Pharmacologic Vitreolysis for Retinal Disease

New options for separating the vitreous from the retina have the potential to improve care in several conditions.

DEREK KUNIMOTO, MD, JD

There are a number of conditions in which inducing a posterior vitreous detachment may be desirable. For example, a PVD can relieve symptomatic vitreomacular adhesion (VMA) or vitreomacular traction (VMT), reduce the risk of macular traction and fibrosis in proliferative diabetic retinopathy, as well as the tractional complications of PDR, and it plays a role in the spontaneous closure of early-stage macular holes.

The primary method for achieving this separation has been natural aging or surgical vitrectomy. However, surgeons have no sway over spontaneous PVD in aging, and the risks and costs of invasive surgery have meant that vitreoretinal specialists often prefer observation.

Moreover, vitrectomy is not always successful in addressing the underlying condition, and it can be very challenging in, for example, pediatric eyes. Therefore, there has long been interest in developing pharmacologic methods of vitreolysis.

Ocriplasmin (Jetrea, ThromboGenics, Iselin, NJ), a proteolytic enzyme that acts on fibronectin and laminin, is thus far the only commercially available agent for vitreolysis. The approved indication for this drug is not full PVD; rather, it is indicated simply for the treatment of symptomatic VMA.

In clinical trials, 26.5% of subjects achieved VMA release within a month of a single ocriplasmin injection vs 10.1% with saline injection.¹ The proportion of VMA resolution was higher in certain subgroups (eg, women, phakic subjects, younger subjects, and those with smaller adhesions or no epiretinal membrane).²

However, a very small but measurable percentage of patients experience permanent loss of vision, intraocular inflammation, or disabling photopsias following intravitreal injection of ocriplasmin. Postmarket studies have shown an acute decline in visual acuity in as high as 17% of cases.³

Testing of this agent in the diabetic eyes that might benefit most from pharmacologic vitreous separation has been limited. For all of these reasons, I have tended to continue to prefer the predictability of vitrectomy.

ANTI-INTEGRIN THERAPY

Another promising pharmacological approach is anti-integrin therapy. The first agent in this class, Luminate (Allegro Ophthalmics, San Juan Capistrano, CA), is now being evaluated in clinical trials, in several of which I am participating as an investigator.

Integrins are cell adhesion and cell signaling receptors that regulate how cells communicate with each other and with the extracellular matrix. Luminate (Figure 1) binds to multiple integrin receptor sites, including three (α_vβ₃, α_vβ₅, α₅β₁) that are closely associated with choroidal or preretinal angiogenesis and one (α₃β₁) that mediates the attachment of the vitreous to the retinal surface.

Figure 1. Luminate (ALG-1001) binds to the α₃β₁ integrin receptor. The proposed mechanism of action is that this competitively inhibits the integrin receptor from attaching to the extracellular matrix, releasing cellular adhesion and inducing posterior vitreous detachment.

Early animal studies showed that targeting integrin α₃β₁ induced vitreous liquefaction and PVD,⁴ and in a phase 1 safety study, six of 11 subjects with DME who had no or only partial PVD at baseline developed total PVD by day 90 following treatment with Luminate.⁵ That finding has led to two additional trials to further investigate the drug’s proposed vitreolytic mechanism of action.

VMA/VMT STUDY

A placebo-controlled, randomized, double-masked, dose-ranging, phase 2 study of the efficacy of Luminate in inducing PVD in eyes with VMA or VMT was recently completed. This study evaluated several doses of Luminate (2.0, 2.5, and 3.2 mg), compared to a control group that received a BSS injection.

Although statistical analysis is ongoing, we already know that 65% of eyes treated with the 3.2-mg dose of Luminate achieved release of VMA or VMT at three months, compared to 10% of those in the control group (P=.0129). Nearly half the eyes had release after the first injection; the average number of injections in the 3.2-mg group was 1.6.

Although there was no change in macular hole size from baseline to time of release, there was a clinically meaningful decrease in central macular thickness in all of the Luminate-treated groups compared to baseline, which can be considered evidence of the drug’s antipermeability properties, in addition to its vitreolytic properties.

What is striking to me about the results is how well tolerated anti-integrin therapy seems to be. So far, with nearly 800 human eyes injected, there have been no reports of intraocular inflammation, retinal tears, or detachment and, most importantly, no photoreceptor dysfunction or neurotoxicity.

If the evidence continues to suggest relatively high treatment efficacy with a good safety profile, pharmacological separation may be warranted earlier and more frequently than I would now recommend vitrectomy.

Advances in retinal imaging have demonstrated how even minor adhesions and traction might be associated with disruption of the underlying retinal architecture, with corresponding metamorphopsia. Additionally, pharmacologic separation of the vitreous as an adjunct to vitrectomy could quickly become the standard of care in pediatric cases, greatly improving the quality of care in young eyes.

DIABETIC RETINOPATHY

Luminate is also in phase 2 trials for PVD in nonproliferative DR. The ongoing study is a randomized, double-masked, placebo-controlled, multicenter, dose-ranging trial that will enroll 100 subjects in all. It is designed to evaluate the safety and efficacy of intravitreal injections of Luminate in patients with NPDR.

Patients can be enrolled regardless of anti-VEGF treatment status. They are randomized to one of four groups that include three Luminate groups (1.0 mg, 2.0 mg, or 3.0 mg) and a placebo group. All of the study subjects will return for examinations every four weeks for three months.

This is an exciting area of research for me. New approaches to DR are still very much needed. While anti-VEGF therapy has proved efficacious in the treatment of DR and DME, it does not generally cause the rapid and significant improvement in vision or the “wow” effect for patients that it has for age-related macular degeneration and retinal vein occlusion.

Furthermore, while a shared disadvantage for anti-VEGF therapy in all of the aforementioned diseases is the burden of a mostly monthly treatment cycle, this burden is aggravated in DR by the large and growing population of diabetic patients, the younger age group of DR patients, and their longer treatment durations.

Several studies have shown that complete PVD can inhibit the development of DR or reduce the chance of progression to PDR.^6-8 Perhaps most notably, Ono and colleagues found that PVD dramatically reduced the rate of progression from NPDR to PDR over a three-year period, from 35% to 40% of subjects without PVD to ≤5% in the presence of a PVD.⁶

The retina community remains divided as to whether inducing a PVD will indeed alter the course of DR, partly because we do not currently have any way to easily and safely induce a PVD.

The first step—as this trial is undertaking—is to determine whether anti-integrin therapy can effectively and consistently induce a PVD (Figure 2). If it can, then it will set the stage for further investigations into the types of patients who might benefit from PVD.

Figure 2. In this ultrasound image, the arrows point to a total PVD with the vitreous surface free-floating and not attached to the retina. The PVD occurred after treatment with Luminate in a DME proof-of-concept study.

One can certainly imagine that PVD could be beneficial at various stages of DR. Early on, it may help to prevent or slow progression to PDR. Moreover, in those patients who already have more advanced forms of DR, it could keep the vitreous from serving as a scaffold for the growth of blood vessels through the vitreous, where their presence can exert the most harmful tractional forces perpendicular to the retina.

OTHER DIRECTIONS

Beyond vitreolysis, anti-integrin therapy is purported to have another, potentially as important, mechanism of action: antiangiogenesis. Early clinical evidence suggests that it is quite effective in drying up leakage from existing neovascularization, inhibiting the growth of abnormal blood vessels, and turning off production of new blood vessels. The drug is currently in phase 2 clinical trials for DME and will soon be in phase 2 wet AMD trials.

Both of these mechanisms of action are very promising, and I look forward to seeing the results of upcoming clinical trials and whether anti-integrin therapy can add to our armamentarium for the treatment of a wide range of vitreoretinal conditions. In particular, a minimally invasive, nonsurgical option for separating the vitreous from the retina could provide an important new option for vitreoretinal surgeons and our patients. RP

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