lucentis and avastin: a new era in treatment -...
Post on 27-Jul-2018
213 Views
Preview:
TRANSCRIPT
rhuFab V2 Investigator Slide Set - TMc
TMc 2003-08 11/16/2015 10:14:06 AM 1
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:
Abdhish R. Bhavsar, MD
-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
rhuFab V2 Investigator Slide Set - TMc
TMc 2003-08 11/16/2015 10:14:06 AM 2
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
rhuFab V2 Investigator Slide Set - TMc
TMc 2003-08 11/16/2015 10:14:06 AM 3
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
rhuFab V2 Investigator Slide Set - TMc
TMc 2003-08 11/16/2015 10:14:06 AM 4
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
rhuFab V2 Investigator Slide Set - TMc
TMc 2003-08 11/16/2015 10:14:06 AM 5
• 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
Abdhish R. Bhavsar, MD
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)
Ranibizumab0.5 mg(n=240)
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)
rhuFab V2 Investigator Slide Set - TMc
TMc 2003-08 11/16/2015 10:14:06 AM 6
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
rhuFab V2 Investigator Slide Set - TMc
TMc 2003-08 11/16/2015 10:14:06 AM 7
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
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
% 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
Ranibizumab 0.3 mg (n=238)Ranibizumab 0.5 mg (n=240)
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
Ranibizumab 0.3 mg (n=238)Ranibizumab 0.5 mg (n=240)
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
Ranibizumab 0.3 mg (n=238)Ranibizumab 0.5 mg (n=240)
Sham (n=238)
17.6 letter difference*
16.9 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
21.4 letter difference*
20.3 letter difference*
+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
Secondary Endpoint:Mean Change in Visual Acuity Over Time
Note: Vertical bars are ± one standard error of the mean.
*P<0.0001(Rounded values)
Sham (n=238) Ranibizumab 0.5 mg (n=240)Ranibizumab 0.3 mg (n=238)
rhuFab V2 Investigator Slide Set - TMc
TMc 2003-08 11/16/2015 10:14:06 AM 8
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.
rhuFab V2 Investigator Slide Set - TMc
TMc 2003-08 11/16/2015 10:14:06 AM 9
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
rhuFab V2 Investigator Slide Set - TMc
TMc 2003-08 11/16/2015 10:14:06 AM 10
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
Ranibizumab0.3 mg(n=140)
Ranibizumab0.5 mg(n=140)
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)
Ranibizumab0.3 mg(n=140)
Ranibizumab0.5 mg(n=140)
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)
Ranibizumab0.3 mg(n=140)
Ranibizumab0.5 mg(n=139)
%*%*
% o
f S
ubje
cts
%
rhuFab V2 Investigator Slide Set - TMc
TMc 2003-08 11/16/2015 10:14:06 AM 11
% o
f S
ubje
cts
5.6
35.740.3
0
10
20
30
40
50
60
70
80
90
100
PDT(n=143)
Ranibizumab0.3 mg(n=140)
Ranibizumab0.5 mg(n=139)
%*%*
%
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)
Ranibizumab0.3 mg(n=140)
Ranibizumab0.5 mg(n=140)
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
Secondary Endpoint:Mean Change in Visual Acuity Over Time
ET
DR
S le
tter
s
Note: Vertical bars are ± one standard error of the mean.
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
Note: Vertical bars are ± one standard error of the mean.
Secondary Endpoint:Mean Change in Visual Acuity Over Time
+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)
Ranibizumab0.3 mg(n=140)
Ranibizumab0.5 mg(n=140)
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)
Ranibizumab0.3 mg(n=140)
Ranibizumab0.5 mg(n=139)
% †
%*%
Other Visual Outcome:≥30 Letter Gain from Baseline at Month 12
*P =0.0018 vs. PDT†P <0.0001 vs. PDT
rhuFab V2 Investigator Slide Set - TMc
TMc 2003-08 11/16/2015 10:14:06 AM 12
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)
Ranibizumab0.3 mg(n=140)
Ranibizumab0.5 mg(n=139)
% 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)
Ranibizumab0.3 mg(n=137)
Ranibizumab0.5 mg(n=140)
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
rhuFab V2 Investigator Slide Set - TMc
TMc 2003-08 11/16/2015 10:14:06 AM 13
• 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
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
*Antiplatelet Trialists’ Collaboration. BMJ. 1994 Jan 8;308(6921):81-106.
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
rhuFab V2 Investigator Slide Set - TMc
TMc 2003-08 11/16/2015 10:14:06 AM 14
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
rhuFab V2 Investigator Slide Set - TMc
TMc 2003-08 11/16/2015 10:14:06 AM 15
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
Diabetic RetinopathyAvastin
• 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 RetinopathyAvastin
• 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
rhuFab V2 Investigator Slide Set - TMc
TMc 2003-08 11/16/2015 10:14:06 AM 16
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 RetinopathyLucentis
• 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 RetinopathyLucentis
• 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
rhuFab V2 Investigator Slide Set - TMc
TMc 2003-08 11/16/2015 10:14:06 AM 17
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.
rhuFab V2 Investigator Slide Set - TMc
TMc 2003-08 11/16/2015 10:14:06 AM 18
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
rhuFab V2 Investigator Slide Set - TMc
TMc 2003-08 11/16/2015 10:14:06 AM 19
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
rhuFab V2 Investigator Slide Set - TMc
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)
rhuFab V2 Investigator Slide Set - TMc
TMc 2003-08 11/16/2015 10:14:06 AM 21
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
rhuFab V2 Investigator Slide Set - TMc
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)
Ranibizumab0.3 mg(n=140)
Ranibizumab0.5 mg(n=139)
%*%*
% 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)
Ranibizumab0.3 mg(n=238)
Ranibizumab0.5 mg(n=240)
%†%†
%
MARINA ANCHOR
Note: Vertical bars are ± one standard error of the mean.
Secondary Endpoint:Mean Change in Visual Acuity Over Time
* 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)
Ranibizumab 0.3 mg (n=140)
Ranibizumab 0.5 mg (n=139)
-9.5
+8.5
+11.3
17.7 *letter benefit
17.0 *letter benefit
18.0 *letter benefit
20.8 *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%)
rhuFab V2 Investigator Slide Set - TMc
TMc 2003-08 11/16/2015 10:14:06 AM 23
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%)
top related