The natural course of posterior vitreous detachment (PVD) involves the separation of the posterior vitreous cortex from the retinal internal limiting membrane.1,2 Although PVD can resolve without symptoms, incomplete PVD may lead to vitreomacular adhesion (VMA) and vitreomacular traction (VMT).3-6 VMA is caused by attachment of the vitreous cortex to the macula, while VMT stems from alterations to the macular structure from the tractional forces of the attachment.7,8 Untreated VMA or VMT can lead to visual symptoms including decreased visual acuity, visual distortion (metamorphopsia), and central scotoma, and is a risk factor for the development of full-thickness macular hole (FTMH).7-12 Historically, treatment options have included watchful waiting and, if symptoms become severe, vitrectomy.7,8 Now there is a pharmacologic treatment option: ocriplasmin (Jetrea, ThromboGenics), a first-in-class pharmacologic agent that is approved by the US Food and Drug Administration for treatment of patients with symptomatic VMA as an alternative to watchful waiting and vitrectomy.7,8

BACKGROUND

Ocriplasmin is a truncated form of plasmin that enzymatically cleaves structural proteins, including laminin and fibronectin, at the interface of the vitreous body and the retina, which leads to vitreous liquefaction and detachment.13,14 Ocriplasmin was initially assessed in a clinical study using escalating doses at 1 to 2 hours, 24 hours, or 7 days before pars plana vitrectomy (PPV) for VMT to determine its effectiveness in the achievement of complete PVD.15 Increasing the length of ocriplasmin exposure was associated with a progressive increase in the frequency of complete PVD achievement, with 50% of eyes achieving total PVD if injected 1 week before PPV.15

Based on these findings, the efficacy and safety of ocriplasmin was then assessed in the phase 3 MIVI-TRUST clinical trials, which showed that a single intravitreal injection of ocriplasmin (125 μg) resulted in a higher proportion of patients achieving VMA resolution (26.5%) at day 28 versus placebo (10.1%).16 A higher proportion of patients treated with ocriplasmin also achieved the secondary endpoints of the trials when compared with those receiving placebo: (1) 13.4% of ocriplasmin-treated versus 3.7% (P < .001) of placebo-treated patients achieved total PVD at day 28; (2) 40.6% of ocriplasmin-treated versus 10.6% (P < .001) of placebo-treated patients who had FTMH at baseline achieved nonsurgical closure of FTMH at day 28; and (3) 12.3% of ocriplasmin-treated versus 6.4 % (P = .02) of placebo-treated patients gained 3 lines or more of visual acuity at month 6. 16

A subsequent analysis of the phase 3 clinical trial data was performed to identify baseline features predictive of VMA resolution at day 28. The baseline characteristics identified as positive predictors from MIVI-TRUST were absence of epiretinal membrane (ERM), VMA diameter 1500 μm or less, presence of FTMH of 400 μm diameter or less, phakic lens status, and age younger than 65 years (Figure).16,17

OCRIPLASMIN REAL-WORLD EXPERIENCE

Efficacy

Because clinical trials are conducted in a stringently selected population that is not always generalizable to real-world clinical practice, it is important to determine whether real-world experience supports clinical trial findings. To determine whether results similar to the phase 3 clinical trials were observed in clinical settings, real-world experience for safety and efficacy, including resolution of VMA at day 28 by baseline predictors at clinical sites, was examined as a cross-sectional representation of current clinical findings. The sites described here were selected with a patient population size of greater than 18 to provide a broad selection of experience.

At the Retina Group of Washington, a retrospective interventional case series was performed, including 35 eyes of 35 patients with symptomatic VMA who underwent intravitreal ocriplasmin injection between February 2013 and November 2013. Of these patients, 43% (15 of 35) achieved VMA resolution, and 17% (1 of 6) achieved macular hole closure.18 Mean preinjection BCVA was 20/57 (0.46 LogMAR), and final BCVA was 20/43 (0.33 LogMAR).18

A retrospective study at the Retina Consultants of Houston evaluated a series of 52 patients with VMA who were treated with ocriplasmin over a 9-month period. Of these patients, 46.2% (24 of 52) achieved VMA resolution and 18.2% (4 of 22) had macular hole closure following treatment with ocriplasmin.19 Mean baseline LogMAR scores of patients with VMA release was 0.469, improving to 0.335 after treatment. The macular hole closure group had baseline and final LogMAR scores of 0.872 and 0.662, respectively.19

The clinical experience at these 2 sites suggests that ocriplasmin treatment in the real world is associated with an improvement in BCVA.

At the New Jersey Retina Vitreous Center, a retrospective review was performed to evaluate a series of eyes (n = 62) treated with ocriplasmin. A total of 41% achieved VMA resolution following ocriplasmin injection.20 Eyes with FTMHs of 400 μm or less and VMA of 750 μm or less had VMA resolution rates of 69% and 51%, respectively.20 However, 40% of eyes with FTMH required surgical closure despite VMA release, and 54% of eyes with FTMH showed enlargement of the width of the FTMH after injection.21 In eyes with FTMH enlargement, the best visual acuity achieved within 8 months following surgery was significantly lower than that achieved by eyes without FTMH enlargement by 8 months after injection (P = .001, mean VA 20/112 vs 20/34, respectively).21

A retrospective, single-center review of patients with symptomatic VMA included 19 patients treated with ocriplasmin at the Bascom Palmer Eye Institute at the University of Miami Miller School of Medicine. A total of 42% (8 of 19) of patients achieved VMA resolution and 50% (3 of 6) achieved FTMH closure following injection with ocriplasmin.22 The study showed VMA resolution rates of 67%, 45%, and 50% for patients with FTMHs of 400 μm or less, absence of ERM, and VMA of 1500 μm or less, respectively.22 These rates of VMA resolution in the real world were higher than those reported in the clinical trials, likely due to the consideration of baseline features during patient selection.

The role of the ERM in modifying the ocriplasmin response to VMA resolution is not clear. The ERM, a membrane lining the ILM, is a pathologic formation induced by remnant vitreous after separation. It is composed of retinal glial cells, astrocytes, myofibroblasts, fibrocytes, macrophages, and retinal pigment epithelium cells.7 The ERM may alter ocriplasmin action on the sites of adhesion of the ILM to the posterior vitreous. ERM presence has been shown to alter the response to retinal pharmacotherapy. For example, studies of bevacizumab (Avastin, Genentech) treatment for age-related macular degeneration have reported that the presence of ERM may be a modifying factor for treatment response.23

The influence of VMA size on response to ocriplasmin may be related to the size of the area of attachment because, with smaller attachments, there is less extracellular matrix to dissolve. Alternatively, the higher resolution rate with VMA size may be due to differences in tractional forces on the macula. A smaller VMA has a larger macular tractional force, and focal VMA may allow more efficient VMA release with ocriplasmin treatment due to the greater pull by the attached posterior vitreous.24

Other Macular Diseases

VMT release with ocriplasmin may play a role in other macular diseases. A 1-year retrospective chart analysis was performed at the Retina Associates of Cleveland, including 24 patients with symptomatic VMT who received intravitreal injection of ocriplasmin. A total of 50% (12 of 24) of patients achieved VMA resolution, and the macular hole closure rate was 77.8% (7 of 9).25 Half of the patients experienced BCVA improvement. Diabetic macular edema (DME) was noted in 3 of 24 eyes prior to receiving treatment with ocriplasmin; 1 patient had improvement of DME in addition to complete VMT resolution.25 It is possible that DME may respond better to conventional therapy (ie, ranibizumab [Lucentis, Genentech] and bevacizumab) following VMT release. This finding is consistent with the recognition that VMT is involved in a variety of macular diseases, including cystoid macular edema, DME, diabetic retinopathy, and age-related macular degeneration.26,27

Real-World Safety

At the William Beaumont Hospital, a retrospective case series analysis was performed that included 37 eyes treated with ocriplasmin between February and September 2013. A total of 43% (16 of 37) of patients achieved VMA resolution, and 70% (7 of 10) achieved macular hole closure following treatment.28 The rate of VMA separation was increased in patients with macular hole (90%).28 Using spectral domain-optical coherence tomography (SD-OCT), subretinal fluid was found following separation in 11 eyes (69%) and continued through 1 month in 9 eyes (56%).28 Alterations of the ellipsoid zone were observed in 20 eyes (54%) at 1 week, 15 eyes (40%) at 1 month, and 6 eyes (16%) at final follow-up.28

Additional Real-World Experience

Other postmarketing ocriplasmin safety and efficacy outcomes have been reported from various sites with significant efficacy outcomes, as shown in the Table.29-33 This compilation of real-world experience shows that ocriplasmin treatment can lead to improved BCVA gain and suggests that ocriplasmin may have clinical utility in other macular diseases. These retrospective studies also help to validate the observations discussed above regarding the improved rates of VMA resolution following ocriplasmin treatment in patients with FTMH of 400 μm or less, no ERM, or focal adhesion.

OCRIPLASMIN SAFETY

Safety data from the phase 3 clinical trials demonstrated that ocriplasmin was generally well tolerated when administered as an intravitreal injection, and most adverse events were ocular and mild to moderate in severity.16 Interestingly, the most common visual adverse events in the phase 3 clinical trials were vitreous floaters (16.8%) and photopsia (11.8%), which are known to be associated with PVD.16 In the phase 3 clinical trials, there was a relatively high rate of visual acuity decrease, with most cases due to VMT or macular hole progression.16 Most cases were transient; by the end of the study, reduced visual acuity was reported in approximately 1% of patients in both ocriplasmin- and placebo-treated groups.16 Furthermore, real-world safety reports and data from the entire clinical trial program have also identified adverse events of special interest, including dyschromatopsia, electroretinogram changes, ellipsoid zone disruption, subretinal fluid presence, retinal tears/detachments, impaired pupillary reflex, retinal vessel changes, and lens subluxation/phacodonesis.34,35 Major studies, including OASIS, ORBIT, and OZONE, have been initiated to understand which patients are more likely to develop these adverse events.36-38 Currently, the postmarketing safety reports are consistent with the adverse event profile reported in the clinical trial program.34,35

CONCLUSION

For patients with symptomatic VMA, ocriplasmin is the only approved pharmacologic treatment. Importantly, real-world experience with ocriplasmin has shown good efficacy and a safety profile comparable to that seen in the clinical trials. Based on positive ocular features for VMA resolution including focal VMA, presence of FTMH, and absence of ERM, increased overall VMA resolution rates have been reported in postmarketing experience at multiple centers. Optimal patient selection is crucial, and these baseline characteristics will guide retinal physicians in selecting patients that may gain the most benefit from ocriplasmin treatment.

Jorge A. Fortun, MD, is an assistant professor of ophthalmology at the Bascom Palmer Eye Institute, University of Miami Miller School of Medicine. He is a member of the Retina Today editorial board. He is a consultant to ThromboGenics. Dr. Fortun may be reached at jfortun@med.miami.edu.

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