The definition of pharmacologic vitreolysis is the intravitreal use of pharmacologic agents to cleave the vitreoretinal interface and alter the molecular organization and structure of the vitreous to reduce or eliminate its role in disease formation.1

The potential treatment benefits to pharmacologic vitreolysis include complete atraumatic posterior vitreous separation, creation of a more physiologic vitreomacular interface, prevention of fibrovascular proliferation, and prophylaxis or treatment of macular edema and exudation. As David F. Williams, MD, MBA, noted in his article, vitreomacular adhesion (VMA) is implicated in many different retinal disease states, including not only macular hole and macular pucker, but possibly also age-related macular degeneration, proliferative diabetic retinopathy and macular edema from diabetic retinopathy and retinal vein occlusion.

Table 1 shows the various agents that have been evaluated for vitreolysis. The evolution of understanding of how these pharmalytic agents work have led to ocriplasmin (ThromboGenics), the only agent that can produce both liquefaction and separation of the vitreous from the retina. Additionally, as seen in the Table, there is no toxicity associated with ocriplasmin, unlike many of the agents that have been investigated for vitreolysis. Lastly, it is the only agent to have successfully gone through phase 3 studies.

Preclinical Data

Ocriplasmin is manufactured with recombinant technology to target fibronectin, laminin, and collagen and cleanly separate the vitreous from the internal limiting membrane (ILM), inducing both liquefaction and vitreous detachment.2 The proof-of-concept studies of ocriplasmin in both postmortem human eyes and mouse eyes evaluated the enzymatic agent for its vitreolytic effect, its efficacy for inducing posterior vitreous detachment, and safety of its intravitreal injection. Figure 1A shows histological studies of a normal mouse eye and Figure 1B shows PVD induction after ocriplasmin injection. Not only did the vitreous separate from the retina surface, but there is less fibronectin and collagen within the vitreous body after ocriplasmin injection. The results of these preclinical studies confirmed the hypothesis that ocriplasmin is a potential pharmacologic therapy for vitreomacular adhesion (VMA).3

Phase 3 Data

The phase 3 studies for ocriplasmin, the MIVI-Trust program, randomized a total of 652 patients to either a single injection of 125 μg ocriplasmin (n=464) or placebo (n=188). The placebo group received an equal volume injection of saline, which negated any volumetric effect on vitreous separation and confirmed that the difference between the 2 arms was indeed a drug effect.

The primary endpoint of the studies was pharmacologic resolution of VMA at day 28. Secondary endpoints included total PVD at day 28, nonsurgical closure of fullthickness macular holes, change in visual acuity, the need for a vitrectomy procedure, and responses on a visual function questionnaire.

Patients were required to be symptomatic. It is important to note that patients with very good baseline visual acuity were allowed into this study, ≤20/25, because this could result in a ceiling effect with regard to visual acuity gains. Additionally, patients with epiretinal membrane could be included in the study. Patients with high myopia (>8 D), prior vitrectomy or laser, macular holes >400 μm, and other retinal diseases that could affect visual function were excluded.

The trials were comprised of 3 different “buckets” of patients: those with macular hole (as noted, they could also have had ERM as well, and 23 patients had baseline macular hole and ERM); patients with ERM (baseline ERM, no baseline macular hole; it is important to note that ERM was not being treated, but that VMA associated with ERM was being treated); and vitreomacular traction (VMT) syndrome (with no baseline macular hole or ERM). All patients were required to have VMA confirmed by a central reading center (Duke Reading Center).

The proportion of patients who had VMA resolution at day 28 was 29.8% vs 7.7% in the active treatment group vs placebo group, respectively. If you take the extent of adhesion into account, the resolution rates in the ocriplasmin group were even higher in eyes with smaller areas of adhesion (≤1500 μm), approaching 34% in patients with smaller adhesions as opposed to broader adhesions. Optical coherence tomography (OCT) imaging demonstrates that smaller adhesions were more easily resolved at day 28 (Figure 2).

In terms of visual acuity outcomes, approximately 41% of ocriplasmin-treated VMT patients who achieved VMA resolution gained 2 or more lines at 6 months, which was from a good baseline visual acuity approaching nearly 68 letters (20/50).

The mean visual acuity gain was 7.3 letters in ocriplasmin- treated VMT patients who achieved VMA resolution. This is significant considering the good baseline visual acuity of these patients. Seven of the patients lost vision, but each of those patients did experience VMA resolution from between day 7 to day 28 and had some other pathology in the study eye, including cystoid macular dystrophy, drusen, cataract, dry age-related macular degeneration, myopia, and dry eye (Figure 3).

Macular Hole Subgroup Analysis

The differences between ocriplasmin and placebo groups were even more pronounced in patients who were included in the macular hole subgroup. These patients were required to have stage 2 full-thickness macular holes, such as these seen on OCT in Figure 4.

In this subgroup, 40% of full-thickness macular holes closed with a single injection of ocriplasmin. These holes closed early (by day 28) and remained closed at month 6.

Smaller macular holes (≤250 um) closed at a much higher rate than did larger holes (>250 um). Again, these holes closed early and remained closed.

In terms of visual acuity, 77% of patients gained 2 or more lines with hole closure at 6 months after a single injection of ocriplasmin, which was to be expected considering the patients' mean baseline visual acuity (54.8 letters, 20/80). It is important to note that vision gains occurred over time, demonstrating that, as is the case with surgery, the drug works quickly to close the macular holes, but the improvement in visual acuity is gradual.

The mean visual acuity gain was 14.1 letters in ocriplasmintreated macular hole patients who achieved hole closure with drug treatment only. Only 1 patient in this subgroup lost vision. This patient's macular hole (387 μm) closed at day 7 and the eye lost 1 letter of vision (74 to ≥73 letters). The patient also had pterygium, cortical cataract, cupping of the optic disc, retinal pigment epithelial changes, vascular narrowing, and macular edema in the study eye at diagnosis.

Figure 5 shows the closing of a macular hole and resolution of VMA in a patient in the macular hole subgroup after a single injection of ocriplasmin.

The rate of macular closure with placebo alone was 17%, as compared to 40.6% in patients with ocriplasmin alone. For patients who received placebo or ocriplasmin and did not have full-thickness macular hole closure and went on to have a vitrectomy, the rates of closure were 92.3% for the placebo group vs 93.1% for the ocriplasmin group, demonstrating that ocriplasmin did not affect the ability to close a macular hole with vitrectomy.

Safety Data

Because many of patients who have the potential to benefit from ocriplasmin are among those who we would watch and wait and not perform surgery, the safety data are critical. From day 0 to day 7 after injection, there were a small number of incidences of floaters, eye pain, photopsia, blurred vision, reduced visual acuity, visual impairment, retinal and macular edema, anterior chamber cell flare, and photophobia in the patients who received ocriplasmin as compared to the lower number or no incidences in the patients who received placebo injection. Beyond 7 days out to 6 months, most of these side effects drop off to where there is little to no difference between the groups. Because of these data, it is apparent that ocriplasmin injection can cause temporary visual acuity changes, and this is why it is important to counsel patients so that they are aware of this transient effect.

In terms of more serious side effects associated with induced PVD, such as retinal tears and detachment, the rates were actually lower in the ocriplasmin group than with placebo.


These data show that a single injection of ocriplasmin results in increased rates of PVD and full-thickness macular hole resolution. Resolution of VMA and macular hole resulted in visual improvement in most patients, and most of the adverse events were transient and occurred in the immediate week following injection.

Further, ocriplasmin did not preclude future vitrectomy if the drug did not result in macular hole closure. Should ocriplasmin become available, pharmacovitreolysis will offer physicians an attractive alternative for our patients who have symptomatic VMA.

Carl D. Regillo, MD, is the Director of the Retina Service of Wills Eye Institute and a Professor of Ophthalmology at Thomas Jefferson University, Philadelphia. He may be reached at +1 800 331 6634; or via email at

  1. Rhéaume MA, Vavvas D. Pharmacologic vitreolysis. Semin Ophthalmol. 2010;25(5- 6):295-302.
  2. Gandorfer A, Rohleder M, Sethi C, et al. Posterior vitreous detachment induced by microplasmin. Invest Ophthalmol Vis Sci. 2004;45(2):641-647.
  3. Data on file, ThromboGenics.