Diabetic Retinopathy Clinical Research Network

Report
AAO Media Briefing
AMD Trials and Treatments:
An Evolving Landscape
ABDHISH R. BHAVSAR, M.D.
Chair
1
Financial Disclosures
 Abdhish R. Bhavsar, MD
 Research support - clinical trials: DRCR, Regeneron,
Genentech
2
Agenda
 Abdhish R. Bhavsar, MD: Welcome/Introductions
 Pravin Dugel, MD: Fovista 2b clinical trial results
• Q/A





Abdhish R. Bhavsar, MD: Update CATT and Eylea
Susan Bressler, MD: Cataract sugery/AMD - no inc risk
Paul Mitchell, MD: Cataract surgery/AMD – inc risk
Edwin Stone, MD: Update on genetic testing for AMD
Media Q & A
3
Study Disclosures
• This study does include research
conducted on human subjects
• IRB approval has been obtained for
each of the studies discussed.
V 2.0; Oct 2012
Integrated
VIEW 1
Investigation of Efficacy and Safety of
Intravitreal Aflibercept Injection in Wet
Age-Related Macular Degeneration (AMD)
7
8
Study Design
Multi-center, active controlled,
double masked trial
VIEW 1 N=1217; VIEW 2 N=1240
Patients randomized
1:1:1:1
Intravitreal
Ranibizumab
Aflibercept
Primary endpoint:
Maintenance of Vision
*After 3 initial monthly doses
Dosing through Week 52
Modified quarterly dosing
through Week 96
Secondary endpoint:
Mean change in BCVA
Study Endpoints
PRIMARY
ENDPOINT
• Proportion of patients who maintained
BCVA (%) (losing <15 ETDRS letters
from baseline)
• Mean change in BCVA as measured
by ETDRS letter score from baseline
KEY
SECONDARY
ENDPOINTS
BCVA: Best-Corrected Visual Acuity
• Proportion of patients who gained at
least 15 letters of BCVA from baseline
• Central Retinal Thickness
V 2.0; Oct 2012
Integrated
VIEW 1
Results
Week 52
16
17
18
20
V 2.0; Oct 2012
Integrated
VIEW 1
Results
Week 52 – Week 96
Treatment Schedule
Re-treatment Criteria –
• 12 weeks since previous injection
• New or persistent fluid on OCT
• Increase in CRT of ≥100 μm compared to the lowest previous value
• Loss of ≥5 ETDRS letters from the best previous score in
conjunction with recurrent fluid on OCT
• New onset classic neovascularization
• New or persistent leak on FA
• New macular hemorrhage
Solid = Injection
Outline = Sham
Hatched = Modified Quarterly Dosing
V 2.0; Oct 2012
Integrated
VIEW 1
Safety
Summary
 Aflibercept noninferior to ranibizumab
 Safety and efficacy was similar amongst the
treatment groups
41
Comparison of AMD Treatments
Trials (CATT): Two Year Results
Abdhish R. Bhavsar, MD
for the Comparison of AMD Treatments Trials
(CATT) Research Group
Supported by Cooperative Agreements from the National Eye
Institute, National Institutes of Health, DHHS
46
Objectives
 To determine the relative efficacy and safety
of intravitreal ranibizumab and bevacizumab
for treatment of neovascular AMD
 To determine if less than monthly dosing of
either drug compromises long term visual
outcomes
- Designed as two-year study with
primary outcome at one year
47
CATT Clinical Sites

1185 patients with neovascular AMD enrolled at 43
sites in the United States
48
Enrollment Criteria More Inclusive
than Previous AMD Trials




CNV not required to be subfoveal as long as
center involved by some component such as
SRF, PED, or blood.
Allowed RAP lesions, juxtafoveal, and
extrafoveal CNV
Allowed eyes with VA 20/25-20/320
No limit on size of lesion
49
Enrollment Criteria More Inclusive
than Previous AMD Trials

Allowed eyes with >50% blood. All other entry
criteria had to be met (VA 20/320 or better and can
identify CNV on FA and fluid on OCT)
50
50
CATT Treatment
(Months)
Year 1
0 1
2
3
4 5
6
7
8
Year 2
9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
ranibizumab
Monthly
bevacizumab
Monthly
ranibizumab
PRN
bevacizumab
PRN
}
Retreat if fluid on OCT or
other signs of active CNV
Primary
Endpoint
Final
visit 51
Treatment in PRN Arms

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.
52
CATT Study Drugs
Ranibizumab supplied
locally
similar to patients
outside of the study
Bevacizumab supplied by
CATT repackaged in
glass vials under IND
Mean Change in Visual Acuity
All Groups
54
Mean Change in Total Retinal Thickness Over Time
All Groups
Percent with No Fluid at 1 Year
100%
Lucentis Monthly (n=284)
90%
Percentage of Patients
80%
Avastin Monthly (n=265)
Lucentis PRN (n=285)
Avastin PRN (n=271)
P < 0.001
70%
60%
50%
43.7%
40%
30%
20%
26.0%
23.9%
19.2%
10%
0%
57
Year 1 Adverse Events



No difference between drugs in rates of death,
stroke, or myocardial infarction
Imbalance in total SAE’s (mostly hospitalizations):
24% bevacizumab vs 19% ranibizumab (p=0.04)
SAEs broadly distributed across all organ systems
with differences present in areas not previously
identified as areas of concern in systemic
bevacizumab trials.
58
Questions at End of Year 1





Would ranibizumab and bevacizumab remain
equivalent for visual acuity in Year 2?
Would wider visual acuity differences emerge
between monthly and PRN dosing in Year 2?
Would the fluid differences between treatments
noted in year 1 impact visual acuity with longer
follow-up?
Would switching to PRN dosing after one year of
monthly treatment maintain or adversely effect
vision?
Would important safety differences emerge with
longer follow-up?
59
Two Year Results
60
Patients
 1107 patients alive who continued in Year 2
 All available monthly treated patients in
Year 1 (n=549) were successfully
randomized to monthly or PRN treatment in
Year 2
 Masking remained robust in Year 2 with
identity of assigned drug known to
ophthalmologist in only 66 of 12,645
evaluations (11 patients)
62
Visual Acuity Results
Same Regimen for Two Years
64
Mean Change in Visual Acuity
Same Regimen for Two years
Patients Without 15 Letter Decrease
Same Regimen for 2 Years
66
Anatomical Results
Same Regimen for Two Years
69
PercentSame
with
No
Fluid
on
OCT
Regimen for 2 Years
71
Typical Amount of Residual Fluid
72
PercentSame
with
Geographic
Atrophy
Regimen for 2 Years
73
Effect of Switching to PRN after
One Year of Monthly Dosing
77
Mean Change in Visual Acuity after Week 52
Monthly Always and Switched to PRN
Percent with No Fluid on OCT
Monthly Always and Switched to PRN
81
Percent with Geographic Atrophy
Monthly Always and Switched to PRN
82
Adverse Events
89
Death and APTC Events
ranibizumab bevacizumab
(N=599)
(N=586) Difference
Death
95% CI
P
32 (5.3%) 36 (6.1%)
0.8%
(-1.9%, 3.5%) 0.62
APTC* 28 (4.7%) 29 (5.0%)
0.3%
(-2.2%, 2.8%) 0.89
*Includes nonfatal myocardial infarction, nonfatal stroke, and
vascular deaths
90
Cumulative Proportion with a Systemic
Serious Adverse Event
91
Any Systemic Serious Adverse Event
Drug
Difference
Unadjusted 2-year rates
ranibizumab 190 /599 (31.7%)
bevacizumab
234 /586 (39.9%)
Adjusted Risk Ratio
8.2%
1.30
95% CI
P
(2.8%, 13.6%)
0.004
(1.07, 1.57)
0.009
Regimen
Unadjusted 2-year rates*
Monthly 199 /587 (33.9%)
PRN
225 /598 (37.6%)
Adjusted Risk Ratio
§
3.7%
1.20
*Regimen as originally assigned
§PRN a time dependent covariate in Cox model
(-1.7%, 9.1%)
0.18
(0.98, 1.47)
0.08
92
Systemic Serious Adverse Events
ranibizumab
(N=599)
bevacizumab
(N=586)
Difference (95% CI)
P
Associated
w/ Anti-VEGF*
Yes
45 ( 7.5%)
62 ( 10.6%)
3.1%
(-0.2%, 6.4%)
0.07
No
170 (28.4%)
202 (34.5%)
6.1%
(0.8%,11.3%)
0.02
* Arteriothrombotic events (myocardial infarction, stroke), systemic
hemorrhage, congestive heart failure, venous thrombotic events,
hypertension, vascular death.
93
Ocular Adverse Events


Endophthalmitis – 0.06% (11 /18,509 injections)
- 11 cases (4 ranibizumab, 7 bevacizumab)
- 10 of 11 cases in monthly treatment group; PRN
case had received 22 injections
Pseudo-endophthalmitis
 ranibizumab 1


bevacizumab - 1
Ocular HTN or Glaucoma
 ranibizumab - 15

bevacizumab - 14
94
Dollars
2-Year Drug Cost Per Patient
50,000
45,000
40,000
35,000
30,000
25,000
20,000
15,000
10,000
5,000
0
Lucentis
Monthly
Avastin
Monthly
Lucentis PRN
Avastin PRN
95
Summary





Ranibizumab and bevacizumab were equivalent for visual acuity at
all time points over a 2-year period.
PRN treatment resulted in less gain in visual acuity (-2.4 letters) at 2
years but vision for all groups was similar at end of 2 years.
PRN dosing resulted in mean of 10 fewer injections over 2 years
than monthly dosing. Bevacizumab patients received mean 1.5
more injections than ranibizumab.
More eyes were completely dry on OCT with monthly dosing with
the highest rate in eyes receiving ranibizumab monthly.
More eyes developed geographic atrophy with monthly dosing with
the highest rate in eyes receiving ranibizumab monthly.
97
Summary





PRN groups had more leakage on FA and more
lesion growth than monthly groups.
Switching to PRN after one year of monthly
treatment produced visual and anatomical results
that were similar to PRN-always.
There were no differences between drugs in rates of
death or arteriothrombotic events.
Bevacizumab treated patients had higher rates of
systemic SAEs than ranibizumab treated patients.
The reason for this difference remains unclear given
the lack of specificity to conditions associated with
inhibition of VEGF.
98
Future




Improved drug delivery systems
Treatments for non-exudative AMD
Targeted treatments with combinations of drugs
Better prevention strategies
110
Additional Questions
 Mary Wade, Academy Science and International PR
Manager
 [email protected]
 Cell: 510-725-5677
111
Thank You!
112

similar documents