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Pharmacological Treatment of Vitreo-Macular Traction
Francesco Bandello, MD, FEBO Lorenzo Iuliano, MD
Department of OphthalmologyUniversity Vita-Salute
San Raffaele Scientific InstituteMilan, Italy
Financial DisclosureAdvisory Board Member for:• Alcon• Alimera• Allergan• Bausch and Lomb• Bayer• Genentech• Hossmann-La Roche• Novagali Pharma• Novartis• Pfizer• Sanofi-Aventis• Thea• Thrombogenics
• Vitreomacular adhesion– perifoveal hyaloid detachment with no detectable change in foveal
contour or underlying retinal tissues
• Vitreomacular traction– perifoveal hyaloid detachment associated with distortion of the foveal
surface, intraretinal structural changes, retinal elevation above the RPE, but no full-thickness interruption of all retinal layers
Definition
Physiologic PVD• PVD is the separation of the posterior vitreous from the ILM
• Processes involved– Synchysis
– Syneresis
– Weakening of the V-R adhesion
• PVD can be asymptomatic, although some patients report floaters
Early liquefaction Extensive liquefaction Separation
Johnson MW. Am J Ophthalmol 2010Schneider EW et al. Clin Ophthalmol 2011
Sebag J. Graefes Arch Clin Exp Ophthalmol 2004Hollands H et al. JAMA 2009
Anomalous PVD
• Sufficient weakening at the V-R interface when the critical level of liquefaction has been achieved
• If not, incomplete (anomalous) PVD can arise
Sebag J. Graefes Arch Clin Exp Ophthalmol 2004Dugel P. Retina Today 2012
Pathophysiology of Anomalous PVD
Stalmans et al. Retina (2013)
Stalmans et al. Retina (2013)
Pathophysiology of Anomalous PVD
• Vitreo-macular traction can coexist with other diseases
Secondary VMT
Bandello F et al. Ophthalmologica 2013
VMT classification
Duker JS et al. Ophthalmology 2013
Natural History
Carpineto P et al. Eur J Ophthalmol 2011Guyer DR et al. Arch Ophthalmol 1992
Hikichi T et al. Br J Ophthalmol 1995Kim JW et al. Am J Ophthalmol 1996
VMAVMA
Total PVDTotal PVD Spontaneous resolution
FTMH3–12%
spontaneous closure
VMA, VMTnon full thickness MH non FTMHnon FTMH
50–84%
PVD
• Only 5% will have 20/50 BCVA or better
• 55–58% will have BCVA of 20/100 or better
• Approximately 40% will have BCVA of 20/200 or worse
• If the FTMH closes (rare), BCVA can recover
• Most patients retain a BCVA of 20/100 to 20/400
Macular Hole Prognosis
AAO Retina Panel (2008)Preferred Practice Pattern®
Idiopathic Macular Hole
The idea
• Standard of care:
• “Watchful waiting”• Vitrectomy
• Alternative:
• Pharmacologic vitreolysis
• Pharmacological vitreolysis was defined by J Sebag
“Weaken or cleave V-R junction before or concurrentlywith liquefaction of core vitreous”
• First animal experience of enzymatic vitreolysis are of 1998
Pharmacologic vitreolysis
Sebag J. Retina 1998Sebag J. Retina 2009
• Several agents have been tested to achieve vitreolysis
• Classified accordingly to their biological effect
Different agents
Bandello F et al. Ophthalmologica 2013
• rtPA: safe only for sub-macular hemorrhages in nvAMD
• Nattokinase: only animal models
• Chondroitinase: no significant biological effect
• Dispase: retinal toxicity, PVR• Hyaluronidase (Vitrase®): no FDA approval, just liquefactant
• Collagenase: retinal toxicity, ILM damage
Bandello F et al. Ophthalmologica 2013
• Most studied agent
• Extracted from patient’s plasma-derived plasminogen
• Action• Non-specific serine-protease
• Degrades fibrin, fibronectin and laminin
• Indirectly increases levels of matrix metalloproteinases
• Safety (histology and electrophysiology) at different concentration (0.03-2 IU)
Autologous Plasmin Enzyme (APE)
• Pediatric population:ROP, X-linked retinoschisis, traumatic macular hole
• Assisting surgery
• Diabetic macular edema
• Retinal vein occlusion
• Vitreo-macular traction
Experience with APE
Margherio AR et al. Ophthalmology 1998Wu WC et al. Am J Ophthalmol 2007
Tsukahara Y et al. Am J Ophthalmol 2007Wu WC et al. Retina 2008Wu WC et al. Retina 2007
Trese MT et al. Am J Ophthalmol 2000Rizzo S et al. Retina 2006
Sakuma T et al. Eur J Ophthalmol 2005Asami T et al. Ophthalmology 2004
Azzolini et al. Am J Ophthalmol 2004Sakuma T et al. Eur J Ophthalmol 2006
Hirata A et al. Sakuma T et al. Retina 2006Udaondo P et al. Arch Ophthalmol 2011
Codenotti M et al. Eye 2013
Codenotti M et al. Eye 2013
intravitreal APE
7 days
30 days
Surgery
24h
Form APE to ocriplasmin
• Recombinant truncated form of the active enzyme
• 1/3 molecular weight
• Retains the catalytic activity
Nagai N et al. J Thromb Haemost 2007de Smet et al. IOVS 2009
• Targets fibronectin, laminin and collagen
• Induces vitreous liquefaction and separation of V-R interface
• Cleanly separate hyaloid from ILM
Form APE to ocriplasmin
Collagen
Laminin, Fibronectin
Collagen
Gandorfer et al. IOVS 2004
• Phase I/II, 60 pts
• Safe
• Well tolerated
MIVI studies
• Phase II, 60 pts
• Best dose of 125 µg
• Capable of PVD inducing
de Smet M et al. Ophthalmology 2009
Stalmans P et al. Retina 2010
Stalmans P et al. NEJM 2012
• Phase III, 652 pts
• Dose of 125 µg
• Superior than sham inj.
The definitive approval
Two multicenter, randomized, double-masked, placebo-controlled, phase III studies
Randomized (N=652)
Ocriplasmin 125 µg (n=464)
Placebo(n=188)
Assessments at baseline, injection day, and Days 7, 14, 28, 90, and 180 after injection
Patients with symptomatic VMA confirmed by optical coherence tomography
Stalmans P et al. NEJM 2012
ocriplasmin placebo
VMT resolution 26.5% 10.1%
PVD induction 13.4% 3.7%
MH closure 40.6% 10.6%
P<0.001 (all)
Stalmans P et al. NEJM 2012
The definitive approval
p<0.001
p=0.113
VMA resolution at day 28 according to adhesion size
Ocriplasmin
Placebo
n= 123 314 41 102
Patie
nts
with
re
solu
tion
of V
MA
(%)
ThromboGenics NV. JETREA (ocriplasmin) Summary of Product Characteristics. 2013
Post-hoc studies
N=35N=86
N=33N=98
N=68N=184
Study 006 Study 007 Study 006 Study 007 Combineddata
N=72N=128
N=47N=142
N=119N=270
Epiretinal membrane No epiretinal membrane
p<0.001p<0.001
p=0.046p=0.180
p=0.289
p<0.003
Combineddata
VMA resolution at day 28 according to epiretinal membrane presence
Stalmans P et al. NEJM 2012
N=35N=86
N=33N=98
N=68N=184
Study 006 Study 007 Study 006 Study 007 Combineddata
N=72N=128
N=47N=142
N=119N=270
Epiretinal membrane No epiretinal membrane
p<0.001p<0.001
p=0.046p=0.180
p=0.289
p<0.003
Combineddata
VMA resolution at day 28 according to epiretinal membrane presence
Stalmans P et al. NEJM 2012
Non-surgical MH closure at day 28 according to MH size
Stalmans P et al. NEJM 2012
p<0.001
n = 4 28 5 28 Day 28 6 Months
>250 µm
p=0.002p=0.200p=0.031
n = 1 14 3 14
% P
atie
nts
% P
atie
nts
Day 28 6 Months≤250 µm
Non-surgical MH closure at day 28 according to MH size
Stalmans P et al. NEJM 2012
• Requirement of vitrectomy at day 180– 17.7% (ocriplasmin) vs 26.6% (sham); p=0.02
• BCVA improvement– >2 lines: 28% (ocriplasmin) vs 17.1% (sham); p=0.003
– >3 lines: 12.3% (ocriplasmin) vs 6.4% (sham); p=0.024
Stalmans P et al. NEJM 2012
• Focal VMT
• Symptomatic VMA
• Non full thickness macular hole
• Full thickness macular hole <400 µm
Actual indications
Side effects
• The difference in the proportion of patients experiencing AEs was driven primarily by those associated with vitreous detachment
• The majority of AEs were transient and mild in severity
Placebo (n=187)
Ocriplasmin (n=465)
p
Any ocular AE, n (%) 100 (53.5) 318 (68.4) <0.001
Any ocular serious AE, n (%) 20 (10.7) 36 (7.7) 0.26
Stalmans P et al. NEJM 2012
Event, n (%)Placebo (n=187)
Ocriplasmin (n=465)
p
Any serious AE 20 (10.7) 36 (7.7) 0.26
Macular hole 16 (8.6) 24 (5.2) 0.15
Retinal detachment 3 (1.6) 2 (0.4) 0.16
Reduced VA 1 (0.5) 3 (0.6) 0.94
Stalmans P et al. NEJM 2012
Side effects
Safety concerns
Kim JE. JAMA Ophth 2014
• ERG abnormalities in 7.8% of pts
• Dyschromatopsia (yellowing vision) in 2% of pts• 1% of these with ERG changes
• Reports of vision loss and panretinal abnormalities
Tibbets M et al. JAMA Ophth 2014Fahim AT et al. JAMA Ophth 2014
• Judicious use
• Careful follow-upPhase IV studies
• Eyes with nvAMD have more than twice chance (OR 2.54) to have concurrent VMT
• Anti-VEGF + ocriplasmin?
Jackson TL et al. Retina 2013
VMT and Neovascular AMD
Conclusion
• “Watchful waiting” of VMT can lead to irreversible retinal damage, cysts and macular hole formation
• Spontaneous separation of VMT occurs rarely
• Vitrectomy indicated if VA loss or disease progression, but surgery is not risk-free
• Pharmacologic vitreolysis may induce VMT resolution and improve vision