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Bandello pharmacological treatment of vitreo macular traction
1. Pharmacological Treatment of
Vitreo-Macular Traction
Francesco Bandello, MD, FEBO Lorenzo Iuliano, MD
Department of Ophthalmology
University Vita-Salute
San Raffaele Scientific Institute
Milan, Italy
3. • 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
4. 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 2010
Schneider EW et al. Clin Ophthalmol 2011
Sebag J. Graefes Arch Clin Exp Ophthalmol 2004
Hollands H et al. JAMA 2009
5. 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 2004
Dugel P. Retina Today 2012
10. Natural History
Carpineto P et al. Eur J Ophthalmol 2011
Guyer DR et al. Arch Ophthalmol 1992
Hikichi T et al. Br J Ophthalmol 1995
Kim JW et al. Am J Ophthalmol 1996
VMAVMA
Total PVDTotal PVD Spontaneous
resolution
FTMH
3–12%
spontaneous
closure
VMA, VMT
non full thickness MH non FTMHnon FTMH
50–84%
PVD
11. • 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
12. The idea
• Standard of care:
• “Watchful waiting”
• Vitrectomy
• Alternative:
• Pharmacologic vitreolysis
13. • Pharmacological vitreolysis was defined by J Sebag
“Weaken or cleave V-R junction before or concurrently
with liquefaction of core vitreous”
• First animal experience of enzymatic vitreolysis are of 1998
Pharmacologic vitreolysis
Sebag J. Retina 1998
Sebag J. Retina 2009
14. • Several agents have been tested to achieve vitreolysis
• Classified accordingly to their biological effect
Different agents
Bandello F et al. Ophthalmologica 2013
15. • 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
16. • 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)
17. • 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 1998
Wu WC et al. Am J Ophthalmol 2007
Tsukahara Y et al. Am J Ophthalmol 2007
Wu WC et al. Retina 2008
Wu WC et al. Retina 2007
Trese MT et al. Am J Ophthalmol 2000
Rizzo S et al. Retina 2006
Sakuma T et al. Eur J Ophthalmol 2005
Asami T et al. Ophthalmology 2004
Azzolini et al. Am J Ophthalmol 2004
Sakuma T et al. Eur J Ophthalmol 2006
Hirata A et al. Sakuma T et al. Retina 2006
Udaondo P et al. Arch Ophthalmol 2011
Codenotti M et al. Eye 2013
18. Codenotti M et al. Eye 2013
intravitreal APE
7 days
30 days
Surgery
24h
19. 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 2007
de Smet et al. IOVS 2009
20. • 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
21. • 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.
22. 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
23. 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
24. p<0.001
p=0.113
VMA resolution at day 28 according to adhesion size
Ocriplasmin
Placebo
n= 123 314 41 102
Patientswith
resolutionofVMA(%)
ThromboGenics NV. JETREA (ocriplasmin) Summary of Product Characteristics. 2013
Post-hoc studies
25. N=35
N=86
N=33
N=98
N=68
N=184
Study 006 Study 007 Study 006 Study 007 Combined
data
N=72
N=128
N=47
N=142
N=119
N=270
Epiretinal membrane No epiretinal membrane
p<0.001
p<0.001
p=0.046
p=0.180
p=0.289
p<0.003
Combined
data
VMA resolution at day 28 according to epiretinal membrane presence
Stalmans P et al. NEJM 2012
26. N=35
N=86
N=33
N=98
N=68
N=184
Study 006 Study 007 Study 006 Study 007 Combined
data
N=72
N=128
N=47
N=142
N=119
N=270
Epiretinal membrane No epiretinal membrane
p<0.001
p<0.001
p=0.046
p=0.180
p=0.289
p<0.003
Combined
data
VMA resolution at day 28 according to epiretinal membrane presence
Stalmans P et al. NEJM 2012
28. p<0.001
n = 4 28 5 28
Day 28 6 Months
>250 µm
p=0.002
p=0.200p=0.031
n = 1 14 3 14
%Patients
%Patients
Day 28 6 Months
≤250 µm
Non-surgical MH closure at day 28 according to MH size
Stalmans P et al. NEJM 2012
29. • 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
30. • Focal VMT
• Symptomatic VMA
• Non full thickness macular hole
• Full thickness macular hole <400 µm
Actual indications
31. 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
32. 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
33. 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 2014
Fahim AT et al. JAMA Ophth 2014
• Judicious use
• Careful follow-up
Phase IV studies
34. • 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
35. 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