Prospects for Nonsurgical Closure of Macular Holes With Ocriplasmin

Clinical trial data shed light on this new option.

Prospects for Nonsurgical Closure of Macular Holes With Ocriplasmin

Clinical trial data shed light on this new option.

Polly A Quiram, MD, PhD

Our understanding of the complex interactions that occur in the vitreous cavity during the creation of a posterior vitreous detachment has seen tremendous progress. The term “pharmacologic vitreodynamics” was coined to explain the mechanical and biochemical changes in the vitreous cavity that occur during and after PVD formation.1,2 Abnormal vitreous traction at the vitreoretinal interface contributes to the retinal pathology seen in macular holes, macular puckers, diabetic macular edema, vitreomacular traction syndrome and retinal tears and detachments.3

Surgical management of these disorders often targets abnormal vitreomacular adhesions (VMAs) by mechanically separating the posterior hyaloid from the internal limiting membrane, thereby creating a PVD. However, mechanical separation of the vitreoretinal interface with vitrectomy may not remove all of the vitreous, resulting in surgical failure.4,5 Better understanding of the vitreous has yielded enzymatic agents, such as ocriplasmin, which induce vitreous liquefaction to create a complete PVD. Recent clinical trials have demonstrated successful nonsurgical closure of macular holes following a single intravitreal injection of ocriplasmin. The drug recently received priority review status from the FDA.

In this article, I will review the clinical trial data on ocriplasmin, updating my article from the July 2009 issue of Retinal Physician.

Polly A Quiram, MD, PhD, is a vitreoretinal surgeon at Vitreoretinal Surgery PA in Minneapolis and an associate professor at the University of Minnesota. She reports no financial interest in any product mentioned in this article. Dr. Quiram can be reached via e-mail at


Plasmin enzyme is an 88-kDa, nonspecific protease capable of hydrolyzing laminin, fibronectin and type 4 collagen, which bridge collagen fibers between the posterior vitreous cortex and the ILM.4,6 A single injection of plasmin enzyme can cleave the vitreoretinal junction without causing structural changes or retinal toxicity. Plasmin enzyme has been used in human subjects in two forms: autologous plasmin and ocriplasmin.

Autologous plasmin enzyme (APE), isolated from the patient’s serum, causes vitreous liquefaction and PVD formation. APE has been extensively studied in humans for the treatment of macular holes, diabetic retinopathy and congenital X-linked retinoschisis.7,8 Ocriplasmin (ThromboGenics Ltd.), previously referred to as microplasmin, is a recombinant protein (29 kDa) containing the active protease site of human plasmin (Figure 1).

Figure 1. Structure of plasmin enzyme, a nonspecific protease capable of hydrolyzing glycoproteins, such as laminin and fibronectin. Ocriplasmin (purple) contains the active domain.

Ocriplasmin induces a PVD in a dose-dependent manner, and its smaller size enables more effective penetration of epiretinal tissues. Ocriplasmin liquefies vitreous and induces a PVD with a single intravitreal injection of 62 µg or 125 µg.9 Ocriplasmin works rapidly to induce a PVD and vitreous liquefaction within 30 minutes.10,11


The European MIVI 2T (Traction) study was a randomized, sham-injection–controlled, double-masked, ascending-dose, dose-range–finding trial of ocriplasmin for nonsurgical treatment of vitreomacular traction.12 The inclusion criterion was evidence of VMT by ultrasound and OCT, with the presence of macular thickening >250 µm. Common conditions included VMT, macular holes and tractional DME. Visual acuity had to be ≤20/40 in the study eye and ≥20/400 in the fellow eye. Two cohorts of 15 patients received either 75 µg or 125 µg of ocriplasmin or sham, with a 4:1 randomization of ocriplasmin vs sham.

Complete VMT resolution occurred in 40% of the subjects, with the best results (50% resolution) seen with the higher dose of ocriplasmin (125 µg). Closure of macular holes without vitrectomy occurred in 50% of eyes (Figure 2). A greater than three-line improvement of visual acuity occurred in 20% of eyes. The MIVI 2T trial results show that ocriplasmin relieves VMT in 40% of eyes with an abnormal vitreoretinal interface.

Figure 2. Results of the MIVI IIT trial, macular hole.
A. OCT demonstrating evidence of a stage 2 macular hole.
B. OCT image three days after intravitreal injection of ocriplasmin. Macular hole is closed with improvement of visual acuity.
C. Resolving subretinal fluid 28 days after injection of ocriplasmin. Visual acuity has improved 11 letters from baseline.


The successful results of the previous study prompted the development of two larger (MIVI-006, MIVI-007), phase 3, international, multicenter, randomized, placebo-controlled, double-masked trials (MIVI-TRUST) to evaluate the safety and efficacy of ocriplasmin for nonsurgical treatment of focal vitreomacular adhesion. The 652 patients enrolled were randomly assigned to receive an intravitreal injection of 100 µL of placebo solution (188 patients) or 125 µg ocriplasmin (464 patients).

The primary endpoint was pharmacologic resolution of VMA by day 28. Secondary endpoints assessed the presence of total PVD at day 28, nonsurgical closure of macular holes, avoidance of vitrectomy, improvement of visual acuity and quality of life assessment. BCVA was required to be ≤20/25 in the study eye ≥20/800 in the non-study eye. The exclusion criteria included a history of prior vitrectomy or prior laser photocoagulation to the macula, other retinal diseases that would affect visual acuity (PDR, exudative AMD, retinal vein occlusion, vitreous hemorrhage, high myopia), macular hole >400 µm, or a history of retinal detachment in the study eye. The follow-up period was six months.

At 28 days, VMA resolved in 27% of the 464 eyes treated with ocriplasmin and 7.7% of the 188 eyes given placebo (P=.001). Approximately 75% of these eyes experienced resolution of VMA within one week of injection. In terms of visual acuity, 25.5% of the treated eyes gained two or more lines, and 10.1% gained three or more lines (Table 1). The safety profile of ocriplasmin was favorable, without significant adverse events compared to sham. Interestingly, a higher incidence of retinal tears and detachments was seen in placebo-treated eyes compared to ocriplasmin-treated eyes: 4.3% vs 1.7%, respectively.

Table 1. Efficacy Outcomes of the MIVI-TRUST Clinical Trial
• 27% of patients had pharmacological resolution of VMA (P <.001)
• 40.6% of patients had pharmacological closure of FTMH (P = .004)
• 58.3% of patients with FTMH ≤250 µm had pharmacological closure
• 13.4% of patients had induction of total PVD (P <.001)
• 23.7% of patients gained ≥2 lines (P <.001)
• 9.7% of patients gained ≥3 lines (P <.001)
• Visual acuity and visual function outcomes favored ocriplasmin

Subgroup analysis of MIVI-TRUST

Subgroup analysis of eyes with full-thickness macular holes (FTMHs) showed closure in 40.6% of eyes following injection of ocriplasmin, compared with 17% of placebo eyes (P=.004) (Figure 3). Approximately 58% of the eyes with FTMHs <250 µm saw closure with ocriplasmin, compared with just 20% in the placebo eyes. Respectively, 76.7% and 51.2% of the eyes in the FTMH subset achieved ≥2- and ≥3-line improvements in visual acuity.

Figure 3. From the MIVI TRUST trial, macular hole.
A: OCT demonstrating evidence of a macular hole with visual acuity of 20/63.
B: OCT image seven days after intravitreal injection of ocriplasmin with a gain of 10 letters.
C: OCT image six months after intravitreal injection of ocriplasmin. Macular hole is closed with minimal subretinal fluid and a gain of 21 letters.

Eyes with significant ERMs were not excluded from the trial, but when subgroup analysis excluded eyes with ERMs, 37.4% of the eyes had resolution of VMA with a single injection of ocriplasmin (P<.003). Further subgroup analysis showed that presence of an ERM significantly reduced the induction of a PVD. When eyes with an ERM were excluded from the analysis, 19.6% of the eyes achieved complete PVD, whereas 5% of the eyes with significant ERMs achieved PVD (P<.001).


Abnormal VMA has been implicated in the pathogenesis of vitreomacular traction syndrome, macular holes, DME, diabetic retinopathy, exudative AMD, RVO and vitreopapillary syndrome. A single intravitreal injection of ocriplasmin has been shown to close 40% of full-thickness macular holes <400 µm and 60% of those <250 µm without surgical intervention. Significant visual improvement was noted in the majority of patients.

Ocriplasmin has potentially significant implications for the management of multiple vitreoretinopathies.13-17 We look forward to promising results from ongoing clinical trials. RP


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