A new injectable treatment for resolving symptomatic vitreomacular adhesion promises to help a significant number of patients avoid surgery.
Vitreomacular adhesion (VMA) is a common finding in older eyes. The vitreous is largely composed of collagen and hyaluronic acid and has a jelly-like consistency. In younger people, it is completely attached to the surface of the retina, most strongly at the optic nerve, ora serrata, around blood vessels, and in the central retina around the macula. With age, however, the vitreous slowly liquefies and cleanly separates from the retina in a process called posterior vitreous detachment.
In most people, a posterior vitreous detachment is uneventful and results in a clean separation of the vitreous; but in some cases the liquefaction and separation are uneven, and the result is traction on the retina at the remaining points of attachment. In the periphery of the retina this can result in a retinal tear. When the macula is involved, the vitreous pulling at the points of adhesion is called vitreomacular adhesion (VMA). VMA can be asymptomatic, but in many cases it produces symptoms, including bright flashes, decreased visual acuity, and optical distortion. In the worst cases, a full-thickness tear in the fovea—a macular hole—can occur.
Symptomatic VMA is one of the more common retinal problems seen in an ophthalmic practice, where patients present due to the sudden, sometimes alarming, visual effects. Imaging with optical coherence tomography (OCT) can clearly delineate the vitreous cortex and locate the points of adhesion on the retina. With OCT the physician can distinguish between VMA in which the retina, although distorted, has no hole and the presence of a macular hole, a distinction that can be difficult to make by clinical examination alone.
Until now, clinicians have had just two options for treating symptomatic VMA: watchful waiting and vitrectomy. Typically, the patient was observed until the traction either resolved on its own or the visual acuity dropped and/or the symptoms became intolerable. At that point, patients were typically sent to a retinal specialist for vitrectomy—which involves the surgical detachment of the vitreous adhesion and removal of the vitreous cortex.
Vitrectomy is effective at relieving the adhesion, but also a technically challenging and delicate procedure that inevitably entails some risk of damage to the retina, in addition to the other risks of intraocular surgery (infection, accelerated cataract development, etc.). Because vitrectomy entails significant risk, clinicians have tended to prefer watchful waiting until the patient’s condition worsened to the point where the risk/benefit ratio tilted in favor of surgery.
A New Option: JETREA®
JETREA (ocriplasmin) is a new drug that, when injected into the vitreous, dissolves the proteins that cause the vitreous to adhere to the retina. In many patients, this is enough to release the vitreous cortex from the retina and relieve the symptoms, making surgery unnecessary.
Ocriplasmin is a genetically engineered form of the protease plasmin, which is a normal component of the blood coagulation cascade. Ocriplasmin has proteolytic activity against laminin and fibronectin, extracellular matrix proteins associated with the adhesion of vitreous to retina. Gelatinase A is a metalloproteinase that resides in the vitreous in a latent state; when activated by ocriplasmin, gelatinase A digests collagen type IV and other basement membrane proteins. Activated gelatinase A also accelerates the liquefaction of the vitreous body.1
JETREA is administered by means of intravitreal injection. Under local anesthesia, 125 µg of ocriplasmin in 0.1 mL is injected over the course of a few seconds through the pars plana, about 3.5 to 4 mm posterior to the limbus. The drug starts working within seconds, and if the traction is going to release, it generally does so within a week or two. As with any intravitreal injection, patients are monitored for post-injection intraocular pressure elevation or intraocular bleeding. Mild and transient intraocular inflammation is seen with ocriplasmin in about 7% of patients.2
Clinical Trial Results
In clinical trials, JETREA resolved symptomatic VMA by 28 days after injection in 26.5% of treated eyes compared to 10.1% of placebo-treated eyes (P < 0.001); JETREA yielded complete posterior vitreous detachment in 13.4% of eyes compared to 3.7% of placebo-treated eyes (P < 0.001). Patients with an associated epiretinal membrane had release with ocriplasmin in 8.7% of cases, which, though modest, was more than the 1.5% seen with placebo treatment (P = 0.046).
Vision improved by 3 or more lines in 12.3% of ocriplasmin-treated eyes, which was about twice the rate seen with placebo (6.4%, P = 0.02). Although loss of acuity is a major problem with symptomatic VMA, the mean pretreatment best corrected visual acuity in the clinical trials was fairly good (20/50), which might have made the statistical detection of improvement difficult. A greater rate of visual acuity improvement was seen in eyes with pretreatment vision worse than 20/50, which might be more reflective of the situation in clinical use.3
The most impressive results were reported from patients who had a full-thickness macular hole less than 400 microns in width and associated VMA; in these patients nonsurgical closure of the macular hole was seen in 40.6% of ocriplasmin-treated eyes compared to 10.6% of placebo-treated eyes (P < .001). In other words, in nearly half the eyes with macular holes the holes were healed without surgery, without a gas bubble injection, and without any face-down positioning that would normally have been required following surgery.
Lower Vitrectomy Rate
Not all patients had release of the adhesions, and some patients in both the ocriplasmin and placebo groups went on to vitrectomy. In the published trials, the decision to perform vitrectomy was left to the discretion of individual patients and their physicians, and many patients in both groups elected not to have surgical procedures. Although the percentage of patients in the ocriplasmin group who went on to vitrectomy within 6 months was lower (17.7%) than that of the control group (26.6%, P = 0.02), the actual effect of ocriplasmin in obviating vitrectomy is not known because of the potential for patient selection bias in the trial.
So, while the avoidance of vitrectomy is a chief reason for using ocriplasmin, at this point clinicians should not use the published rate of vitrectomy reduction as a guide for discussion with patients. If surgery is ultimately needed, previous ocriplasmin treatment appears not to interfere with later vitrectomy—there is even a possibility that it may facilitate the surgery, although at present ocriplasmin should be considered an alternative, rather than an adjunct, to surgery.4
Few Adverse Events
Patients given ocriplasmin had a higher rate of ocular adverse events than those given placebo, but many of these events, such as an increase in the incidence of floaters and flashing lights (photopsia), were actually the result of the action of ocriplasmin as it dissolved the vitreous adhesion. Injection-related eye pain was reported in about twice as many patients in the ocriplasmin group (13.5%) as in the placebo group (5.9%). The majority of these cases were transient and mild in severity.
There was no increase in the level of serious adverse events from ocriplasmin. Patients should be told to expect some transient symptoms from the injection, consistent with the mechanism of the drug, and that the symptoms should subside within about a week.
What JETREA Means to Clinicians
On the basis of current trial results, JETREA appears to be a welcome alternative to watchful waiting and should be offered as an option to patients who present to the clinic with symptoms arising from VMA. Although patients may resist the idea of an injection into the eye, the procedure is generally painless, and less invasive and disruptive to the patient’s life than surgery would be.
Because JETREA is safer than vitrectomy, we can now treat patients much earlier, hopefully before damage to the retina has occurred (eg, macular hole formation). Earlier and less disruptive treatment of symptomatic VMA promises to be a great advance for patients.
Because some vitreomacular adhesions resolve without treatment, JETREA should not be offered to asymptomatic patients in whom adhesion is noted as an incidental finding on an OCT performed for other reasons. Physicians administering this treatment should be comfortable using OCT and administering intravitreal injections. Should one injection of JETREA not resolve the condition, vitrectomy should be considered—repeated injections of JETREA are not recommended at this time.
In the future JETREA may find application in the areas of diabetic macular edema and exudative macular degeneration, conditions where vitreous adhesion is associated with poorer outcomes. Clinical trials with JETREA are under development for both those conditions. Further trials and clinical experience may also refine the characteristics of the patients who benefit most from ocriplasmin.
THE BOTTOM LINE
Jetrea® is an appropriate alternative to watchful waiting for any patient with symptomatic VMA, and offers the promise of reducing the need for vitrectomy.
Peter K. Kaiser, MD, holds the Chaney Family Endowed Chair for Ophthalmology Research and is a professor of ophthalmology at the Cleveland Clinic Lerner College of Medicine. He is also the Founding Director of the Digital Optical Coherence Tomography Reading Center at the Cole Eye Institute. He is a consultant for Alcon, Novartis, and Bausch+Lomb. Freelance writer Zaid Smith, PhD, assisted in the preparation of this article.
1. Tsui I, Pan CK, Rahimy E, Schwartz SD. Ocriplasmin for vitreoretinal diseases. J Biomed Biotechnol. 2012;2012:354979.
2. Jetrea prescribing information. Iselin, NJ: ThromboGenics, Inc. October, 2012.
3. Stalmans P, Benz MS, Gandorfer A, et al. Enzymatic vitreolysis with ocriplasmin for vitreomacular traction and macular holes. N Engl J Med. 2012;367:606-15.
4. 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;117:791-7.