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Pharmacologic vitreolysis may be option for vitreomacular adhesion
Ocriplasmin has also been effective in closing full-thickness macular holes.
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In recent years, the vitreous has been found to have increasing importance in a host of vitreoretinal disorders. As more is discovered about the composition of vitreous and how its structure changes with age, new modalities are evolving to manipulate the vitreous. Pharmacologic vitreolysis is an exciting area investigating the use of enzymatic 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.
The vitreoretinal interface is the site of adhesion between the posterior cortical vitreous and the internal limiting membrane. The vitreoretinal interface is composed primarily of collagen, laminin and fibronectin. Within the vitreous gel, the related processes of synchysis (liquefaction) and syneresis (fibrillar collapse) result in vitreoretinal separation. Multiple studies have shown that the majority of the population younger than 60 years has an intact vitreoretinal interface, while after 60 years there is likely a weakened adhesive force between the retina and vitreous, which can lead to posterior vitreous detachment. In some, the adhesive protein matrix may be bound tightly and lead to residual vitreoretinal adhesions. When this residual adhesion happens in the macula area, it is referred to as vitreomacular adhesion (VMA). Depending on the degree of traction exerted on the retina at the site of adhesion, various complications can result, including vitreomacular traction, macular hole, tractional diabetic macular edema, vitreopapillary traction syndrome, vitreous hemorrhage and retinal tears.
Benefits of vitreolysis
Early interest in pharmacologic vitreolysis focused on the benefit as an adjunct to vitrectomy. However, it has been recognized to have great potential as a standalone therapy. There are numerous potential benefits to pharmacologic vitreolysis, including complete separation of the vitreous from the retina, less manipulation at the vitreoretinal interface compared with current vitrectomy techniques, and a well-defined cleavage plane that prevents the development of fibrovascular membranes. Vitreolysis is also believed to facilitate enhanced oxygen supply due to the alteration of the molecular flux, which could potentially be prophylactic or preventative for the development of neovascularization in age-related macular degeneration, diabetic retinopathy and other retinal disorders.
Researchers have attempted to use a variety of pharmacologic agents to produce both the liquefaction and separation of the vitreous, including dispase, nattokinase, hyaluronidase, chondroitinase, collagenase and autologous plasmin. Jetrea (ocriplasmin, ThromboGenics), a truncated form of human plasmin, is a recombinant enzymatic protein that is smaller than plasmin, stable, sterile and clinically scalable to achieve dependable dosing. It is an enzyme and hydrolyzes fibronectin, collagen and laminin in the vitreous and the vitreoretinal interface.
Baruch D. Kuppermann
Of the various agents studied, only ocriplasmin has been able to meet the objectives of both liquefaction and detachment of the vitreous at the vitreoretinal interface while maintaining an acceptable safety profile. In preclinical studies, it succeeded in cleanly separating the vitreous from the internal limiting membrane and achieving therapeutic posterior vitreous detachment. Ocriplasmin has been shown to be effective and generally well tolerated in two large phase 3 clinical trials, the MIVI-TRUST program.
MIVI-TRUST
The program compared a single-injection of 125-µg ocriplasmin (100 µL) to a single placebo injection (100 µL) for the treatment of symptomatic VMA in 652 patients in Europe and the U.S. Patients with VMA, full-thickness macular hole at baseline, and visual acuity of 20/25 or worse were included in the clinical trials. Patients with epiretinal membranes were not excluded. Of the 464 patients who were given a single injection of ocriplasmin, 26.5% achieved VMA resolution by day 28 compared with 10.1% of the 188 subjects in the control group who received 100 µL of placebo. In 74% of responders, VMA resolution was achieved by day 7. Of the 270 patients without epiretinal membranes who received an ocriplasmin injection, 37.4% achieved resolution of VMA, compared with 14.3% of 119 subjects in the control group.
Ocriplasmin was also shown to be effective in closing full-thickness macular holes in a significant proportion of patients after a single injection. Of 106 patients with full-thickness macular holes at baseline, 40.6% experienced closure by day 28 and sustained it through the entire 6-month follow-up of the study compared with 10.6% of 47 subjects in the placebo group. For the subset of patients with a macular hole of less than 250 µm, 58.3% of 48 ocriplasmin-treated patients achieved closure of full-thickness macular holes compared with 16% of 25 subjects in the placebo cohort. The visual acuity and visual function outcomes favored the ocriplasmin group.
Pharmacological option
Ocriplasmin provides a pharmacological option for many patients in the clinic compared with the current approach in which clinicians monitor patients and wait for worsening visual symptoms and disease progression to complications such as macular hole in order to proceed to vitrectomy. In the early stages of the disease, patients with VMA typically complain of visual symptoms such as metamorphopsia despite good visual acuity. Appropriately, retina specialists are hesitant to perform vitrectomy in such patients due to the risk of complications and side effects such as cataract formation associated with vitrectomy. However, a pharmacological agent that is well tolerated could facilitate treatment of early disease, limit disease progression and restore vision in patients.
Pharmacologic vitreolysis has the potential to decrease the burden of disease on the global health care system. Decreased costs can be potentially achieved by inhibiting disease progression and reducing surgical rates. This in turn reduces patient exposure to vitrectomy-related complications such as endophthalmitis, cataracts, retinal breaks and retinal detachments, which would reduce the burden of treatment for the patient, caregiver and physician. It not only expands the treatment options available to patients and vitreoretinal specialists, but it may reduce risk to the patient, as well as increase the numbers of patients who could benefit from treatment compared with the current options of observation and surgery.