1. health and fitness
2. disease

Age Related Macular Degeneration:
Overview of AMD



Update on Established Treatments and Evolving Therapies
and Evolving Therapies

Impact
Classification –
Classification – Dry and Wet
Pathophysiology
Treatment for Wet
What drug?
What
drug?
What interval?
 Is treatment effective? Making the decision to treat


Polly A. Quiram MD, PhD
Vitreoretinal Surgery, PA
VRS Update
Saturday, Jan 31st 2015


Treatment for Dry
Novel therapies you will hear about
AMD Classification
Age‐related Macular Degeneration (AMD)




Two main types of AMD
 Dry = ~ 90% of those affected
#1 cause of blindness in those >65 years old
#1 cause of blindness in those >65 years old
This group expected to grow most rapidly in the This group expected to grow most rapidly in the next 30 years
next 30 years Large % of Medicare $ spent fighting this disease
 Vision loss due to atrophy
 ~10% of those with severe vision loss
 Wet = ~ 10% of those affected
 Vision loss from bleeding and leakage from abnormal blood vessels  ~90% of those with severe vision loss
Dry AMD with Atrophy
AMD Possible Risk Factors
Dry AMD with Drusen

Non‐‐modifiable
Non
Genetic
Gender –– female
Gender  Age


WetAMD with heme, fibrosis

Modifiable
Diet – low anti‐
Diet –
low anti‐oxidant intake
Cigarette smoking Cigarette smoking –– 4x
 Physical activity/obesity


Vision not affected
1
AREDS II Results



Wet AMD: Why does this happen?
Lutein (10mg)/Zeaxanthin
(10mg)/Zeaxanthin (2mg)
No beta‐‐carotene
No beta
No additive improvement with omega 3
Development of CNV

CNV is more than a vascular disease‐ complicated process

CNV is a complex process that also involves nonvascular components  RPE cells
 Macrophages and other inflammatory cells
p g
y
 Myofibroblasts


Oxidative Stress may contribute to CNV
Oxidative Stress
Involves components of wound healing response

Inflammation

Angiogenesis

Fibrosis

Drusen accumulate between Bruch´s membrane and RPE: 
Abnormalities in complement cascade also involved –
CHF and ARMS2 genetic markers


CNV Progression
Complement deposition with loss of complement regulation
Oxidative and inflammatory processes
Blood‐retina barrier break down
AMD Treatment Options
Oxidative Stress
Lampa
Inflammatory Mediators
and Proangiogenic Cytokines
VEGF
Fovista
Inappropriate Vessel Growth

There is currently no true cure for macular degeneration
Exudation and Hemorrhage
Discoid Scar Formation
Bainbridge JW et al. Clin Sci. 2003;104:561-575.
Schlingemann RO. Graefes Arch Clin Exp Ophthalmol. 2004;242:91-101.
Ferris FL III et al. Arch Ophthalmol. 1984;102:1640-1642.
Ambati J et al. Surv Ophthalmol. 2003;48:257-293.
2
Wet AMD: Anti‐VEGF Agents
Treatment for Wet

What drug?
VEGF: vascular 
Avastin
endothelial growth factor

Lucentis
g
Controls growth of abnormal blood vessels in 
Eylea



What interval?
wet AMD

Inhibiting VEGF prevents 
Monthly – fixed interval
Monthly –
PRN
 Extend and treat
and targets newly formed 
blood vessels
What if it doesn’t work

Switch therapies
Ranibizumab (Lucentis™) Bevacizumab (Avastin®)
What drug?








Anti-VEGF-A
Murine Mab
VIEW
IVAN
HARBOR
ANCHOR
7 up
PRONTO
CATT
LUCAS
(~150 kDa)
Lucentis
(ranibizumab)
(48 kDa)
Affinity
maturation
(140x)
Insertion of murine
anti-VEGF-A
sequences into a
full-length human
IgG framework
Humanization
Avastin
(bevacizumab)
(149 kDa)
Presta, LG, 1997. Cancer Res.57:4593; Chen Y. 1999 J.Mol. Biol.293:865
Comparison of AMD Treatments Trials (CATT)
Lucentis‐Avastin Trial
Ranibizumab (Lucentis)
0.5 mg (n=240)
Sham (n=238)
15
+6.6*
10
5
0
Humanization
rhu Fab
V1
Insertion of murine
anti-VEGF-A
sequences into a
human FAb
framework
Mean Change in VA over Time
ETDRS
S letters

2
4
6
8
10
12
14
16
18
20
22
24
21.4
letter
benefit *
P<0.01
-5
Patients treated with Lucentis and
Avastin have identical visual outcomes
-10
−14.9
-15
Month
Note: Vertical bars are ± one standard error of the mean.
Supported by Cooperative Agreements from the National Eye Institute, National Institutes of Health, DHHS
3
Change in Visual Acuity‐ GEE Model
Eylea ‐ Aflibercept
All Groups All Groups ––Averaged over Weeks 12 ,24, 36, 52
15
Lucentis Monthly
Avastin Monthly
Lucentis PRN
Avastin PRN
Le
etters
10
7.2
7.3
6.4
6.1
(0.7)
(0.8)
(0.6)
(0.7)
1
2
3
4
5
6
7
8.5
+8.5
8.0
+8.0
6.8
+6.8
5.9
+5.9
5
1
2
3
4
5
6
7
 Fusion protein of key domains from
human VEGF receptors 1 and 2 with
human IgGFc
Fc
VEGF Trap
Kd < 1 pM
 Blocks all VEGF-A isoforms and
placental growth factor (PlGF)
 High affinity - binds VEGF-A and
PlGF more tightly than native
receptors
 Binds VEGF between its arms
without risk of complex formation
0
0
4
8
12
16
20
24
28
32
36
40
44
48
52
VEGFR-1
Kd 10-30 pM
Week
 Intravitreal aflibercept is specially
purified and formulated to be isoosmotic for intravitreal injection
VEGFR-2
Kd 100-300 pM
Equivalent, prn 4-5 fewer injections, more eyes completely dry with Lucentis, no SS diff SAEs
Proportion of Patients Who
Gained > 15 letters* at Week 52
Mean Change in Visual Acuity
10.9* 2q4
10
8
6
4
8.1
7.9†
6.9†
Rq4
2q8
0.5q4
9.7†
94
9.4
8.9†
7.6†
0.5q4
R 4
Rq4
2q8
2q4
VIEW 1 (n=1210)
2
0
0
4
8
12
16
20
24
28
32
36
40
44
48
52
12
10
8
6
4
VIEW 2
2
(n=1202)
0
0
4
8
12
16
20
24
28
32
36
40
44
48
52
9.3
8.7
8.4
8.3
Integrated
(n=2412)
LOCF; Full analysis set; *P = 0.0054 vs. Rq4 †P = NS vs. Rq4
2q4
Rq4
2q8
0.5q4
Minor intergroup differences
are not reproduced between
studies
VIEW 1
VIEW 2
Integrated
Proportion of Patients
E
TD
R
Sletters
12
RBZ
0.5q4
IAI
2q4
IAI IAI
0.5q4 2q8
RBZ
0.5q4
IAI
2q4
IAI IAI
0.5q4 2q8
RBZ
0.5q4
IAI
2q4
IAI
0.5q4
IAI
2q8
*Compared to baseline; LOCF; Full Analysis Set
Wet AMD: Lucentis efficacy

Anti VEGF efficacy (Lucentis/Avastin/
Lucentis/Avastin/Eylea
Eylea):
):
25‐40% visual 25‐
40% visual improvement
improvement
 >90% visual >90% visual stabilization
>90% visual stabilization
 Best treatment to Best treatment to date
date

If all are the same, why not just use Avastin?
Different mechanism of action
4
Avastin vs Lucentis vs Eylea

Cost






Monthly
PRN
Extend and Treat
Reduce risk of endophthalmitis
Prevent additional damage due active CNVM
 Reduce vision loss secondary to possible VEGF related atrophy

diminished therapeutic response to a drug following repeated administration over time



Insurance coverage
Access to safely compounded Avastin
Efficacy
Efficacy in certain ARMD subtypes
in certain ARMD subtypes
Tachyphylaxis

What interval?

Retina. Jun 2009; 29(6): 723––731. Retina. Jun 2009; 29(6): 723
Durability?
The PrONTO Study
Visual Acuity Results at Month 12 (N=40)
Number o
of Letters Gained
“If I want to avoid recurrences, why not just inject monthly”
Day 14
Mean + 6 letters
p< 0.001
Month 12
Mean +9.3 letters
p< 0.001
Mean
Median
0
1
2
3
4
5
6
7
8
9
10
11
12
Months Since Initial Injection
Fung et al. AJO 2007;143(4):566-583
Marina/Anchor – 12 injections, PRN – mean of 6 injections
Change in Visual Acuity‐ GEE Model
LUCAS
All Groups All Groups ––Averaged over Weeks 12 ,24, 36, 52
15
Le
etters
Lucentis Monthly
Avastin Monthly
Lucentis PRN
Avastin PRN
10
7.2
7.3
6.4
6.1
(0.7)
(0.8)
(0.6)
(0.7)

8.5
+8.5
8.0
+8.0
6.8
+6.8
5.9
+5.9
5




0
0
4
8
12
16
20
24
28
32
36
40
44
48
52
Treat and extend protocol validated with Level 1 evidence

Monthly until dry, extend by 2 weeks until 3 months
Lucas‐ extend and treat, +8 letters
Lucas‐
Anchor –– monthly, Anchor monthly, lucentis
lucentis +10 letters
Ivan‐‐ monthly,PRN
Ivan
monthly,PRN, , lucentis
lucentis, , avastin
avastin +7
+7‐‐8
CATT ‐‐ Monthly, PRN, CATT Monthly, PRN, lucentis
lucentis, , avastin
avastin +6
Week
January 2015 Volume 122, Issue 1, Pages 146–
146–152
Equivalent, prn 4-5 fewer injections, more eyes completely dry with Lucentis, no SS diff SAEs
5
LUCAS
Evidence


CATT, IVAN, 7 UP –
CATT, IVAN, 7 UP – progression of dry component of ARMD with long term treatment
CATT and IVAN
CATT and IVAN
Pts that underwent monthly injections Pts that underwent monthly injections –– more atrophy than atrophy than prn
prn group
 1/3 pts increase in atrophy  Majority of pts with gradual, sustained visual loss

January 2015 Volume 122, Issue 1, Pages 146–152
Percent with Geographic Atrophy
Percent with Geographic Atrophy
Geographic Atrophy
Same Regimen for 2 Years
Baseline
Week 104
33
34
Atrophy following anti‐VEGF



?disease process
?Macular atrophy associated with CNVM
?Anti VEGF

Increased atrophy with monthly vs prn
Increased atrophy with monthly vs prn
dosing
Risk for GA in CATT trial Ophthalmology, 2014
36-107 000 104
Management of ARMD




One dosing strategy or drug is not appropriate for every patient
“Customizable therapy”
“C
i bl h
”
Based on experience of treating thousands of patients
What drug/overtreat
What drug/
overtreat//undertreat
undertreat/stop?
/stop?
6
20/100 20/25
Cases

Case 1 –
Case 1 – 67 year old recently retired male presents with loss of vision OD

Dr. X is doing these injections. Can I get my injections with him?


Patient returns 1 year later
Loss of vision OS
Patient returns with end stage scar OD

Patient now wit h high risk PED OS 20/25

Patient returns with end stage scar OD
7
Recommendation






Returns 1 year later
Patient with high risk ARMD OS
Disciform scar OD
Requires close monitoring
RTC 2 months or sooner if changes


Presents with loss of vision OS
s/p 3 avastin
s/p 3 avastin injections with injections with Dr.X
Dr.X – sent for emergency referral, 20/100
Now Disciform scar OD, poor vision with active lesion OS active lesion OS –– Avastin in not working!
Switch to Switch to Eylea
Eylea

20/20
Pt getting monthly Eylea, increase in SRF when extends to q5weeks
Case 2

I saw Dr. X for glasses. He did the same scan in the office and says I don’t need these injections anymore.




82 year old woman with bilateral active CNVM s/p avastin
CNVM s/p avastin X 25
20/25 OU
W
Worsening despite monthly injections‐
Worsening despite monthly injections
i d
i
hl i j i
‐
tachyphylaxis
Switch to Eylea
Switch to Eylea
Wet ARMD has periods of quiescence/activity
Some patient require hypervigilant monitoring/aggressive treatment
8



Vision declined to 20/30
following 3 monthly
injections of avastin
Doing well on Eylea
Doing well on Eylea
Insurance changes terms Insurance changes terms –– pt now has 20% copay and doesn’t qualify for assistance program
Wants to switch back to Avastin
3 monthly injections of
avastin
VA declined to 20/40
Case 3

Stable for two months on Avastin, but then significantly worsens



OD – 20/25 OD –
20/25 ‐‐‐‐‐
‐‐‐‐‐20/30
20/30
OS – 20/25
OS –
OS 20/25‐‐‐‐‐‐
‐‐‐‐‐‐20/40
20/40


79 year old author/medical malpractice lawyer treated with lawyer treated with avastin
avastin q4
q4‐‐6 weeks
20/25 OD, 20/200 OS
Now has secondary insurance that covers Eylea
Not every drug works for every patient, tailor management
9


Significant worsening despite monthly treatment with Avastin
Switch to Switch to Eylea
Eylea



Stable with q4‐6 week Stable with q4‐
6 week Eylea
Eylea
Relatively quiescent disease
If develops more active disease ‐‐ decrease If develops more active disease i
interval
l
Treatment of Wet ARMD summary



It is complicated!
One dosing strategy or drug is not appropriate for every patient
i
f
i
“Customizable therapy”
Periods of inactivity/activity
Patients can have very poor outcomes without close monitoring
CNV Progression
Oxidative Stress
Lampa
Inflammatory Mediators
and Proangiogenic Cytokines
W at is o t e o i o ?
What is on the horizon?
VEGF
Fovista
Inappropriate Vessel Growth
Exudation and Hemorrhage
Discoid Scar Formation
Bainbridge JW et al. Clin Sci. 2003;104:561-575.
Schlingemann RO. Graefes Arch Clin Exp Ophthalmol. 2004;242:91-101.
Ferris FL III et al. Arch Ophthalmol. 1984;102:1640-1642.
Ambati J et al. Surv Ophthalmol. 2003;48:257-293.
10
Clinical Trials in the Pipeline‐ Drugs you will be hearing about…..

“Extended release” medications for wet ARMD
Ophthotech – “Fovista” – Anti ‐PDGF

Dry ARMD – trials ongoing


Acucela‐ emixustat – modulate visual cycle, decrease A2E (toxic fluorophores) accumulation
Lampalizumab – anti‐factor D, Mahalo decrease 20%
Fovista + anti‐VEGF



Monotherapy with Anti‐
with Anti‐VEGF may not be adequate
Chronic treatment results in maturation of CNVM ––
Chronic treatment results in maturation of CNVM pericytes
Combination treatments alters NV
 Anti Anti ‐‐ PDGF
PDGF‐‐B/PDGFR
B/PDGFR‐‐β –
β – strip strip pericytes
pericytes
 Anti
Anti‐‐VEGF VEGF –– regression of neovascularization g


Now pericyte
Now pericyte‐‐deficient vessels are more permeable and susceptible to anti‐VEGF therapy
and susceptible to anti‐
Decrease scarring and atrophy
MDRTC‐ Macular Degeneration Research and MDRTC‐
Treatment Center
Penfold PL et al. Clin Exp Immunol. 2000;121:458-465.
Kaiser PK. Curr Med Res Opin. 2005;21:705–713.
Clinical Trials in the Pipeline‐ Drugs you will be hearing about…..

Abicipar – DARPin (Allergan
Allergan))
Engineered mimetic protein, high affinity
REACH study



DRY ARMD Trials



Conbercept
C b
t – “Lumitin
L iti ”
Lumitin”
Higher affinity anti
Higher affinity anti‐‐ VEGF
 PHOENIX trial PHOENIX trial –– approved in China


Lampalizumab (anti‐factor D): Selective inhibitor of the alternative complement pathway
Classical pathway
C1q
Alternative pathway
C3
MBL pathway
fD
Amplification
C3a
Inflammation
Bb
C2a
C3b
AFD
fB
fH
C4b
C3b
C5
C5a
Inflammation
MAC*
C5b
Bb
C2a
C3b
C3b
C4b
C3b
fH
AFD
fB
fD
Molecule

Fab of a humanized monoclonal antibody

Targets ccomplement factor D of the Targets alternative pathway
Wet AMD: It’s complicated!

Wet ARMD is chronic disease with periods of Target

Complement factor D is a rate‐‐limiting Complement factor D is a rate
enzyme in the alternative pathway and y
p
y
present in relatively low abundance
Scientific Rationale

Genetic polymorphisms in alternative complement pathway proteins are associated with the risk of AMD

Complement hyperactivity has been implicated in AMD
No animal models
Preserve the RPE, photoreceptors and choroid by modulating the immune system
Genetic associations ‐‐ ARMS2, CFH: modulate the Genetic associations complement system
complement system
Lampalizumab‐‐ antifactor D
Lampalizumab
quiescence and activity

Detect it early

Complex management strategies to avoid overtreat//undertreat
overtreat
*Membrane Attack Complex
11
AMD Classification
•
Two main types of AMD


• Dry • Wet+Dry
• ALL ARMD is Dry!
•
Summary


All ARMD is DRY
There is no “cure” Complex disease process involving complex treatment strategies to maintain vision in i
i i i i i
patients over the long term
Evolving treatments for ARMD promising
Progressive atrophy despite successful treatment of CNVM Thank you!
Thank you!
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