainers/losers/ OCT change from baseline VFQ score changechange from baseline VFQ score change
104 study centers in US104 study centers in US
6 month data due by end of the year6 month data due by end of the year
Lucentis in Central Retinal Vein OcclusionLucentis in Central Retinal Vein Occlusion
CRUISE ( CRVO with macular edema)CRUISE ( CRVO with macular edema)Again prospective randomized double masked trialAgain prospective randomized double masked trial
390 patients needed, fully recruited390 patients needed, fully recruited3 arms Lucentis0.5mg vs ranibizumab 0.3 mg vs shame3 arms Lucentis0.5mg vs ranibizumab 0.3 mg vs shamePrimary Outcome mean visual acuity change from baseline Primary Outcome mean visual acuity change from baseline secondary outcomes same as BRAVOsecondary outcomes same as BRAVO
105 study sites105 study sites6 month data also expected by end of the year6 month data also expected by end of the year
Avastin Therapy in BRVO/CRVOAvastin Therapy in BRVO/CRVO
Again no head to head trials with Lucentis plannedAgain no head to head trials with Lucentis plannedPrager BJO Dec 2008Prager BJO Dec 2008
29 BRVO /8 CRVO average patient received 8 out of 29 BRVO /8 CRVO average patient received 8 out of possible 13 injections over one year Mean VA possible 13 injections over one year Mean VA increased 15.8 letters and OCT improved average of increased 15.8 letters and OCT improved average of 249 microns249 microns
Jaissie Graefes Jan 2009 similar results in 23 eyesJaissie Graefes Jan 2009 similar results in 23 eyes
Russo Retina Jan 2009 Avastin better than focal laser for Russo Retina Jan 2009 Avastin better than focal laser for perfused BRVO in 30 eyes in this prospective randomized perfused BRVO in 30 eyes in this prospective randomized case seriescase series
Avastin in Proliferative RetinopathiesAvastin in Proliferative Retinopathies
Proliferative Diabetic RetinopathyProliferative Diabetic RetinopathyPreoperative Avastin 4Preoperative Avastin 4--7 days before 7 days before vitrectomy surgery may limit intraoperative vitrectomy surgery may limit intraoperative bleeding and facilitate membrane removal bleeding and facilitate membrane removal (Avery)(Avery)
CRVO with Neovascular GlaucomaCRVO with Neovascular GlaucomaAvastin treatment results in rapid regression Avastin treatment results in rapid regression of iris neovascularization, allowing panretinal of iris neovascularization, allowing panretinal laser photocoagulation to be placed soon laser photocoagulation to be placed soon thereafterthereafter
SummarySummary
Retinal Specialists now have two new potent anti VegF agents witRetinal Specialists now have two new potent anti VegF agents with h which to treat wet AMD, DME and RVO with macular edemawhich to treat wet AMD, DME and RVO with macular edemaIn the absence of head to head trial data, we must choose our In the absence of head to head trial data, we must choose our therapeutics based on the available literature/safety/ frequencytherapeutics based on the available literature/safety/ frequency of of treatments and costtreatments and costWith AMD , the higher level of evidence of the Lucentis data vs With AMD , the higher level of evidence of the Lucentis data vs that that of the Avastin data, I prefer Lucentis as first line therapy forof the Avastin data, I prefer Lucentis as first line therapy for wet wet AMD in patients undergoing a monotherapy regimenAMD in patients undergoing a monotherapy regimenI use Avastin in BRVO/CRVO and still use IVK in DME sometimes I use Avastin in BRVO/CRVO and still use IVK in DME sometimes Avastin as well in recalcitrant casesAvastin as well in recalcitrant cases
Since not covered by most insurances AvastinSince not covered by most insurances Avastin’’s cheap cost drives thiss cheap cost drives this
Oh yeah Avastin costs about 50 dollars, Lucentis 1950 dollars BOh yeah Avastin costs about 50 dollars, Lucentis 1950 dollars BTWTW
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