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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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