Презентация на тему New and Emerging Therapies for Retinal Diseases


Disclosures No financial interests to disclose Dr. Chiu has been a consultant to Alimera Sciences

Слайд 1New and Emerging Therapies for Retinal Diseases
Toufic Melki, M.D.
Richard Chiu, D.O.

Centers of Washington
Locations in Rockville, Arlington, and Georgetown University

Слайд 2Disclosures
No financial interests to disclose
Dr. Chiu has been a consultant to

Alimera Sciences

Слайд 3Outline
I. Diabetic Macular Edema
A. Anti-VEGF therapies
B. Corticosteroids and role of inflammatory

mediators in DR
1. Ozurdex
2. Iluvien
A. Sustained delivery devices
B. Platelet derived growth factor inhibition (anti-PDGF therapy)
C. Gene therapy
D. Complement cascade inhibition
E. Squalamine topical therapy
A. Anti-VEGF therapies and differences with DME, wAMD therapy
B. Corticosteroids
IV. Case presentations

Слайд 4Diabetic macular edema
26 million Americans with diabetes
2 million new cases of

DM diagnosed every year
19% of current diabetics are undiagnosed
About 10% of patients with DM develop DME in their lifetime
72,000 new cases of DME diagnosed each year

Слайд 5Prevalence of diagnosed DM in US adults

Слайд 6Prevalence of diagnosed DM in Maryland adults


0 - 6.3
6.4 – 7.5

– 8.8
8.9 – 10.5
≥ 10.6

Слайд 7Diabetic macular edema
“Standard of care”
Focal/grid laser
Clinically significant diabetic macular edema
Focal/grid laser

decreased 3-year risk of moderate vision loss from 24% to 12%
Visual acuity did not improve

Слайд 8Anti-VEGFS

Слайд 9Ranibizumab(Lucentis) for DME
FDA approved for diabetic macular edema (DME) in August

Monthly injection
0.3 mg dose (different than 0.5 mg used for RVO and AMD)
$1100 per dose (vs $1900 for 0.5 mg)

Слайд 10RIDE and RISE studies
36 month Phase III studies for MONTHLY injection

of ranibizumab
759 patients
VA ranging from 20/40 to 20/320
OCT > 275 microns
Focal laser allowed at 3 months

Слайд 11RISE
Sham group received Lucentis from mo 24-36

24 month data

Not so impressive findings
23% treated patients still had central macular thickness

of ≥ 250 microns
40% had not achieved VA ≥ 20/40

Слайд 14In the real world…
Treatment burden
Patient tolerance
Do we really need to inject

every month?
DRCR-net Protocol I

Слайд 15Aflibercept (Eylea)
FDA approved for diabetic macular edema (DME) in July 2014

mg dose (same as RVO and AMD dose)
Monthly injection x 5 doses, Q 2 months thereafter
$1850 per dose

Слайд 16VIVID (EU and Japan)/VISTA (US) studies
Phase III studies comparing Eylea 2.0

mg MONTHLY and Q2 MONTHS (after 5 initial monthly injections) to sham
VIVID 461 patients, VISTA 466 patients
3 year study
“Rescue” laser given if VA declined >=15 letters at any 1 visit or >= 10 letters in 2 consecutive visits

Слайд 17VISTA

Слайд 18Bevacizumab (Avastin)
$42 per dose for intravitreal
Cost of treatment for colon CA

is $40,000-100,000 annually
Efficacy in wAMD demonstrated to be comparable in CATT study

Слайд 19BOLT study
24 month prospective study for bevacizumab (Avastin)
Mean change in BCVA

(q 6 weeks) +8.6 letters
Laser -0.5 letters
15 letter or more gain
Treatment group 32%
Laser group 4%

Слайд 20DRCR.net Protocol T
NIH sponsored studying comparing 660 patients randomly assigned to

treatment with Eylea, Lucentis, and Avastin
Identical retreatment criteria
AAO 2014
“Teaser” for 12 month data
Eylea treated patients significantly better by 2 ETDRS letters than Lucentis and Avastin treated patients
Eylea treated patients received one fewer injection than Lucentis and Avastin treated patients
Rate of ATE (arteriothromboembolic events) was 2% Eylea, 4% Avastin, 5% Lucentis
Results pending verification prior to publication

Слайд 21Corticosteroids

Слайд 22Corticosteroids
Role of inflammatory cytokines BESIDES VEGF in DR
Anti-VEGF therapy may not

fully address the pathophysiology of DR

Слайд 23Fluocinolone (Iluvien)
Alimera Sciences
Non-biodegradable implant, releases 0.2 mcg/day
3 year duration of effect

rejected by FDA in 2011 citing adverse events (IOP, glaucoma)
In use in several E.U. countries
FDA approval September 2014 for DME previously treated with corticosteroids s significant IOP elevation
Available in US 1st quarter 2015, cost $8000 (?)

Слайд 24FAME study
Two 3 year Phase III studies for Iluvien
15 letter or

more gain
Treatment group 28.5-32.4%
Sham 13.4%
82-88% of phakic patients received cataract surgery
38-42% required IOP lowering meds
4.8-8.1% required glaucoma surgery

Слайд 25Dexamethasone (Ozurdex)
Injectable biodegradable intravitreal implant, 3-6 mo duration of effect
$1300 per

FDA approved for DME June 2014

Слайд 26MEAD study
3 year phase III study
Retreatment allowed q 6 mo
Mean 4.1

injections over 3 year study period
Adverse outcomes
59% treated patients needed cataract surgery (vs 7% in sham group)
41% required IOP lowering medication
0.7% needed glaucoma filtration surgery

Слайд 27MEAD study – pseudophakic/anticipated cataract surgery participants

Слайд 28Corticosteroids
Consider using if/when DME patients are:
Pseudophakic or anticipating cataract surgery

to maintain near monthly follow-up/injections frequently required for anti-VEGF treatment
Poorly responsive or tachyphylactic to anti-VEGF monotherapy

Слайд 29AMD
How far we have come
What do we do (with what we

Where we are going

Слайд 30AMD – How far have we come
Bloch SB, et al. Am

J Ophthalmol 2012; 153: 209-213
Population based observational study, Denmark
Incidence of legal blindness from AMD decreased by 50% from 2000-2010
Most of the decrease occurring after 2006 (i.e. after introduction of anti-VEGF therapy)

Слайд 31AMD – How far have we come
MARINA study
Monthly ranibizumab (Lucentis) injection

x 2 years
+10.7 ETDRS letters
-14.9 letters with sham
-9.8 letters with photodynamic therapy (ANCHOR)

Слайд 32AMD – How far we have come
Phase III study comparing aflibercept

(Eylea) to ranibizumab (Lucentis)
Year 1: Eylea q 8 weeks (after 3 initial monthly doses) vs Lucentis q 4 w
Year 2: PRN with monthly evaluation

Слайд 33AMD – What do we do (with what we have)
2 key

Comparison of bevacizumab (Avastin) with ranibizumab (Lucentis)
Monthly vs PRN dosing of each
24 month results
Monthly dosing favored over PRN
2.4 letters
Switching to PRN after 1 year of monthly injection resulted in -2.2 letters over continued monthly dosing
VA outcomes slightly favor Lucentis (1.4 letters) but was not statistically significant

Слайд 34IVAN (“British CATT”)
2 key questions
Comparison of bevacizumab (Avastin) with ranibizumab

Continuous (monthly) vs discontinuous (PRN)
24 month results (The Lancet, 382: 1258-1267)
Bevazicumab (-1.37 letters) was “neither inferior nor non-inferior to ranibizumab”
Discontinuous (-1.63 letters) was “neither inferior nor non-inferior to continuous”

AMD – What do we do (with what we have)

Слайд 35AMD- What do we do (with what we have)
HARBOR study
Ranibizumab (Lucentis)

mg vs 2.0 mg (“high dose”)
Monthly vs PRN after 3 monthly doses
Retreatment if OCT demonstrated fluid or if VA decreased by ≥ 5 letters
24 month results
No significant difference between 0.5 mg and 2.0 mg dose
In year 2, PRN treated group had similar visual outcomes with average of 9.9 weeks between injections

0.5 mg dose

Слайд 36AMD - Where are we going
Sustained release
Quest for the “Everlasting Gobstopper”

Слайд 37AMD – Where are we going
Encapsulated Cell Technology (Neurotech)
Genetically engineered RPE

cells line which can be modified to produce specified protein
Encapsulated non-biodegradable delivery device
Initial device produced ciliary neurotrophic factor (CNTF) for retinitis pigmentosa and dry AMD
Adaptable to produce all classes of biotherapeutics (anti-VEGF, PDGF, etc.)

Слайд 38Encapsulated cell technology (ECT)

Слайд 39AMD – Where are we going
VEGF receptor decoy (NT-503) –

Affinity for VEGF similar to aflibercept (Eylea)
Phase 1
Dose escalation studies
Double implant vs single
2 line gain with double implant at 10 months
150 micron decrease in central subfield on OCT with double implant vs 50 micron with single
Phase 2 study with new generation implant with 2-3x release rate
Future implants could combine more than 1 therapy (e.g. anti-VEGF + anti-PDGF)

Слайд 40AMD – Where are we going
Nanostructured Tethadur (pSivida)
Implantable silicone porous silicone

Diameter of pores “tuned” to affect sustained release
“Tube of tennis balls”
Faster release with ping pong balls
Slower release with tennis balls
Drug (e.g. Avastin, Eylea, etc) withdrawn from vial and mixed with Tethadur particles
Animal studies – sustained release of bevacizumab for 6 months

Слайд 41Nanostructured Tethadur

Слайд 42AMD – Where are we going
Port delivery system (PDS)
Developed by Genentech

in collaboration with ForSight VISION 4
Subconjunctival implant, placed in pars plana
10 minute procedure
Minimally invasive office based refill procedure
Phase 1 study
Average improvement of 2 lines at 1 year
Average 4-5 refills in 12 months
Phase 2 underway
Higher dose
Goal of 4 month interval

Слайд 43AMD – Where are we going
MicroPump (Replenish)
Drug reservoir chamber
Refill port accessible

with transconjunctival 31 g needle
Intraocular canula releases microdose into vitreous cavity
Phase 1 study

Слайд 44AMD – Where are we going
Beyond VEGF
Anti-Platelet derived growth factor (anti-PDGF)

Therapy/Stem Cell
Topical therapy

Слайд 45Anti-platelet derived growth factor therapy
The problem with anti-VEGF monotherapy
Withdrawal or undertreatment

results in recurrent neovascularization in a vast majority because:
Anti-VEGF treatment decreases vascular permeability…
BUT does not cause regression of the NV complex

Слайд 46Anti-PDGFs

Слайд 47Platelet derived growth factor (PDGF)
What’s in a neovascular complex?
Endothelial cells
“bricks and

Expresses PDGF
Pericyte recruitment
“armor against anti-VEGF”
Promotes endothelial cell survival through chemical signaling
Inflammatory cells

Anti-VEGF therapy

Слайд 48How can we dismantle NV?

Слайд 49PDGF antagonist (E10030), Ophthotech

Слайд 50Combined anti-VEGF/anti-PDGF treatment

Слайд 51Fovista (Ophthotech)
Fovista bound to PDGF
Fovista + Anti-VEGF combination therapy
Pericyte coverage protects

NV complex from anti-VEGF induced disruption

Fovista is injected

Fovista binds PDGF leading to stripping away of pericytes

Regression of NV complex!


Слайд 52Fovista (Ophthotech)
Phase 2 study
24 week endpoint
Comparison of Fovista/Lucentis vs Lucentis monotherapy

letters for combination therapy
+6.5 for Lucentis monotherapy
Development of subretinal fibrosis
10% in combination group
51% in Lucentis monotherapy group
Phase 3 study underway

Слайд 53Anti-PDGF
Also being developed by:
Neurotech using Encapsulated Cell Technology (ECT) implants
MedImmune as

a combination anti-VEGF/anti-PDGF injection with goal of lasting 6 months
REGN2176-3 (Regeneron) combination with aflibercept (Eylea) in Phase 1 studies
DE-120 (Santen) anti-VEGF/anti-PDGF in Phase 1 studies

Слайд 54Gene Therapy

Слайд 55Gene therapy
Therapy in which genetic material is introduced into cells to

effect protein transduction by the cells
Compensate for structurally abnormal or missing genes
Also can be used to induce target host cells to secrete a naturally occurring or engineered therapeutic protein (as alternative to repeated injections)

Слайд 56Gene therapy
Desirable features of viral vectors
Able to introduce and transfer target

cells with cDNA
No activation of immune response
Vector incapable of causing disease
Much of the vector’s genetic material can be replaced by the therapeutic gene
Adeno-associated virus (AAV)

Слайд 57Gene therapy

Слайд 58Gene therapy
Advantages of the eye
It’s small (i.e. low volume, large effect)

Low systemic side effects
Direct delivery of therapy

Слайд 59Ongoing retinal gene therapy trials
Leber’s congenital amaurosis
Stargardt’s disease
Usher syndrome
Retinitis pigmentosa

Слайд 60AAV2-sFlt01
Intravitreal Therapy (Genzyme/Sanofi)
Induces expression of a modified VEGF receptor 1

Preclinical primate models
Binds VEGF with high affinity
Expresses VEGFR1 for at least 18 months after 1 injection

Слайд 61AAV2-sFlt01
Subretinal therapy (Avalanche Biotech)
Phase 1 study (6 pts) treated with low/high

dose plus control arm
2 initial monthly Lucentis injections
Day 380

Слайд 62AAV2-sFlt01

Слайд 63Stem cell transplantation
hESC (human embryonal stem cell)
Pluripotent (any germ layer)
Derived from

human embryos (blastocyst stage) 5 days after feritilization
Results in destruction of embryo
iPSC (induced pluripotent stem cell)
Derived from adult cells
More tumorigenic than ESC (teratoma formation)
Amniotic and cord blood stem cells

Слайд 64hESC
5 Days

Слайд 65Stem cell transplantation
Ocata Therapeutics (formerly Advanced Cell Technology)
Phase 1/2 studies –

primary endpoint of safety and tolerability
Mean 22 months follow up, 3 dose cohorts (50K, 100K, 150K cells)
Human embroynal stem cell (hESC) derived RPE cells
9 pts c Stargardt’s/9 pts c dry AMD (VA ≤ 20/400 in worse vision cohorts and ≤ 20/100 in better vision cohort)
Wills, Bascom Palmer, UCLA

Слайд 66Stem cell transplantation
Safe, well tolerated (i.e. no rejection by immune system

or teratoma formation)
Stargardt’s: HM to 20/800
dAMD: +7 ETDRS letters

Слайд 67Complement cascade inhibition
Geographic atrophy
Loss of macular RPE
Complement cascade hyperactivity (?)
Chronic inflammation/overactivation

of immune system in macula
Complement factor H and I (CFH and CFI) work together to deactivate the cascade that triggers inflammatory response and cell death
Genetic polymorphisms in CFH, CFH are associated with advanced AMD risk

Слайд 68Complement cascade inhibition
Lampalizumab (Genentech)
Inhibits alternative complement cascade by targeting Complement Factor

MAHALO study, Phase 2 study
Sham vs monthly injection
Primary endopoint – change in GA area
Relationships between genetic polymorphisms with treatment assessed
20.4% reduction in GA progression in ALL lampalizumab treated pts
44% reduction in GA progression in pts positive for CFI biomarker
57% of DNA tested pts were CFI+
Phase 3 underway

Слайд 70Topical therapy

Слайд 71Squalamine
Originally derived from dogfish shark liver, now chemically synthesized
Inhibits both

Initial wet AMD trials
Intravenous infusion
Weekly x 4 weeks, monthly thereafter
Effective gains in VA/maintenance of VA
RAPID plasma clearance – posterior ocular therapeutic concentration requires > 1 IV infusion treatments per week

Слайд 72Squalamine eye drops
Ohr Pharmaceutical
Rapid uptake
Trough levels >> threshold to inhibit angiogenesis

2 IMPACT study
9 month data
Topical squalamine/Lucentis injection vs sham/Lucentis injection
Initial Lucentis injection and PRN injection thereafter

Слайд 73Retinal vein occlusion (RVO)
Aflibercept (Eylea)
FDA approved for BRVO, October 2014
FDA approved

for CRVO, September 2012
VIBRANT study, Phase 3

Слайд 74Retinal vein occlusion (RVO)
Similar results for the other anti-VEGFs
Lucentis 0.5 mg


Слайд 75Inflammatory cytokines, VEGF and RVO

Слайд 76Combination treatments
Intravitreal bevacizumab (Avastin)/dexamethasone (Ozurdex)
Maturi, et al. Clin Ophthalmol. 2014; 8:

6 month study
Initial Avastin followed by Ozurdex vs sham
PRN Avastin injection q month

Слайд 77Maturi, et al. Clin Ophthalmol. 2014; 8: 1057–1064

Слайд 78Conclusions
Most patients with wet AMD, DME, RVO can now benefit from

effective and proven treatments
Many patients still fall through the cracks
Poorly responsive
Overall burden of treatment
Knowledge is power

Слайд 79DME

+ 1 year
+ 2 years
+ 3 years
63 y.o. female with DM2

monthly Avastin injection
Subtenons kenalog injection
IVA q2 months
STK q 3-4 months

Слайд 80

67 y.o. male with DM2
Initial monthly Avastin injection
Subtenons kenalog injection
Retreated PRN

q 2-4 months
STK q 3-4 months


+ 1 year

+ 2 years





Слайд 81CRVO
56 year old male with BRVO
Did not show for scheduled Avastin

injection for 1 month







+ 1 month

+ 2 months

Слайд 82CRVO
46 y.o. male with CRVO
Initial observation no edema

2 months
4+ months

#2 + STK


5+ months






6+ months

7+ months

Слайд 83wAMD
77 y.o. female with classic CNVM

Слайд 84wAMD
1 month
2 months
3 months

Слайд 85Thank you

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