COMMENTARY

Ocriplasmin: A Promising Option for Vitreomacular Adhesions

Julia A. Haller, MD

Disclosures

September 18, 2012

Editorial Collaboration

Medscape &

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I am Julia Haller, Ophthalmologist-in-Chief at the Wills Eye Institute and the senior author of the recent New England Journal of Medicine article on the 2 phase 3 trials of ocriplasmin for vitreomacular adhesion.[1] I am here to discuss that article and those trials for Medscape.

The treatment protocol addressed symptomatic vitreomacular adhesion -- that is to say, eyes with partial vitreous detachments with focal adhesion at the macula causing symptomatology, metamorphopsia, and decreased vision. This included a subset of eyes with full-thickness macular holes, as long as the holes were 400 microns or less in diameter.

Currently, the standard treatment for this type of condition is vitrectomy. Because of the drawbacks to vitrectomy, including risks for infection, hemorrhage, retinal detachment, and the certainty of cataract progression, many eyes with symptomatic vitreomacular adhesion are simply followed until the patient becomes so symptomatic and the vision decreased so much that vitrectomy is deemed to be warranted by the clinician and the patient. This is, of course, a risk-benefit analysis. In these studies, because the treatment involved only an intravitreal injection into the eye, patients could be enrolled with ETDRS (Early Treatment Diabetic Retinopathy Study) visual acuity of 20/25 or worse with symptomatic vitreomacular adhesion. The vitreomacular adhesion had to be documented by OCT (optical coherence tomography), and these were all read and graded at the Duke Reading Center headed by Dr. Glenn Jaffe.

Ocriplasmin is a recombinant version of microplasmin. Microplasmin is a protease with activity against components of the vitreomacular interface, specifically laminin and fibronectin. Ocriplasmin causes liquefaction of the vitreous and it helps dissolve the biological glue holding the vitreous onto the retina. In this particular study, 125 µg of ocriplasmin were injected into the vitreous in the patients who were randomly assigned to the treatment arm of the study. In the control arm of the study, patients received an intravitreal injection of the vehicle without the ocriplasmin in it. Both arms of the trial included an intravitreal injection.

Patients were enrolled in 2 large multinational trials. In one, they were randomly assigned [at a ratio of] 3:1 [active treatment group:control group] and in the other trial, they were randomized at a ratio of 2:1. About 464 patients were assigned to ocriplasmin and 188 were assigned to receive the placebo injection. The primary endpoint was separation of the vitreomacular adhesion at 28 days. Other endpoints included total posterior vitreous detachment, judged by the clinician on the basis of an ultrasound, and how many patients went on to vitrectomy, how many were spared vitrectomy by the injection of the intravitreal ocriplasmin, visual acuity outcomes, and finally, quality-of-life outcomes using the VFQ-25 scale. We then followed the patients up to 6 months, primarily looking at safety outcomes.

The results of the trial showed that at the 28-day primary endpoint, just about 25%, almost 1 in 4 of the eyes injected with ocriplasmin had complete release of the vitreomacular adhesion, and this was a statistically significant result. Interestingly, even in the placebo-treated arm, with an intravitreal injection, about 10% had release of the traction, but the difference was statistically significant. There was also a statistically significant difference in terms of total posterior vitreous detachment. Very significantly, 40% of eyes with a macular hole achieved complete closure of the macular hole after injection of ocriplasmin and without vitrectomy. This was stunning in terms of an anatomic result.

On the safety side, we looked carefully at retinal tears, retinal detachments, and other complications or potential complications of the injection and found no statistically significant difference between the groups, except in terms of the symptomatology within the first week to 10 days. Compared with the placebo group, patients who had the ocriplasmin injected did have the type of symptoms that you would expect with a posterior vitreous detachment. That is to say, they developed flashing lights, floaters, some blurring of vision, and some disturbance in visual function that was temporary and that resolved but was attributable to the development of an acute posterior vitreous detachment. There was no significant difference in terms of retinal tear or retinal detachment. In fact, more patients in the placebo group developed those complications because more of those patients went on to require vitrectomy, even within the first 6 months, which was the extent of follow-up in these particular trials. No cases of infection and no significant cases of inflammation occurred.

We also looked at the rate of cataract progression. Again, in the placebo group, there was more cataract progression, even over that 6-month period, than in the ocriplasmin-treated group, which was attributable to more of those patients [in the placebo group] requiring vitrectomy, which accelerates cataract progression, particularly nuclear sclerosis. The conclusion of the study was that ocriplasmin shows potential to become the first pharmacologic approach to treat vitreomacular adhesions, including macular holes.

Where is ocriplasmin going? What is the chance that we as retina specialists will have it in our hands in the next months to a year or so? The most recent update is from July 2012, when the FDA panel voted to recommend ocriplasmin for approval. We are still awaiting news of final approval, and so the drug is not currently available. We hope it will become available soon and that seems likely.

When it does become available, how will this fit into our treatment paradigm and how will it impact clinical practice? I believe it will change things tremendously. That is to say, when patients have a focal vitreomacular adhesion that is causing symptoms, we now have a new option for them. We can offer intravitreal injection. In the patients included in this pair of studies, 25% of the time, in 1 out of 4 patients, the ocriplasmin injection alone led to the release of the vitreomacular adhesion. This changes our previous strategy, which was careful, watchful waiting as the disease progressed.

In patients with macular holes, at least those with small macular holes, this approach becomes the treatment of choice, because we know with an intravitreal [ocriplasmin] injection alone, without vitrectomy, without a gas bubble, we achieved closure of 40% of those holes. If you look at the subset of holes that were 400 microns or smaller, the closure rate was closer to 50%. That may radically change the options for our patients.

If injection of the drug fails, if the patient has no release of the vitreomacular adhesion, there is no downside. They return to the usual treatment paradigm. We can either follow them carefully until things get bad enough to warrant vitrectomy or we can proceed with a vitrectomy immediately. We were not able to identify any downside risk to that.

I believe this will be a very useful drug. I don't know about the rest of you, but I am seeing more and more patients who have vitreomacular adhesion. I think this is partly because our colleagues in clinical practice, particularly comprehensive ophthalmologists, are more likely to have OCT machines in their offices and they are picking up eyes with vitreomacular traction at a higher rate than previously. Of course, we know that about 1 in 50,000 people develop a macular hole.

In this study, patients who were very highly myopic were excluded, so we will need more studies to figure out exactly where the drug fits into an expanded patient population. That will be a very exciting research avenue for the future.

On behalf of Wills Eye Institute and Medscape Ophthalmology, thank you.

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