January 2013




Retinal pharmacotherapy for the anterior segment surgeon

A new era in pharmacologic vitreolysis

by Michelle Dalton EyeWorld Contributing Writer

Pravin U. Dugel, M.D.

Jeffrey S. Heier, M.D.

J. Sebag, M.D.


Dissected vitreous from a 9-month-old Source: J. Sebag, M.D.

Ocriplasmin is a truncated form of the human serine protease plasmin that retains its enzymatic properties.

Source: ThromboGenics

Armed with the knowledge that the vitreous plays a larger role in retinal disease than realized, retinal specialists are rapidly embracing ocriplasmin as a treatment for the right patient

Posterior vitreous detachment (PVD) is an age-related occurrence that usually is asymptomatic or mildly symptomatic. But an incomplete (or anomalous) PVD can cause vision loss, experts say. "People with relatively good visionsay 20/40 to 20/50who were symptomatic were usually followed rather than treated surgically," said Jeffrey S. Heier, M.D., director, Vitreoretinal Service, Ophthalmic Consultants of Boston, and co-director, vitreoretinal fellowship, Ophthalmic Consultants of Boston. Jetrea (ocriplasmin, ThromboGenics, Heverlee, Belgium) provides "a relatively atraumatic means to help patients without surgery," Dr. Heier said.

Jetrea has been approved in the U.S. for symptomatic vitreomacular adhesion (VMA), which occurs as a result of anomalous PVD and can sometimes lead to edema, metamorphopsia, visual impairment, and/or severe vision loss. Ocriplasmin has been in development for more than a decade, and almost 1,000 people have been injected with the drug in the course of the clinical studies, said Pravin U. Dugel, M.D., managing partner, Retinal Consultants of Arizona, Phoenix, and clinical associate professor of ophthalmology, Doheny Eye Institute, Los Angeles.

"There are really three forces that are colliding at this momentone is the drug itself. Second, imagingthe importance of vitreomacular traction (VMT) or VMA was not well known before we had sophisticated imaging. Thirdtreatment burden," Dr. Dugel said. Because anti-vascular endothelial growth factor (VEGF) doesn't confer any permanent structural change in the retina, patients need continuous dosing, Dr. Dugel said. The introduction of Jetrea may prove useful in combination with the anti-VEGFs like Lucentis (ranibizumab, Genentech, San Francisco) and might be able to decrease the treatment burden in patients with both VMA and chronic diseases such as diabetic macular edema, neovascular macular degeneration, or retinal vein occlusion, he said. J. Sebag, M.D., founding director, VMR Institute, Huntington Beach, Calif., and professor of clinical ophthalmology, University of Southern California, Los Angeles, first described anomalous PVD more than a decade ago (for more on his description, see sidebar). It's imperative ophthalmologists continue to think about the vitreous as an organ, not a space, Dr. Sebag said. Surgery had become the de facto standard method for removal when necessary, but with the development of ocriplasmin, retinal specialists are experiencing a transition to pharmacotherapy, he added.1 "In a patient with anomalous PVD that has caused any of a variety of vitreoretinopathies [see sidebar], we hope to be able to use Jetrea to treat it, rather than doing surgery," Dr. Sebag said.

Simplifying treatment for VMA by using intravitreal injections in lieu of surgery is "doing patients a great service," Dr. Dugel said.

PVD pharmacotherapy

The "biggest issue" with macular holes currently is that while surgery has a "very high" success rate, it involves patients having to face the floor post-op so that a bubble can tamponade the hole closed. "That is incredibly arduous for the patient," Dr. Sebag said. An intravitreal injection mandates no surgery center or hospital visit and no need to face the floor. Remarkably, Jetrea is successful in 40-60% of cases, he said. "This drug does not give us the ability to treat something we could not treat before, but it does give us the opportunity to obviate the need for surgery, and it's much easier for patients," Dr. Sebag said. "That's always a recipe for success."

Additionally, Dr. Dugel said studies on ocriplasmin were conducted before much was known about VMT; current studies would be designed differently. "Remember that the drug works in vitreomacular adhesion (VMA). Therefore, ocriplasmin should only be used in patients with VMA," Dr. Dugel said. "When ocriplasmin becomes available in the first quarter of 2013, we should first start using ocriplasmin in those patients in whom we know it works best, where there's level 1 evidencepatients who have a macular hole less than 400 microns in diameter. Also in this group are patients with vitreomacular adhesion of 1,500 microns or less. In both these patient types, there's about a 50% chance of success with a single injection."

"If we're planning on taking the patient to surgery anyway and the drug is safe, we have little to lose if we opt for the injection first," Dr. Dugel said. Published study results2 "really paralleled the results of surgery," Dr. Dugel said, but noted patients were only enrolled for six months and surgical results may take about a year for final vision improvement. There are some universal characteristics that are more likely to indicate someone is symptomatic taut vitreoretinal adhesions, where there's distortion of the foveal anatomy, for example, Dr. Heier said. "Even with those adhesions, these patients may still have good vision; they may be 20/25 or 20/30 but with noted metamorphopsia. Early stage macular hole with a focal vitreoretinal attachment may benefit from intravitreal injection."

The role of the vitreous

"Anomalous PVD is not really a disease, it's a finding that's associated with a variety of diseases," Dr. Sebag said. "Any pharmacologic vitreolysis agent that does not induce concurrent dehiscence at the vitreoretinal interface in conjunction with gel liquefaction can cause undue traction upon the retina with a variety of potential untoward manifestations. Thus, the wrong pharmacologic vitreolysis agent in the wrong patient at the wrong time in the natural history of disease could make matters worse rather than better." That's what happened with hyaluronidase when it was used in young patients with type 1 diabetes and one of the reasons why the drug failed FDA testing, he said. Dr. Heier agreed, saying Jetrea is not a drug that will be appropriate for everyone with anomalous PVD. "Patients who are symptomatic for epiretinal membrane will not respond well. It may help with their focal attachment, but it's not going to help with the epiretinal membrane. Patients with large, broad attachments are not likely to respond," he said.

In addition to ocriplasmin, a small study (n=15) showed intravitreal injection of 0.3 mL 100% perfluoropropane "could offer a minimally invasive alternative to pars plana vitrectomy" in symptomatic and persistent VMA.3

Longer-term results

Dr. Sebag said longer-term results and evaluations are under way on the patients who were in the Phase II and Phase III ocriplasmin studies so somewhere between 2-4 years of follow-up after the initial injection. Patients with diabetes are being evaluated as well, Dr. Heier said. "Intuitively, patients who are being treated with anti-VEGF who have incomplete responses (when the fluid doesn't resorb) may have such a response because of these types of attachments. The ongoing attachment renders them incapable of full response."

The diabetic vitreous and the way it attaches to the retina is chemically and structurally different from other situations, and Dr. Sebag predicts "there will be some individuals who will require more than one type of drug to achieve the objective of pharmacologic vitreolysis."

"There's good preliminary evidence that VMA may play a role in neovascular AMD, retinal vein occlusion, and diabetic macular edema," Dr. Dugel said, cautioning that there is no level 1 evidence yet of efficacy in patients with these diseases. But he added the results of several preliminary studies are encouraging and further scientific rigor is required.

Dr. Heier said in those patient populations, the VMA may be what's preventing an adequate patient response to intravitreal injections. "This is just the tip of the iceberg," Dr. Dugel said. "We're in an entirely new domain. Jetrea is not another Lucentis. It's a new dimension of drug. We don't have a better mousetrap, we have an entirely new mousetrap."


1. Sebag J. Pharmacologic vitreolysispremise and promise of the first decade. Retina 2009;29(7):871-4.

2. Benz MS, Packo KH, Gonzalez V, et al. A placebo-controlled trial of microplasmin intravitreous injection to facilitate posterior vitreous detachment before vitrectomy. Ophthalmology. 2010;117(4):791-797.

3. Rodrigues IA, Stangos AN, McHugh DA, Jackson TL. Intravitreal injection of expansile perfluoropropane (C3F8) for the treatment of vitreomacular traction. Am J Ophthal. In press.

Editors' note: Dr. Dugel has financial interests with ThromboGenics. Dr. Heier has financial interests with ThromboGenics. Dr. Sebag has financial interests with ThromboGenics.

Contact information

Dugel: pdugel@gmail.com
Heier: 617-367-4800, jsheier@eyeboston.com
Sebag: 714-901-7777, jsebag@vmrinstitute.com

A new era in pharmacologic vitreolysis A new era in pharmacologic vitreolysis
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