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Abstract: The vitreous may play an important role in the pathogenesis of various retinal disorders. Pharmacologic vitreolysis uses intravitreal pharmacologic agents to provide liquefaction of the vitreous and complete vitreoretinal separation. Ocriplasmin, a genetically engineered version of plasmin, has been shown in clinical trials to be able to safely release vitreomacular adhesion and close Stage 2 macular holes in a signicant number of patients. Advancements in the development of this safe and effective method of vitreolysis have provided an alternative, nonsurgical treatment option to physicians who manage these patients. A roundtable of clinical investigators convened to discuss and summarize recent progress in pharmacologic vitreolysis. Preclinical studies, and efcacy and safety data from controlled clinical trials of ocriplasmin were presented and discussed. Case studies were then presented to provide an opportunity for experts to reveal their specic thoughts regarding ocriplasmin for the treatment of vitreomacular adhesion and resulting vitreomacular traction and macular holes, based on their own interpretation of current clinical data and experience. RETINA 32:S225S231, 2012

onverging lines of evidence suggest that vitreomacular adhesion (VMA) and associated tractional forces may play a role in a spectrum leading from vitreomacular traction (VMT) to full-thickness macular hole and other sight-threatening conditions.14 With optical coherence tomography, these abnormalities may be identied early in the course of disease.5 Armed with current knowledge, physicians may now have a new tool to preserve vision by the way of pharmacologic vitreolysis. Some of the clinical objectives of pharmacologic vitreolysis include complete vitreoretinal separation resulting in a clean internal limiting membrane, less mechanical manipulation at the vitreoretinal interface (VRI) compared with current vitrectomy techniques, creation of a well-dened cleavage plane at the vitreal side of the internal limiting membrane to remove brocellular traction, provision of better oxygen supply because of an alteration in the molecular ux caused by pharmacologically
From the Retina Service at the Gavin Herbert Eye Institute, Department of Ophthalmology, University of California, Irvine, California. Financial Disclosure: Clinical Research Support: Alimera, Allergan, Genentech, GlaxoSmithKline, Regeneron, ThromboGenics. Dr. Kuppermann is a consultant for Alimera, Allegro, Allergan, Fovea, Genentech, Glaukos, Neovista, Novagali, Novartis, Ophthotech, Pzer, Regeneron, ThromboGenics. Reprint Requests: Baruch Kuppermann, MD, PhD, Retina Service at the Gavin Herbert Eye Institute, Department of Ophthalmology, University of California, Irvine, California; e-mail:

induced vitreous liquefaction, minimization of trauma to the vitreous and retina, and the potential for a preventive treatment regimen for the development of proliferative diabetic retinopathy, age-related macular degeneration, and other retinal disorders.68 Ocriplasmin Ocriplasmin is a truncated form of the human serine protease plasmin that retains proteolytic activity. It targets major components of the VRI, such as bronectin and laminin (Figure 1). Ocriplasmin works via a two-step mechanism involving vitreoretinal separation and vitreous liquefaction.911 Figure 2 shows an example of ocriplasmin-induced pharmacologic vitreolysis in mouse eyes. It also shows the VRI and an induced posterior vitreous detachment (PVD). Another example in a human postmortem eye demonstrated a clean retinal surface after treatment with ocriplasmin (formerly known as microplasmin; Figure 3). In Phase 2 clinical trials, either a single intravitreal injection of 125 mg or 3 monthly repeated intravitreal doses (125 mg) of ocriplasmin were able to induce VMA resolution and were well tolerated.12,13 Pivotal Trials: MIVI-TRUST After extensive preclinical and Phase 2 research, the MIVI-TRUST [MIcroplasmin for Vitreous Injection



Fig. 1. Ocriplasmin has a dual action of liquefaction and separation through its effect on the macromolecules at the VRI. Ocriplasmin exerts proteolytic effects on bronectin, laminin, and collagen brils, breaking protein bonds to resolve VMA.

(MIVI), Traction Release Without Surgical Treatment (TRUST)] program was launched. In these 2 Phase 3 clinical trials evaluating the safety and efcacy of a single 125-mg injection of ocriplasmin in patients with VMA, 2 key subsets of patients were examined:

those with VMT and those with full-thickness macular holes. Patients had to show evidence of VMA on optical coherence tomography, as determined by the central reading center, and the investigator had to conrm that symptoms such as metamorphopsia, distorted

Fig. 2. A histology image showing that ocriplasmin causes the vitreous body to separate from the retina.



Fig. 3. Ocriplasmin induces detachment of the vitreous gel from the retinal surface and liquefaction of the vitreous gel in preclinical studies.

vision, and central visual eld defect were caused by VMA. Highly myopic eyes were excluded. Patients with macular holes .400 mm were excluded as well. Patients with epiretinal membrane were allowed. Mean baseline best-corrected visual acuity was approximately 20/50, and patient age was comparable between the placebo and the ocriplasmin groups. Patients with best-corrected visual acuity of $20/25 were allowed into the study. Patients had a 6-month follow-up. The overall results for eyes with VMT were as follows: 30% of ocriplasmin-treated patients showed resolution of VMA by Day 28, compared with 8% of placebo-treated patients. It should be noted that a 100mL active control was injected into the eye as placebo. The placebo response could be the result of hydrodynamic/mechanical effect exerted by the volume injected into the eye. For VMT patients who had VMA resolution, 41% had a 2-line improvement in visual acuity and 14% had a 3-line improvement in visual acuity.15 Resolution of VMA was typically seen within 7 days of injection. When resolution of VMA occurred, in 70% of the time, it occurred within 7 days, and 100% of the time within 28 days of ocriplasmin injection.15 The following gures describe a patient successfully treated with ocriplasmin in the clinical trial program. Figures 4 and 5 show a 58-year-old woman with VMA. Figure 5

shows Day 7 after ocriplasmin injection; optical coherence tomography reveals traction release. Figure 6 shows Day 28 after injection; PVD was induced. Figure 7 shows Month 6 after injection. Bestcorrected visual acuity in the right eye was 20/20 with continued morphologic improvement. For the macular hole subset, the data were stratied by hole size (250 mm). Fifty-eight percent of eyes with macular holes #250 mm closed within 28 days after a single ocriplasmin injection, compared with 25% of eyes with holes .250 mm. Overall, only 11% of eyes

Fig. 4. Case study: optical coherence tomography and clinical ndings at presentation.



Fig. 5. Case study: optical coherence tomography and clinical ndings at 7 days after ocriplasmin injection.

Fig. 7. Case study: optical coherence tomography and clinical ndings at 6 months after ocriplasmin injection.

with placebo injection had macular hole closure after 28 days.15

Safety Safety data showed that the majority of adverse events were generally mild and occurred in the rst week after treatment (Figures 8 and 9). The most commonly reported adverse events included vitreous oaters, eye pain, photopsia, blurred vision, and decreased vision.14 Three patients experienced temporary signicant visual acuity reduction.15 One patient had visual acuity of 20/25 at baseline; 1 day after injection, it decreased to 20/200, and then 1 month later, visual acuity improved to 20/20. Another patient had visual acuity of 20/80 at baseline, which decreased to hand motion 2 days after injection but improved to 20/60 a month

later. A third patient had visual acuity of 20/50 at baseline, 20/200 at 1 day after injection, and 20/32 after 2 weeks without any other treatment. Figure 10 illustrates one of these cases. At Day 0, VMT was present. At Day 1, the VMT had not yet released, and the subretinal uid was worse. On Day 7, VMT was released, and residual but decreasing subretinal uid was present. The resolution of this process could explain the transient decrease in vision. A higher incidence of retinal tears and detachments occurred in the placebo-treated patients, likely because of an increased rate of vitrectomy (Figure 11).14 Overall, ocriplasmin was very well tolerated and beneted a signicant number of patients in the trial. Importantly, if ocriplasmin did not release VMA, it was still possible to take the patient to the operating room and perform vitrectomy without any apparent additional complications.14 Discussion Brucker: Because you are the last speaker, can I have you address the issue of vitreous liquefaction versus detachment and how you see it in relationship to many of the diseases that we are talking about? Kuppermann: Liquefaction of the vitreous increases the oxygenation of the retina, and oxygen very effectively inhibits and clears vascular endothelial growth factor from the eye. However, vitreous liquefaction does not necessarily remove or alter the mechanical barrier, which is the VRI. Liquefaction achieves many of the goals we are looking for except in situations where there is a mechanical component involved, such as VMT, macular hole, epiretinal membrane, and myopic traction maculopathy. In diseases like diabetes, how much of the retinopathy is due to the

Fig. 6. Case study: optical coherence tomography and clinical ndings at 28 days after ocriplasmin injection.



Fig. 8. The incidence of adverse events for the entire patient population between Day 0 and Day 7.

oxygenation of the vitreous versus the mechanical structure up against the retina? We do not really know yet. In a study we did in Mexico evaluating the role of vitreous liquefaction and PVD induced by Vitrase (ISTA Pharmaceuticals, Irvine, CA) in inhibiting the progression of disease in patients with moderately severe diabetic retinopathy, there was a strong effect of vitreous liquefaction on halting

the progression of diabetic retinopathy without necessarily correlating it to PVD induction. One would theoretically want to have both vitreolytic features, that is, cleave the VRI and liquefy the vitreous. Brucker: So, if you have a rm vitreoretinal adhesion, whether it be in the macula or otherwise, and you cause liquefaction of the vitreous, that will result in traction because the vitreous collapses on itself. It may

Fig. 9. The incidence of adverse events for the entire patient population from Day 8 to the end of study (Month 6).



Fig. 10. Illustrative case: optical coherence tomography at baseline, at Day 1, and Day 7 after ocriplasmin injection.

Fig. 11. Proportion of patients with any retinal tear or retinal detachment.

make things even worse than they already are, or it may mechanically disinsert the vitreous from whatever it is attached to. The alternative is to chemically disinsert by using a lytic agent. Spaide: When you liquefy collagen, maybe you are decreasing an anteriorposterior tractional force caused by collagen bers. Johnson: I do not buy this. If you look at ultrasound in a Stage 3 PVD, the vitreous is loose, and it is moving around dramatically with eye movement. Dynamic vitreous traction is the critical factor. It is not a static anteriorposterior traction that pulls the vitreous off the disk. It is eye rotations that move the vitreous around, causing repeated jerking traction until it nally lets go of the peripapillary retina. Brucker: If I pull your sleeve real hard, and you jerk around a lot, you are more likely to have a torn sleeve in that scenario. Johnson: You do not see anteroposterior tractional lines going through the vitreous and pulling on the disk. In the absence of brocellular organization, it is only during the eye movement that you see vitreous traction on the disk. Brucker: How many patients have you seen who are driving along or watching television, they get a burst of light, and they have a retinal tear? They are not moving, they are not playing soccer, and they are not jogging. That one scenario does not have to apply to everyone. We all move our eyes from the day we are born. So, there are a lot of other issues besides the kinetic movement. Johnson: I respectfully disagree. Without vitreous movement, there is no signicant traction associated with age-related PVD. We may not be jogging or playing soccer, but we are all making saccadic eye movements virtually all the time. Once the vitreous

has separated from the retina surrounding a focal area of rm vitreoretinal adhesion, the dynamic traction is concentrated sufciently to create a retinal tear. It is a similar type of concentration of dynamic vitreous traction that nally pulls the vitreous off of its rm attachment to the peripapillary retina to produce a Weiss ring. Russell: I would agree with you that it is a dynamic movement. It is just like the last straw that breaks the camels back. The way I describe it to patients is like bending a wire. You bend a wire once, it does not break. You bend a wire twice, it does not break. You bend a wire 1,000 times, it does not break. You bend a wire a million times, it will break. It also depends on what kind of wire. You change the wire composition slightly, and it will break at 500,000 instead of 1,000,000. There are factors that affect the process that are very subtle and are going to have an impact, even though they do not seem obvious. Johnson: What about safety? One of the concerns is that there were a small number of patients who had really signicant vision loss transiently. Thompson: Were these inammatory responses? Kuppermann: None of these were inammatory responses. It is important to note that this phenomenon was only apparent in patients that had resolution of VMA. The common theme identied in all of these patients was rapid resolution of VMA. Johnson: My biggest concern about ocriplasmin is still the safety issue. If you tell me that even 1% of eyes are going to have transient hand motion vision with an afferent pupillary defect and I know I am injecting a nonspecic protease, I am worried that I am injuring the retina or the optic nerve. Histologically, did you see retinal dissolution or optic nerve damage at any dose?



Gandorfer: I am not aware of any damage seen. In histologic terms, we have not seen any damage but we personally only went to 188 mg. Kuppermann: No damage to the retina was noted in these patients on subsequent examinations. The bottom line for ocriplasmin is that if you have VMT and no epiretinal membrane, then resolution from a single injection was nearly 40%. If you have a Stage 2 macular hole that is 250 mm or smaller, resolution was nearly 60% from a single injection. Those are the key target populations for this agent. Brucker: Is that enough of a percentage for you to do an injection before doing the vitrectomy? Kuppermann: Stage 2 macular hole, ,250 mm, 60% chance of resolution, would you do it? Spaide: Probably for that subset, but still it has to come down to cost. Thompson: How soon could you operate on them after injection? Did you operate on them at 35 days? Kuppermann: You were allowed to operate after 28 days. When we refer to the study data, we are careful to differentiate eyes that had hole closure from ocriplasmin injection and those that closed from vitrectomy. Thompson: A lot of patients did not have the vitrectomy until 6 months later. Kuppermann: Correct. Thompson: What about Stage 2 holes where there is no visible tractionsimply a hole with some cystic changes in the edges? Kuppermann: Eyes without VMA were not allowed in the study. They all had VMA and also, potentially, full-thickness macular hole or an epiretinal membrane. Thompson: Did these holes stay closed? Kuppermann: The eyes were followed only for 6 months in the study, but we did not see any decay between 28 days and 6 months, and subsequently, we did not get reports from investigators that the holes were opening up later. Kuppermann: So, in conclusion, increasing awareness of the role of the vitreous and the promise of agents for pharmacologic vitreolysis really highlights a potential change in how VMA and associated diseases may be treated in the near future. The encouraging results in patients with VMT and macular hole from the MIVI-

TRUST trials of a single intravitreal injection of ocriplasmin coupled with good tolerability may mean that the era of pharmacologic vitreolysis may soon become a reality. Key words: vitreolysis, vitreoretinal, vitreomacular adhesion, posterior vitreous detachment, ocriplasmin. References
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