lucentis and avastin: a new era in treatment -...

rhuFab V2 Investigator Slide Set - TMc

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Lucentis and Avastin: A New Era in Treatment

Abdhish R. Bhavsar, MD

Director of Clinical Research, Retina Center, PAPast Chair, Phillips Eye Institute

Minneapolis, Minnesota

•Financial Disclosure:


-Principal Investigator, Phase II FOCUS Trial, Phase III MARINA TrialRAPTR, DRCR LRT

Trials-Consultant to Genentech, Eyetech, Novartis

FDA ApprovedAnti-VEGF Treatments

• Anti-VEGF inhibitors– Aptamer: Pegaptanib sodium (Macugen)– Antibody fragment: Ranibizumab

(Lucentis™)– Antibody full length: Bevacizumab

(Avastin)

Off Label Discussion

• Anti-VEGF inhibitors– Bevacizumab (Avastin)

• Ranibizumab (Lucentis)/ Bevacizumab (Avastin)– Vein occlusions: CRVO, BRVO– Diabetic retinopathy: DME, PDR– NVG

What Is Angiogenesis?

Angiogenesis is the process by which capillariessprout from existing blood vessels, and it is required for a variety of conditions

• Normal: menstrual cycle, pregnancy

• Corrective:

– wound healing/bone repair

– New vessel growth p MI

• Pathologic: vascularization, growth, metastasis

– e.g., cancer, AMD

Angiogenesis: A Balanced Process

Angiogenesis and vascular maintenance are regulated by a balance of angiogenesis activators and inhibitors.

Activators Inhibitors

Angiopoietins 1 and 2 AngiostatinTie-2 EndostatinAlpha-5 integrins Interferons-, , and Matrix metalloproteinases Interleukins-4, 12, and 18Nitric oxide Platelet factor 4COX-2 SPARC fragmentTGF- and receptors TIMPSVEGF and receptors Vasostatin

Calreticulin

Selected Angiogenesis Activators and Inhibitors


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Angiogenesis: Cascade of Events Vascular Endothelial Growth Factor (VEGF)

• Secreted endothelial cell mitogen and angiogenic factor– regulated by hypoxia

• Major regulator of physiologic and pathologic angiogenesis– important during growth and development (VEGF knockout, even

partial, is embryonically lethal)– role in tumor angiogenesis

• Enhances vascular permeability– first identified as a vascular permeability factor

Upstream activators of VEGF synthesis

Downstreamsignaling pathways

VEGF Is a Key Mediator of Vascular Permeability and Angiogenesis Evidence That VEGF Is a Required

Angiogenic Growth Factor

VEGF antagonists block• Embryonic development• Bone morphogenesis• Female reproductive cycling• Corneal angiogenesis• Growth of several tumor types in animal

models

VEGF Elevated in Ophthalmic Disease

1994 – Aiello…Ferrara et al. NEJM paper describing elevated VEGF in several retinal disorders.

New England Journal of Medicine. 331(22):1480-7, 1994 Dec 1.

VEGF in Ocular Neovascularization• VEGF fundamental to retinal neovascularization (Aiello et al, 1995)

– VEGF intravitreal injection in normal eyes leads to iris and retinal neovascularization (Adamis et al, 1998)

– high vitreous VEGF levels in eyes with CNV (Wells & Gregor 1996) and high VEGF levels in excised human choroidal neovascular membranes (Lopez et al, 1998)

• VEGF overexpression demonstrated in a primate laser retinal injury model of choroidal neovascularization

• VEGF correlated with active retinal neovascularization in retinopathy of prematurity and proliferative diabetic retinopathy


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VEGF as a Therapeutic Target in the Eye

• VEGF is secreted, freely diffusible, and mitogenic for endothelial cells

• Multiple retinal cell types make VEGF• Retinal endothelial cells have receptors for

VEGF• Blood-retinal barrier breakdown is both

prevented and reversed through VEGF inhibition• Extensive data support the role of VEGF in

ocular neovascularization & vascular permeability

Ferrara et al. Endocr Rev. 1992 ; Qaum e al. IOVS. 2001 Amano et al. IOVS. 1998; Adamis et al. Arch Ophthalmol. 1996; Aiello et al, Proc Natl Acad Sci USA. 1995;Krzystolik et al. Arch Ophthalmol. 2002.

VEGF Isoforms in the Human

• VEGF (VEGF [A]) is a single gene that codes for multiple protein isoforms (defined as a related protein)

• Isoforms differ in expression patterns and biological/biochemical properties

– Pathologic

– Physiologic

• The human VEGF isoforms are:

– 121, 145, 165, 189, and 206

• The isoform number refers to the number of amino acids contained in the mature, secreted protein

Robinson, Stringer. J Cell Sci. 2001; Neufeld et al. Faseb J. 1999.

Anti-VEGF Inhibition of Ocular Neovascularization

• VEGF inhibition using intravitreal antibody injection prevents experimental iris neovascularization

• VEGF inhibition using intravitreal soluble receptors or antisense oligonucleotides markedly reduces retinal neovascularization

• VEGF gene produces alternatively spliced mRNA variants

T Usui et al. Invest Ophthalmol Vis Sci 2004 Feb;45(2): 368-374

VEGF isoforms

121 aa

165 aa

189 aa

206 aa

1 2 3 4 5 6 7 8

–26 1 13 79 105 115 183 206

VEGF isoforms

• VEGF110 is a cleavage product

– Soluble and bioactive form of VEGF

– Biologically similar to VEGF121

Heparin-binding domain

1 165

165 1

Plasmin

VEGF-receptor binding site

1

1

110

110

VEGF165 VEGF110

Ruckmann, et al. J Biol Chem. 1998;273:20556-20567.

Anti-VEGF Antibodies

• rhuMAb VEGF– full-length humanized monoclonal antibody: 2 antigen binding

regions and a complement binding (Fc) region

– completed Phase III trials for cancer

– Bevacizumab: Avastin

• rhuFab V2– second generation antibody with higher VEGF affinity

– Fab= antibody fragment: one antigen binding region, no Fc region

– fully penetrates retina and reaches choroid after intravitreal injection

– Ranibizumab: Lucentis


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Molecule Structure: rhuMAb VEGF and rhuFab V2

IgGMW 150 KD

FabMW 48 KD

rhuFab V2 Showing Mutations thatEnhance Affinity for VEGF

Journal of Molecular Biology 293, 865 (1999)

Lucentis Summary

Lucentis

Chen, et al. Journal of Molecular Biology, Vol. 293, No. 4( 865-881) Nov 1999

Kim …Ferrara Nature 362, 841-844.(1993)

HumanizedAntibody

Monoclonal

Antibody

Human

Monoclonal

Antibody

Mouse

Presta…Ferrara Cancer Res. 47:

4593-4599.1997

Monoclonal AntibodyA.4.6.1

Humanization

V1 -> V2Improved VersionPreparing Fab

Chen, et al. Journal of Molecular Biology, Vol. 293, No. 4( 865-881) Nov 1999

Fab fully penetrates the Retina

Fab IgG

FabMW 48,000

IgGMW 148,000

Lucentis penetrates through all retinal layers while IgG only penetrates superficially.

Mordenti et al. Toxicologic Pathology. 27(5):536-44, 1999 Sep-Oct.

Herceptin

Lucentis – What it does:•VEGF binds receptors

•Vascular LEAKAGE and and swelling

•ANGIOGENESIS

•Lucentis blocks VEGF•Decreased LEAKAGE and

and swelling•Blocks ANGIOGENESIS

VEGFVEGF

VEGFVEGF VEGF VEGF

Lucentis Binds all VEGF isoforms

165 121 110 1

1651211101

Lucentis

Lucentis

VEGF

VEGF

189 206

189206

Lucentis binds near AA 80 thus it can inactivate all isoforms of VEGF

( 110, 121, 165, 189,206)Chen et al. J Mol Biol 293:865-881 1999


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• VEGF expression is elevated in AMD and thought to be responsible for

• Vascular proliferation

• Vascular leakage

• rhuFab V2 is a recombinant humanized Fab fragment that has been optimized to avidly bind and inactivate VEGF

Rationale

Chen, et al. Journal of Mol. Biol., Vol. 293, No. 4(865-881) Nov 1999

rhuFab V2VEGF

Phase III Program

• N = 720

• 24 monthly intravitreal injections

• File with “% losing <15 letters” at 12 months

300 ugrhuFab V2

500 ugrhuFab V2

ShamInjection

Min Classic/Occult

• N = 426• 24 monthly intravitreal injections• File with “% losing <15 letters”

at 12 months

Program consists of one MC/O and one PC trial

ReadingCenter Study 2598

Randomized 1:1:1

ShamPDT

300 ugrhuFab V2

500 ugrhuFab V2

ShamInjection

ReadingCenter

Predom Classic

Study 2587

Randomized 1:1:1

Verteporfin ShamPDT

Phase Ic

• N = 168

• 24 monthly intravitreal injections

• File with safety & tolerability and “% losing <15 letters” at 12 mos

500 ugLucentisTM

ShamInjection

LucentisTM and Verteporfin PDT combination Rx in PC

Study 2428 Predom/Classic

Randomized 1:2

Verteporfin PDT@ Day 0

PDT prnq3 mos

PDT prnq3 mos

(Investigator determination)

Randomized, Controlled Phase III Study of Ranibizumab for Intravitreal Injection for Minimally Classic or Occult Neovascular AMD: Two-Year Results of the MARINA

Study


Study Design and Objectives

• Phase III, randomized, multi-center, double-masked, sham-controlled study

• Evaluation of the efficacy and safety of the investigational drug ranibizumab in subjects with minimally classic or occult with no classic subfoveal choroidal neovascularization (CNV) secondary to AMD

Trial Design

Ranibizumab0.3 mg(n=238)


Minimally classic or occult with no classic lesions

(N=716)

Reading center confirms angiographic eligibility

Randomization 1:1:1

Investigator identifies potential subjects

Sham(n=238)


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PDT at investigator discretion if:• Conversion to predominantly classic CNV, or• Loss of ≥20 letters on 2 consecutive visits and

small (≤4 DA), minimally classic or occult with no classic lesions, with presumed recent disease progression

October 2005• All subjects offered ranibizumab• 12 Sham subjects crossed over at Month 22 or 23

Treatment Schedule:First Subject Randomized 3/03 – Last Subject

Visit 12/05Month

Ranibizumab0.5 mg

Sham

0 1 12 24

Finalvisit

PrimaryEndpoint

Ranibizumab0.3 mg

13 14 15 16 17 18 19 20 21 22 23

Primary Endpoint

Proportion of subjects who lose <15 letters at month 12 compared with baseline in the best corrected

visual acuity (VA) score

Key Secondary EndpointsMonth 12 and Month 24

• Visual acuity– Proportion gaining ≥15 letters in VA– Mean change from baseline in VA over time– Proportion with 20/200 Snellen VA or worse– Proportion losing <15 letters (at Month 24)

• Anatomy– Mean change from baseline in the total area of

CNV – Mean change from baseline in the total area of

leakage* from CNV*Includes intense, progressive staining of RPE (leaking fibrovascular pigment epithelial detachment)

Principal Eligibility Criteria: Study Eye

• Age ≥50 years • VA (Snellen equivalent) 20/40 to 20/320• Subfoveal CNV secondary to AMD• No prior PDT• Lesion composition by fluorescein angiography

– Area of CNV must be ≥50% of total lesion– Minimally classic or occult with no classic

• Evidence of presumed recent disease progression– Blood, recent growth by FA, or recent VA loss

• Lesion size ≤12 disc areas (DA)

Efficacy*:Through Month 24

* Analyzed based on the intent-to-treat population (ITT) with the last observation carried forward (LOCF) for missing data.

Primary Endpoint*:Subjects Losing <15 Letters from Baseline

0

10

20

30

40

50

60

70

80

90

100

% o

f su

bje

cts

62%

95%† 95%†

Month 12 Month 24

Ranibizumab 0.3 mg (n=238)Ranibizumab 0.5 mg (n=240)

Sham (n=238)

*Month 12 was the primary endpoint, month 24 was a secondary endpoint.†P<0.0001 vs sham


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Primary Endpoint*:Subjects Losing <15 Letters from Baseline

0

10

20

30

40

50

60

70

80

90

100

62%

95%† 95%†

53%

92%†90%†

Month 12 Month 24


Sham (n=238)

*Month 12 was the primary endpoint, month 24 was a secondary endpoint.†P<0.0001 vs sham

% o

f su

bje

cts

Secondary Endpoint:Subjects Gaining ≥15 Letters from Baseline

0

10

20

30

40

50

60

70

80

90

100

% o

f su

bje

cts

5%

34%*

4%

25%* 26%*33%*

Month 12 Month 24

*P<0.0001 vs sham


Sham (n=238)

Exploratory Endpoint:Subjects Gaining ≥30 Letters from Baseline

0

10

20

30

40

50

60

70

80

90

100

% o

f su

bje

cts

*P=0.008, †P=0.002, ‡P=0.0015, §P =0.0007 vs sham

0%4%†

0.4%3%* 5%‡ 6%§

Month 12 Month 24


Sham (n=238)

Exploratory Endpoint:Subjects with VA 20/40 or Better

0

10

20

30

40

50

60

70

80

90

100

% o

f su

bje

cts

*P<0.0001 vs sham

15%11%

15%11%

6%

34%*40%*39%*

42%*

Month 12 Month 24Baseline


Sham (n=238)

17.6 letter difference*


Note: Vertical bars are ± one standard error of the mean.

*P< 0.0001

Secondary Endpoint:Mean Change in Visual Acuity Over Time

2 4 6 8 10 12

Month-15

-10

-5

0

5

10

–10.4

+6.5+7.2

Sham (n=238) Ranibizumab 0.5 mg (n=240)Ranibizumab 0.3 mg (n=238)

ET

DR

S le

tter

s



+7.2

+6.5

-10.4

2 4 6 8 10 12 14 16 18 20 22 24

Month-15

-10

-5

0

5

10

ET

DR

S le

tter

s

-14.9

+5.4+6.6



*P<0.0001(Rounded values)

Sham (n=238) Ranibizumab 0.5 mg (n=240)Ranibizumab 0.3 mg (n=238)


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Safety:Through Month 24

Key Ocular Serious Adverse EventsCumulative through

month 12Cumulative through

month 24

Ranibizumab Ranibizumab

Sham

(n=236)

0.3 mg

(n=238)

0.5 mg

(n=239)

Sham

(n=236)

0.3 mg

(n=238)

0.5 mg

(n=239)

Presumed Endophthalmitis

Culture Positive 0 0 0 0 0 0

Culture Negative 0 0 2 (0.8%)* 0 1 (0.4%) 3(1.3%)*

Culture Not Done 0 1(0.4%) 0 0 1 (0.4%) 0

Uveitis 0 2 (0.8%) 1 (0.4%)† 0 3 (1.3%) 3(1.3%)†

Rheg. Retinal Detachment

0 0 0 1 (0.4%) 0 0

Retinal Tear 0 1 (0.4%) 1 (0.4%) 0 1 (0.4%) 1 (0.4%)

Vitreous Hemorrhage 0 1 (0.4%) 1 (0.4%) 2 (0.8%) 1 (0.4%) 1 (0.4%)

Lens Damage 0 0 1 (0.4%) 0 0 1 (0.4%)

*One case was reported as uveitis by investigator; †One subject had 2 episodes. Cumulative through month 24 non-serious AE of retinal tear in 7 subjects: 2 (Sham), 2 (0.3 mg) and 3 (0.5 mg).

DeathsRanibizumab

Sham(n=236)

0.3mg(n=238)

0.5 mg (n=239)

Year 10 1 (0.4%)

• Myocardial infarction (1)

2 (0.8%)• Small bowel infarct (1)

• Chronic asthma/COPD (1)

Year 2

6 (2.5%)• CVA* (2)

• Unknown cause (1)

• CHF† (1)

• Renal failure (1)

• Respiratory failure (1)

4 (1.7%)• Myocardial infarction (1)

• Unknown cause (1)

• NHL‡ complications (1)

• Pneumonia (1)

4 (1.7%)• CVA* (1)

• Hemorrhagic CVA* (1)

• MVA§ head injury (1)

• Sepsis (1)

Total deathsin study

6 (2.5%) 5 (2.1%) 6 (2.5%)

Deathsout of study

1 (0.4%)• Cardiac arrest 15 days after completing month

24

1 (0.4%)• Dropped out 50 days after

month 22 (subject’s decision). Died of lung cancer 4 months

after dropout

1 (0.4%)• Dropped out 35 days after

month 23 (Lost to follow-up). Died of lung cancer 2 months

after dropout.

*CVA=cerebrovascular accident; †CHF=congestive heart failure; ‡NHL=Non-Hodgkin’s lymphoma; §MVA=motor vehicle accident;

Key Systemic Findings:Cumulative Through Month 24

Ranibizumab

Sham

(n=236)

0.3 mg

(n=238)

0.5 mg

(n=239)

Hypertension adverse event 38 (16.1%) 41 (17.2%) 39 (16.3%)

Blood Pressure (mm Hg)

Baseline mean SBP/DBP 138/77 137/77 141/76

Month 24 mean SBP/DBP 135/74 135/74 136/75

Mean change in SBP/DBP § -3/-4 -3/-3 -4/-1

Proteinuria adverse event 0 0 0

Nonocular Hemorrhagic adverse event *

13 (5.5%) 22 (9.2%) 21 (8.8%)§Rounded values*Examples include epistaxis, hematoma, ecchymosis, rectal hemorrhage, hematuria,vaginal hemorrhage, GI hemorrhage, etc.

• Non-fatal myocardial infarction

• Non-fatal strokeIschemic

Hemorrhagic

• Vascular death (from any potential

vascular or unknown cause)

Used during FDA Cox-2 Inhibitor Advisory Panel Meetings Feb’05

*Antiplatelet Trialists’ Collaboration. BMJ. 1994 Jan 8;308(6921):81-106.

Antiplatelet Trialists’ Collaboration (APTC)*Arterial Thromboembolic Events

Antiplatelet Trialists’ Collaboration (APTC)Arterial Thromboembolic Events (ATEs)

Cumulative throughmonth 12*

Cumulative throughmonth 24

Ranibizumab Ranibizumab

Sham

(n=236)

0.3 mg

(n=238)

0.5 mg

(n=239)

Sham

(n=236)

0.3 mg

(n=238)

0.5 mg

(n=239)

Vascular deaths 0 1 (0.4%) 1 (0.4%) 4 (1.7%)† 3 (1.3%)‡ 3 (1.3%)

Nonfatalmyocardial infarction

1 (0.4%) 2 (0.8%) 1 (0.4%) 4 (1.7%) 6 (2.5%)§ 3 (1.3%)**

Nonfatalischemic stroke

1 (0.4%) 1 (0.4%) 3 (1.3%) 2 (0.8%)† 3 (1.3%)‡, †† 5 (2.1%)

Nonfatalhemorrhagic stroke

0 0 0 0 0 1 (0.4%)**

Total2

(0.8%)

4

(1.7%)

5

(2.1%)

9

(3.8%)

11

(4.6%)

11

(4.6%)

* Based on the study final database† One subject had a prior non-fatal ischemic stroke, then a fatal stroke‡ One subject had a nonfatal ischemic stroke and died later of unknown cause§ One subject had two events of nonfatal myocardial infarction** One subject had a non-fatal myocardial infarction and a non-fatal hemorrhagic stroke†† One subject had a non-fatal ischemic stroke in year 1and a transient ischemic attack in year 2 that progressed to a

stroke after month 24 visit.


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Systemic Immunoreactivity

Ranibizumab

Time PointSham

(n=236)0.3 mg(n=238)

0.5 mg(n=239)

Screening1/215

(0.5%)

2/215

(0.9%)

0/218

(0%)

Month 63/201

(1.5%)

3/211

(1.4%)

3/207

(1.4%)

Month 124/206

(1.9%)

6/222

(2.7%)

4/218

(1.8%)

Month 242/182

(1.1%)

9/206

(4.4%)

13/208

(6.3%)

Systemic Immunoreactivity:Subgroup Analysis Based on Immunoreactivity

to Ranibizumab• Efficacy: No association with outcomes

– Proportion losing <15 letters– Mean VA change

• Safety: No association with outcomes– Intraocular inflammation: AE, SAE, slit lamp– Other potential ocular immune AE or SAE

• e.g. Dry eye, eyelid edema, contact dermatitis

– Nonocular potential immune AE or SAE• e.g. Pruritis, rash, arthralgias

Conclusions:Cumulative Data Through Month 24

• Efficacy– Effect maintained over 2 years (visual acuity, FA)– Difference between ranibizumab and sham increases over 2 years

• Safety– No imbalance in deaths between sham and ranibizumab groups

– Low rate of ocular serious adverse events• Presumed endophthalmitis (≤1.3%) and uveitis (1.3%)

– Low rate of nonocular serious adverse events

– Similar rates of APTC ATEs observed in sham (3.8%) and ranibizumab 0.3 mg (4.6%) and 0.5 mg (4.6%) groups

– Immunoreactivity• Low rate of immunoreactivity observed at 24 months• No apparent association with efficacy or safety outcomes

A Phase III Study of Ranibizumab (Lucentis™) vs

Verteporfin (Visudyne®) PDT in Predominantly Classic Subfoveal Neovascular AMD

— Year 1 Results —

Study Design and Objectives

• Phase III, randomized, multi-center, double-masked, active treatment-controlled study

• Comparison of efficacy and safety of the investigational drug ranibizumab with verteporfin PDT in subjects with predominantly classic, subfoveal CNV due to AMD

Primary Endpoint

Proportion of subjects* who lose <15 lettersat month 12 compared with baseline

in the best corrected VA score

*Intent to treat population with last observation carried forward


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Key Secondary Endpoints

• Proportion of subjects who gain ≥15 letters in VAat month 12 compared with baseline

• Proportion of subjects with a VA of 20/200 or worse at month 12

• Mean change from baseline in VA over time up to month 12

* CNV lesion is defined as CNV detectable by FA plus any associated subretinal hemorrhage, serous PED, fibrosis or other blocked fluorescence

Principal Eligibility CriteriaStudy Eye

• Age ≥ 50 years • VA (Snellen equivalent) 20/40 to 20/320• Primary or recurrent subfoveal CNV* lesion

secondary to AMD in the study eye• No prior PDT• Lesion composition by fluorescein angiographyClassic CNV ≥ 50% of the total lesion area

(predominantly classic lesion)Total lesion ≤ 5400 µm in greatest linear dimension

ShamPDT



Reading Center confirmsangiographic eligibility

Predominantly classic lesions(n=423)

Randomized 1:1:1

VerteporfinPDT

ShamPDT

Shaminjection(n=143)

Investigator identifies potential subjects

Trial Design Treatment Schedule: Year 1

Primary endpoint

Group 1

0 1 2 3 4 5 6 7 8 9 10 11 12

Group 3

Month

Group 2

0.5 mg ranibizumab Sham injection Sham PDT PDT0.3 mg ranibizumab

*Sham PDT or PDT when CNV fluorescein leakage

* * * *

* * * *

* * * *

Subject Demographics andBaseline Characteristics

PDT(n=143)



Gender (% women) 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 (letter score) 45.5 47.0 47.1

Mean VA (~Snellen equivalent) 20/125 +1 20/125 +2 20/125 +2

CNV classification

Predominantly classic 98.6% 95.7% 96.4%

Minimally classic 1.4% 3.6% 3.6%

Occult 0 0.7% 0

Mean lesion size (DA) 1.88 1.89 1.79

Primary Endpoint:Subjects Losing <15 Letters from Baseline at

Month 12

*P <0.0001 vs. PDT

64.3

94.3 96.4

0102030405060708090

100

PDT(n=143)



%*%*

% o

f S

ubje

cts

%


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% o

f S

ubje

cts

5.6

35.740.3

0

10

20

30

40

50

60

70

80

90

100

PDT(n=143)



%*%*

%

Secondary Endpoint:≥15 Letter Gain from Baseline at Month 12

*P <0.0001 vs. PDT

Secondary Endpoint:VA of 20/200 or Worse at Month 12

PDT(n=143)



32.225.0 23.0

60.1

22.116.4

0

10

20

30

40

50

60

70

80

90

100

Baseline Month 12 Baseline Month 12 Baseline Month 12

%

%

% %* %%*%

of

Sub

ject

s

*P <0.0001 vs. PDT


ET

DR

S le

tter

s


PDT (n=143)

–9.5

Month

-15

-10

-5

0

5

10

15

0 1 2 3 4 5 6 7 8 9 10 11 12



+11.3

+8.5

–9.5

20.8letterdifference*

18.0 letterdifference*

* P < 0.0001

PDT (n=143) Ranibizumab 0.3 mg (n=140) Ranibizumab 0.5 mg (n=139)

ET

DR

S le

tter

s

Month-15

-10

-5

0

5

10

15

0 1 2 3 4 5 6 7 8 9 10 11 12

Other Visual Outcome:VA 20/40 or Better at Month 12

PDT(n=143)



0.0 1.4 4.32.8

31.438.6

0

10

20

30

40

50

60

70

80

90

100

Baseline Month 12 Baseline Month 12 Baseline Month 12

% % %

%*

%

%*

% o

f S

ubje

cts

*P <0.0001 vs. PDT

% o

f S

ubje

cts

06.4

12.2

0

10

20

30

40

50

60

70

80

90

100

PDT(n=143)



% †

%*%

Other Visual Outcome:≥30 Letter Gain from Baseline at Month 12

*P =0.0018 vs. PDT†P <0.0001 vs. PDT


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13.3

0 00

10

20

30

40

50

60

70

80

90

100

Other Visual Outcome:≥30 Letter Loss from Baseline at Month

12

PDT(n=143)



% o

f S

ubje

cts

%* %*

%

*P <0.0001 vs. PDT

Pre-Specified Subgroup Analyses:Subjects Losing <15 Letters from Baseline at

Month 12

82

4944

67

95 94 95 9497 96

10096

0

10

20

30

40

50

60

70

80

90

100

<45 letter score(worse than

20/125)

³45 letters (20/125 or better)

Predominantlyclassic with occult

Predominantlyclassic no occult

% o

f Sub

ject

s

n= 66 63 60 77 77 79 16 21 18 127 119 121

* P =0.018; † P <0.01; § P <0.001; ‡ P <0.0001 vs. PDT

%

%§%§

%

%‡%‡

%

%†%*

%

%‡ %‡

Year 1 Safety Results

Key Ocular Serious Adverse Events

PDT

(n=143)

Ranibizumab

0.3 mg(n=137)

Ranibizumab0.5 mg

(n=140)

Presumed Endophthalmitis*

Culture Positive

Culture Not Done

0

0

0

0

1 (0.7%)

1 (0.7%)†

Uveitis 0 0 1 (0.7%)†

Rheg. Retinal Detachment 1(0.7%)‡ 1 (0.7%) 0

Retinal Tear 0 0 0

Vitreous Hemorrhage 0 1 (0.7%) 0

Lens Damage 0 0 0

*Defined as cases in which intravitreal or systemic antibiotics were administered.†Same subject had 2 episodes each reported as uveitis. Received systemic antibiotics once.‡Same subject had 2 episodes.

Intraocular Inflammation:Slitlamp Examination

Most severe inflammationobserved in year 1

(regardless of cause)PDT

(n=143)



None 138 (96.5%) 120 (87.6%) 116 (82.9%)

Trace 4 (2.8%) 11 (8.0%) 13 (9.3%)

1+ 1 (0.7%) 3 (2.2%) 8 (5.7%)

2+ 0 1 (0.7%) 1 (0.7%)

3+ 0 2 (1.5%) 1 (0.7%)

4+ 0 0 1 (0.7%)

Key Systemic Adverse Events

PDT

(n=143)

Ranibizumab0.3 mg

(n=137)

Ranibizumab0.5 mg

(n=140)

Hypertension 12 (8.4%) 3 (2.2%) 9 (6.4%)

Mean change in SBP/DBP (mmHg) 0.1 / 0.3 -2 / -2 -2 / 1

Death 2 (1.4%) 3 (2.2%) 2 (1.4%)

Cause of death• Cardiac arrest

• COPD

• Cardiac arrest

• Resp arrest

• Viral syndrome

• Cardiac failure

• Chronic heart failure


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• Non-fatal myocardial infarction

• Non-fatal strokeIschemic

Hemorrhagic

• Vascular death (from any potential

vascular or unknown cause)

Used during FDA Cox-2 Inhibitor Advisory Panel Meetings Feb’05




6 (4.3%)3 (2.2%)3 (2.1%)Total

000Nonfatal Hemorr. Stroke

1 (0.7%)1 (0.7%)1 (0.7%)NonfatalIschemic Stroke

3 (2.1%)1 (0.7%)1 (0.7%)NonfatalMyocardial Infarction

2 (1.4%)1 (0.7%)1 (0.7%)Vascular Death

Ranibizumab 0.5 mg

(n=140)

Ranibizumab 0.3 mg

(n=137)

PDT

(n=143)

Serious adverse events


Conclusions: 12 Month Safety

• Low rate of ocular serious adverse events

• No imbalance of non-ocular adverse events overall, except APTC arterial thromboembolic events only in 0.5 mg dose * PDT: 3 subjects (2.1%) 0.3 ranibizumab: 3 subjects (2.2%) 0.5 ranibizumab: 6 subjects (4.3%)

• Results consistent with previous ranibizumab trials

*Not powered to distinguish differences in rates of rare events among treatment arms

Conclusions:12 Month Ranibizumab Vision Outcomes

• Clinically & statistically significant benefit vs PDT in predominantly classic CNV

~95% lost fewer than 15 letters

8.5-11.3 letter improvement in mean VA

36-40% improved 15 or more letters

6-12% improved 30 or more letters

Day 140: 20/63 (+17 letters)Day 0: 20/125

RT=457 µ RT=166 µ

Lucentis Activity

RT = retinal thickness as measured by OCT.Courtesy of Dr. P. Rosenfeld, BPEI, Miami, FL.

Avastin

• Bevacizumab


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Avastin

• What we do not know

• What we do know

Avastin

• The Beginning:•Systemic Avastin IST, Phil Rosenfeld, MD•Case reported ASRS mtg - Montreal July 2005

•Within 6 months:•THE STANDARD OF CARE

Avastin

• Michels, Rosenfeld, Puliafito et al– Ophthalmology, June 2005 112(6):1035-47– Open label, uncontrolled study– 9 pts– Systemic bevacizumab 5 mg/kg

• Baseline and 1 - 2 doses at 2 wk intervals– Results:

• 6 wks: mild inc. BP; improved by 12 wks• 1 wk: improved VA• 12 wks: median VA improved by 8 letters; OCT

dec. by 59 µm

Avastin• Rosenfeld, Moshfeghi, Puliafito

– Ophthalmic Surgery, Lasers & Imaging Jul-Aug 2005, 36(4):331-5

– 1 patient– Responded poorly to pegaptanib (Macugen)– 1.0 mg– 1 wk:

• VA stable• OCT resolution SRF, improved macular contour

– 4 wks:• VA stable• OCT maintained

Avastin• Avery, Pieramici, Rabena et al.

– Ophthalmology,March 2006, 113(3): 363-372.e5– 81 eyes/79 pts– 1.25 mg q month until macular edema, SRF, or PED resolved– 1 wk:

• 55% reduction of > 10% of baseline retinal thickness• OCT dec. central thickness by 61 µm

– 4 wks:• 30/81 eyes complete resolution of macular edema, SRF, PEDs• Mean VA improved from 20/200 to 20/125• OCT dec. central thickness by 92 µm

– 8 wks• Median VA improved from 20/200 to 20/80• OCT dec. central thickness by 89 µm

Avastin

• Costa, Jorge, Calucci et al.– Investigative Ophthalmology and Visual Science,Oct. 2006,

47(10):4569-4578.– 45 pts, prospective, nonrandomized open label study– 1.0, 1.5, 2.0 mg – BCVA improved at wk 1, wk 6, wk 12– 79.1% Stable or Dec. lesion area – 74.4% Stable or Dec. CNV area– Wk 12

• 1.0 mg: BCVA improvement by + 0.3 lines• 1.5 mg: BCVA improvement by + 0.6 lines• 2.0 mg: BCVA improvement by + 1.0 lines

– No systemic adverse events


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Avastin

• What we do not know:• Systemic Safety?• Duration of clinical effects?• Optimal dosing?• Level 1 Evidence: ABC Trial

– Presented by Tufail, Retina Congress October 2009

Avastin vs LucentisComparison of AMD Treatment Trial

• > 1000 subjects enrolled at present (goal 1200)• Randomization:

– Avastin q month– Lucentis q month– Avastin variable– Lucentis variable

• Enrollment expected to be completed by the end of 2009

• Primary outcome: Mean change in VA• 1 year results to be reported in 2011

Lucentis or Avastin

• Other diseases– Diabetic Retinopathy

• DME• PDR

– CRVO• CME• NVI, NVG

– BRVO• CME• NVI, NVG

Diabetic RetinopathyAvastin

• Proliferative Diabetic Retinopathy– Avery et al. Ophthalmol 2006;113(10):1695-1705.e1-

15– 44 eyes/32 pts regression of leakage on FA– Complete resolution NVE 59%, NVD 73%, NVI 82%– Recurrence of NV as early as 2 wks p Avastin


• Proliferative Diabetic Retinopathy: small series– Speeds resolution and dec extent of NV

• Jorge et al. Retina. 2006;26:1006-1013 • Tonello et al. Acta Ophthalmol 2008;86:385-389• Mirshahi et al. Eur J Ophthalmol 2008;18:263-269

– Speeds resolution of VH• Spaide et al. Retina 2006;26:275-278• Moradian et al. Graefes Arch Clin Exp Ophthalmol

2008;246:1699-1705

– Dec intraop heme during PPVx as adjunct rx• Ishikawa et al. Eye 2009;23:108-111• Chen et al. Retina 2006;26:699-700• Rizzo et al.Graefes Arch Clin Exp Ophthalmol 2008;246:837-842


• Diabetic Macular Edema– Arevalo et al. Ophthalmology 2007;114:743-750– 78 eyes/63 pts, retrospective review– f/u 6-9 months, 72% had 1 injection– 55% gain ≥ 10 or more lines ???– Mean 387 to 276µ


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Diabetic RetinopathyLucentis

• Diabetic Macular Edema: Lucentis– Nguyen et al. Am J Ophthalmol 2006;142:961-969

• Nonrandomized trial• 10 pts, 0.5 mg at baseline, 1,2,4,6 months• CFT 503µ to 257µ at 7 months• VA improvement 20/80 to 20/40


• Diabetic Macular Edema: Lucentis– READ 2 Study: Nguyen et al. Ophthalmology 2009

• Randomized clinical trial, 126 pts, 1:1:1– 0.5mg baseline, months 1,3,5– Focal laser baseline and month 3– Focal laser + lucentis baseline and month 3

• Month 6: gain BCVA 7.24 letters; -0.43 letters; +3.8 letters• Excess foveal thickness reduced by: 50%, 33%, 45%


• Diabetic Macular Edema: RESOLVE Study– Randomized phase II trial– 151 pts w/ ≥ 300µ CMT

• Group A: 42 pts analyzed at 6 months• Groups B: 109 pts analyzed at 12 months

– 0.3mg vs 0.5mg vs sham: injections q month x 3– Treat to resolution; could double dose if DME present– 70% pts double-dose; mean 10 injections– Group B: VA gain 7.6 letters vs 1.2 letters at 12 mo’s– Group A/B: Mean 10.3 letter gain vs -1.4 letters – CMT decreased from baseline -200µ vs -50µ

Retina Vein OcclusionsAvastin

• Macular Edema: Avastin– Wu, Arevalo, Roca et al., RETINA 28:212-219;2008

• 45 eyes, BRVO, ME (mean dx 26 mo’s, mean f/u 35 wks)• 1.25 mg, 24 eyes, 5.1 lines inc BCVA; 461 – 277µ at 6

mo’s, 1.5 injections • 2.5 mg, 21 eyes, 4.8 lines inc BCVA;385 – 240µ at 6 mo’s,

2 injections

– Chung, Hong, Lee, Graefes Arch Clin Exp Ophthalmol 2008.246:1241-1247• 50 eyes, BRVO, ME, retrospective review• 28 eyes ≥ 5 letters gain, 13 eyes 2 inj• 22 eyes < 5 letters gain or worse VA 14 eyes 2 inj

Retina Vein OcclusionsAvastin

• Macular Edema: Avastin• Hoeh, Ach, Schaal et al. Graefes Arch Clin Exp

Ophthalmol.2009;online;• 61 pts (CRVO 27 pts; BRVO 34 pts) • mean f/u 60 wks±29 wks (min 25 wks)• CRVO: 748±265µ to 372±224µ, gain VA 1.9±3.2 lines• BRVO: 601±206µ to 386±178µ

• 33% CRVO, 15% BRVO: no ME ≥ 25 wks• 37% CRVO, 50% BRVO: ME recurrent within last 25 wks• 30% CRVO, 35% BRVO: ME no complete resolution x 3

injections


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97

Supported by Cooperative Agreements from the National Eye Institute, National Institutes of Health, DHHS

Comparison of AMD Treatments Trials (CATT): Lucentis – Avastin

TrialAbdhish R. Bhavsar, MD

for the Comparison of AMD Treatments Trials (CATT) Research Group

Abdhish R. Bhavsar, MDfor the Comparison of AMD Treatments Trials

(CATT) Research Group

Objectives

• To determine the relative efficacy and safety of intravitreal Lucentis and Avastin for treatment of neovascular AMD

• To determine if less than monthly dosing of either drug compromises long term visual outcomes

98

CATT Clinical Sites

99

1208 patients with neovascular AMD enrolled at 44 sites in the United States

Major Eligibility Criteria

• Neovascular AMD with either choroidal neovascularization (CNV) or its sequelae (fluid, blood, PED) subfoveal

• Visual acuity (VA) 20/25-20/320

• ≥1 drusen (>63μ) in either eye or late AMD in fellow eye

• Fibrosis < 50% of lesion; no limit on hemorrhage

• No previous treatment for CNV in study eye

• Age ≥ 50 yrs

100

Goal was to be as inclusive and simple as possible

CATT Treatment

101

Month

LucentisMonthly

0 1 2 3 4 5 6 7 8 9 10 11 12 23 24

AvastinMonthly

LucentisPRN

AvastinPRN

Finalvisit

PrimaryEndpoint

OCT-guided retreatmentInject monthly unless dry}

300 patients per arm (N=1200)

Treatment in PRN Arms

102

Treat to a dry OCT – zero tolerance for intraretinal, subretinal, or sub-RPE fluid.

May also treat if there is other evidence of CNV activity

New subretinal or intraretinal hemorrhage

Leakage or increased lesion size on FA

Unexplained decrease in visual acuity with no obvious atrophy or subretinal fibrosis.

No retinal thickness threshold (100 microns) as used in many neovascular AMD treatment

studies.

Treat to a dry OCT – zero tolerance for intraretinal, subretinal, or sub-RPE fluid.

May also treat if there is other evidence of CNV activity

New subretinal or intraretinal hemorrhage

Leakage or increased lesion size on FA

Unexplained decrease in visual acuity with no obvious atrophy or subretinal fibrosis.

No retinal thickness threshold (100 microns) as used in many neovascular AMD treatment

studies.


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CATT Study Drugs

103

Ranibizumab (Lucentis ®) 0.5 mg (0.05 mL) dose

Locally supplied; same as for patients outside of the study

Billed to primary and supplemental insurance providers

Residual co-pay paid by NIH No out of pocket expense for drug

Ranibizumab (Lucentis ®) 0.5 mg (0.05 mL) dose

Locally supplied; same as for patients outside of the study

Billed to primary and supplemental insurance providers

Residual co-pay paid by NIH No out of pocket expense for drug

CATT Study Drugs

104

Bevacizumab (Avastin®)

1.25 mg (0.05 mL) dose 2 cc vial containing 0.25 cc, IND #100,476 Compounded by an aseptic fill and finish

company (Formatech)

Bevacizumab (Avastin®)

1.25 mg (0.05 mL) dose 2 cc vial containing 0.25 cc, IND #100,476 Compounded by an aseptic fill and finish

company (Formatech)

Masking

Masked to drug and schedule

Visual acuity examiner

OCT and photograph graders

Masked to drug

Ophthalmologist

Patient initially, billing statements may unmask

105

Outcome Measures

Primary Mean change in VA at 1 year (non-inferiority limit

of 5 letters)

Secondary Maintenance of vision (< 15 letters lost) 3-line gain in VA (15 letters on ETDRS chart) Change in fluid on OCT Change in lesion size on fluorescein angiography Number of treatments Incidence of endophthalmitis, retinal detachment,

cataract, uveitis Incidence of systemic serious adverse events Cost

106

Patients

1208 patients with neovascular AMD Enrolled at 44 clinical sites in US February 2008 to December 2009 (21.5 months) DSMC recommended exclusion of all patients (23)

at one site due to protocol non-compliance All results reported on 1185 patients

107

Baseline Characteristics

Mean age for Lucentis was 78.8 versus 79.7 for Avastin

Groups were balanced for gender, race, baseline visual acuity, lesion type, and central foveal involvement by CNV.

More patients assigned to Avastin had HTN, diabetes, were current smokers, had emphysema, had a history of MI, TIA, or arrhythmias.

108


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Masking

22,138 patient visits during the first year Drug identity known to treating ophthalmologist

at only 46 visits (0.2%) Two patients accounted for half (23) of the these

instances Robust masking also in place for VA Examiners

and Reading Center graders

109

Visual Acuity Results

110

0

5

10

15

0 4 8 12 16 20 24 28 32 36 40 44 48 52

Lucentis Monthly

Avastin Monthly

Mean Change in Visual AcuityLucentis Monthly and Avastin Monthly

Let

ters

99.2% CI: (-3.9, 2.9)

Week

+8.5

+8.0

0

5

10

15

0 4 8 12 16 20 24 28 32 36 40 44 48 52

Lucentis PRN

Avastin PRN

Mean Change in Visual AcuityLucentis PRN and Avastin PRN

Let

ters

99.2% CI: (-4.1, 2.4)

Week

+6.8

+5.9

0

5

10

15

0 4 8 12 16 20 24 28 32 36 40 44 48 52

Lucentis Monthly

Lucentis PRN

Mean Change in Visual AcuityLucentis Monthly and Lucentis PRN

Let

ters

99.2% CI: (-4.7, 1.3)

Week

+8.5

+6.8

0

5

10

15

0 4 8 12 16 20 24 28 32 36 40 44 48 52

Avastin Monthly

Avastin PRN

Mean Change in Visual AcuityAvastin Monthly and Avastin PRN

Let

ters

99.2% CI: (-5.7, 1.6)

Week

+8.0

+5.9


TMc 2003-08 11/16/2015 10:14:06 AM 20

0

5

10

15

0 4 8 12 16 20 24 28 32 36 40 44 48 52

Lucentis Monthly

Avastin PRN

Mean Change in Visual AcuityLucentis Monthly and Avastin PRN

Let

ters

99.2% CI: (-5.9, 0.8)

Week

+8.5

+5.9

0

5

10

15

0 4 8 12 16 20 24 28 32 36 40 44 48 52

Avastin Monthly

Lucentis PRN

Mean Change in Visual AcuityAvastin Monthly and Lucentis PRN

Let

ters

99.2% CI: (-4.5, 2.1)

Week

+8.0

+6.8

8.58.0

Week

Let

ters

6.85.9

0

5

10

15

0 4 8 12 16 20 24 28 32 36 40 44 48 52

Lucentis Monthly

Avastin Monthly

Lucentis PRN

Avastin PRN

Mean Change in Visual Acuity

117

All Groups

+8.5+8.0+6.8+5.9

8.58.0

Week

Let

ters

6.85.9

0

5

10

15

0 4 8 12 16 20 24 28 32 36 40 44 48 52

Lucentis Monthly

Avastin Monthly

Lucentis PRN

Avastin PRN

7.2 (0.7)

7.3 (0.8)

6.4 (0.6)

6.1 (0.7)

Change in Visual Acuity- GEE Model

118

All Groups –Averaged over Weeks 12 ,24, 36, 52

+8.5+8.0+6.8+5.9

99.2% CI for Mean Change in VA at Year 1

119

All Groups

120

Patients Without 15 Letter Decrease

93.7% 93.2% 94.1%91.6%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Per

cen

tag

e o

f P

atie

nts

Lucentis Monthly (n=284) Avastin Monthly (n=265) Lucentis PRN (n=285) Avastin PRN (n=271)


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15-Letter Change from Baseline at 1 Year

121

15-Letter Change from Baseline Over Time

122

123

Distribution of Visual Acuity Conclusions

• Lucentis and Avastin were equivalent at all time points when administered at the same dosing regimen

• The proportion of patients with 3 line gain, <15 letter loss, or 20/40 or better was the same when either drug was administered with the same dosing regimen.

• Lucentis PRN was equivalent to Lucentis monthly (-1.7 letters)

• Avastin PRN was equivalent to Avastin monthly through 36 weeks but was inconclusive at 52 weeks for visual acuity (-2.1 letters)

124

Visual Acuity at One Year

Summary

• New ERA of more effective anti-VEGF agents• Lucentis• Avastin

Future

• Randomized clinical trials: Level 1 Evidence– DRCR Laser-Ranibizumab-Triamcinolone trials– DRCR Protocol N, VH anti-VEGF vs control inj

• More effective anti-VEGF agents• Combination therapies• Sustained release vehicles • Less frequent dosing regimens• Better prevention strategies


TMc 2003-08 11/16/2015 10:14:06 AM 22

Thank You!

Additional Slides

Primary Endpoint:Subjects Losing <15 Letters from Baseline at

Month 12

64.3

94.3 96.4

0

20

40

60

80

100

*P <0.0001 vs. Sham†P <0.0001 vs. PDT

PDT(n=143)



%*%*

% o

f Sub

ject

s

%62.2

94.5 94.6

0

20

40

60

80

100

% o

f Sub

ject

s

Sham(n=238)



%†%†

%

MARINA ANCHOR



* P < 0.0001 vs. Control

1 2 3 4 5 6 7 8 9 10 11 12

-12

-10

-8

-6

-4

-2

0

2

4

6

8

10

12

ETD

RS le

tter

s

Sham (n=238)

Ranibizumab 0.3 mg (n=238)

Ranibizumab 0.5 mg (n=240) -10.5

+6.5+7.2

1 2 3 4 5 6 7 8 9 10 11 12

-12

-10

-8

-6

-4

-2

0

2

4

6

8

10

12

Verteporfin PDT (n=143)



-9.5

+8.5

+11.3

17.7 *letter benefit




MARINA ANCHOR

Key Ocular Serious Adverse Events

†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.

MARINA ANCHORRanibizumab Ranibizumab

Sham

(n=236)

0.3 mg

(n=238)

0.5 mg

(n=239)

PDT

(n=143)0.3 mg(n=137)

0.5 mg

(n=140)

Presumed Endophthalmitis

Culture Positive

Culture Negative

Culture Not Done

0

0

0

0

0

1 (0.4%)

0

2 (0.8%)†

0

0

0

0

0

0

0

1 (0.7%)

0

1 (0.7%)‡

Uveitis 02

(0.8%)1

(0.4%)§0 0 1 (0.7%)‡

Rheg. Retinal Detachment

0 0 0 1(0.7%)§ 1(0.7%) 0

Retinal Tear 01

(0.4%)1 (0.4%) 0 0 0

Vitreous Hemorrhage 01

(0.4%)1 (0.4%) 0

1 (0.7%)

0

APTC* ATEs

*Antiplatelet Trialists’ Collaboration. BMJ. 1994 Jan 8;308(6921):81-106

MARINA ANCHORRanibizumab Ranibizumab

Sham

(n=236)

0.3 mg

(n=238)

0.5 mg

(n=239)

PDT

(n=143)

0.3 mg

(n=137)

0.5 mg

(n=140)

Vascular Death 01

(0.4%)1 (0.4%) 1 (0.7%)

1 (0.7%)

2 (1.4%)

NonfatalMyocardial Infarction

1 (0.4%)1

(0.4%)1 (0.4%) 1 (0.7%)

1 (0.7%)

3 (2.1%)

NonfatalIschemic Stroke

1 (0.4%)1

(0.4%)3 (1.3%) 1 (0.7%)

1 (0.7%)

1 (0.7%)

Nonfatal Hemorr. Stroke

0 0 0 0 0 0

Total 2 (0.8%)3

(1.3%)5 (2.1%) 3 (2.1%)

3 (2.2%)

6 (4.3%)


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APTC* ATEs

*Antiplatelet Trialists’ Collaboration. BMJ. 1994 Jan 8;308(6921):81-106

Pooled MARINA and ANCHORRanibizumab

Control

(n=379)

0.3 mg

(n=375)

0.5 mg

(n=379)

Vascular Death 1 (0.3%) 2 (0.5%) 3 (0.8%)

Nonfatal Myocardial Infarction

2 (0.5%) 2 (0.5%) 4 (1.1%)

Nonfatal Ischemic Stroke

2 (0.5%) 2 (0.5%) 4 (1.1%)

Nonfatal Hemorrhagic Stroke

0 0 0

Total 5 (1.3%) 6 (1.6%) 11 (2.9%)

lucentis and avastin: a new era in treatment -...

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