Enzymatic vitreolysis could mark beginning of new era in treating vitreomacular interface diseases

Pharmacotherapy may set a new standard of care for symptomatic vitreomacular adhesion and vitreomacular traction-related macular hole, according to recent findings.

“We are at the beginning of a new era. Attempts to produce enzymatic vitreolysis have been made for many years without success. Ocriplasmin is the first drug to have proved safe and effective, but research is ongoing, and in the future other drugs will follow,” Peter Stalmans, MD, PhD, said.

Vitreomacular traction (VMT) is an age-related progressive disease. Vitreous detachment is part of the natural aging process, beginning in the majority of people around the age of 50 years. However, in some cases, parts of the vitreous remain attached to the retina, mostly in the macular region, and start exerting traction. Typical symptoms are metamorphopsia and decreased visual acuity. Further progression may lead to central scotoma due to the formation of a macular hole.

“Because focal vitreomacular adhesion (VMA) is rarely symptomatic, it is often first discovered during routine optical coherence tomography evaluation of middle-aged or elderly patients. OCT imaging has been a tremendous step forward also in this pathology, as it allows us to verify the presence of VMA before symptoms of metamorphopsia or visual acuity deterioration are detectable,” Stalmans said.

Image: Stalmans P

Demographic data on the prevalence of VMT and VMT-related macular hole are lacking.

According to José Maria Ruiz Moreno, MD, there are potentially as many as 250,000 people in Europe with VMT.

“We also have no data on the incidence and risk rate of macular hole in VMT pathology. In some cases, VMT has no evolution. Sometimes it resolves spontaneously, and in some other cases, it develops into a macular hole. There are no prognostic and predictive factors we can rely on yet,” he said.

The recent advances in VMT management have raised new interest in this field, and research is likely to bridge knowledge gaps in the near future.

“We are now working on our database, analyzing the over 1,000 cases of patients diagnosed with VMT in our hospital over the last 3 years. Since ocriplasmin has not been an option so far, these patients were only followed, and we’ll be able to see in what percentage the disease resolved spontaneously or progressed,” Stalmans said.

Another study, based on population screening, will provide information on VMT incidence.

“It’s a project we have developed within the Science Week in [Belgium]. Our hospital department will be opened, and we’ll have five OCTs to provide free examination to all visitors. We are expecting more than 1,000 visitors, and this should give us a fair idea of how often VMA and VMT occur in the general population,” Stalmans said.

A new option

Until recently, observation and vitrectomy were the only two options for patients with VMT and/or macular hole.

“Watchful waiting means that following diagnosis, patients may undergo a period of observation. In the best case, VMT resolves spontaneously and the patient will not require a surgical intervention. However, the prolonged process of monitoring patients until their visual symptoms deteriorate carries the risk of disease progression, complications and, in some cases, serious irreversible macular damage. Furthermore, watchful waiting often negatively impacts the patient’s physical symptoms and quality of life,” Albert J. Augustin, MD, said.

Pars plana vitrectomy, on the other hand, carries potential risks and complications. Thus, surgery was performed only in patients who were greatly affected by the symptoms of VMT and/or macular hole. These patients were usually in the later stages of the disease, he said.

The choice of whether and when to do surgery was based entirely on personal criteria, Julia A. Haller, MD, said.

“The worsening of vision was a very generic parameter, and everybody had a different measure of what was considered appropriate. For most people it was severe vision loss or full-thickness tear in the retina. Visual acuity could be recovered to a certain extent, but the longer you wait and the worse the vision is, the harder it is to recover it,” she said.

“With 20/200 vision, which was on average the moment we recommended surgery, we were already at a stage where VMT had caused permanent damage to the retina, and the best we could achieve in terms of visual acuity was 20/50 to 20/40,” Stalmans said.

Enzymatic vitreolysis is a third option that can potentially replace surgery and allow for earlier intervention and a better visual acuity gain, he said.

About ocriplasmin

Ocriplasmin, formerly known as microplasmin, is a recombinant, truncated form of the human serine protease plasmin. It is four times smaller and contains only the active part of the plasmin molecule.

Preclinical studies have shown that ocriplasmin primarily targets the fibronectin, laminin and collagen fibers that make the vitreous adhere to the retina. Compared with mechanical separation by vitrectomy, this pharmacological option may provide a bare internal limiting membrane with no residual vitreous, adhesions or collagen remnants, Augustin said.

The MIVI-TRUST studies

In August 2012, the Microplasmin for Intravitreous Injection-Traction Release without Surgical Treatment (MIVI-TRUST) study group published the results of two multicenter, randomized, double-masked, phase 3 clinical trials comparing a single intravitreal injection of ocriplasmin (125 µg) with a placebo injection in patients with symptomatic vitreomacular adhesion. Primary endpoint of the studies was resolution of vitreomacular adhesion at day 28. Secondary endpoints were total posterior vitreous detachment, nonsurgical closure of a macular hole at 28 days, avoidance of vitrectomy and change in best corrected visual acuity.

In total, 652 patients were enrolled. Resolution of vitreomacular adhesion was obtained in 26.5% of ocriplasmin-injected eyes vs. 10% of placebo-injected eyes. Macular hole closure was achieved in 40.6% of ocriplasmin-injected eyes vs. 10.6% of placebo-injected eyes. At 6 months, fewer patients in the ocriplasmin group (17.7%) had undergone vitrectomy compared with the placebo group (26.6%).

In the total study population, an improvement of three or more BCVA lines was reported in 12.3% of eyes injected with ocriplasmin vs. 6.4% of eyes injected with placebo.

“Contrary to what it may appear, this gain is significant if we take into account the so-called ceiling effect. Many of the patients had good visual acuity, up to 20/30, and these patients could not gain more than one line. That’s why the primary outcome of the trial was not VA but the release of traction on OCT,” Stalmans said. “The MIVI-TRUST was the first clinical trial ever where the [U.S. Food and Drug Administration] approved that OCT and not VA could be used as the primary outcome.”

Ocular adverse events were reported in 68.4% of eyes in the ocriplasmin group and 53.5% of eyes in the placebo group. They were predominantly mild and transient, mainly related to vitreous separation, which induced flashes, floaters and some visual disturbance. After 1 week, the incidence of adverse events was significantly decreased, and no significant difference was observed between the two groups.

“You inject into the eye an enzyme that digests the protein fibers contained in the vitreous; therefore, patients start seeing floaters, and when the vitreous detaches, they see flashes,” Stalmans said.

A temporary decrease in visual acuity, even down to counting fingers, was reported in some patients in the first 24 hours after the treatment, probably due to the rapid hyaloid detachment temporarily affecting the photoreceptors.

“It is a rare event but quite scary to the patients, who should be reassured because vision always comes back the day after,” Stalmans said.

Yellowish vision, which can last several months but eventually resolves, was also seen in a few cases.

“The results of the trial were so dramatic and significant that they compelled the FDA to approve the drug,” Haller said.

Marketing clearance and reimbursement

With the brand name of Jetrea, ocriplasmin was launched in the United States in January 2013, and in March, it was approved by the European Medicines Agency. Shortly after, it was launched by Alcon, ThromboGenics’ international partner, in the United Kingdom, followed by Germany, Denmark, Finland, Norway and Sweden.

“Hopefully by the end of the year it will be launched in all countries, and national health care authorities should move fast for reimbursement. Since there is no other treatment for VMT besides surgery, it should be considered cost-effective enough to be adopted without unnecessary delays,” Ruiz Moreno said.

“I have started injecting commercial Jetrea, but patients have to pay out of pocket 3,300. I recommend it only to those I think are really good candidates. I have injected 13 patients now and 11 were successful cases, with a rigorous patient selection,” Stalmans said.

Improving success rate

“From the trial and from personal experience, we have learned which OCT parameters should be looked at to determine who the best responders are,” Stalmans said. “We have learned that patients with epiretinal membranes are not good candidates, and one-third of the patients in the MIVI-TRUST had epiretinal membranes. This brought down the success rate. We also know that larger macular holes, typically more than 250 µm, are less likely to close. The study included large macular holes, and also this brought down the success rate.”

There was significantly more success in phakic eyes. This could be explained by looking back on the effects of cataract surgery on vitreomacular adhesion, according to Stalmans.

“Since the artificial lens is much smaller in size compared to the natural lens, the size of the vitreous cavity is enlarged, the vitreous gets more space and, as a result, will detach spontaneously from the macula in a significant number of patients. Those that survive cataract surgery are the strong adhesion cases,” Stalmans said.

Smaller size adhesion and age younger than 70 years are other predictive factors for successful surgery, he said.

A new classification system for vitreomacular interface disorders, entirely based on OCT parameters, was developed recently by an international panel of 10 retina specialists from the U.S. and Europe.

“Our research on enzymatic vitreolysis and the capabilities offered by [spectral-domain] OCT to visualize structures and subtle changes have stimulated us to develop a classification system, not based on symptoms but on objective findings,” Stalmans, who is a member of the panel of specialists, said.

The new system encompasses the whole range of pathologies related to anomalous age-related vitreous separation, such as VMT, full-thickness and lamellar macular hole, epiretinal membrane and myopic macular schisis.

“It will help us to speak a common language on the basis of SD-OCT findings and clinical signs as well as symptoms,” Augustin said.

“We will also be able to better define the role of ocriplasmin and the characteristics of best responders, leading to a higher rate of success,” he said.

Vitrectomy still plays a role

Although careful patient selection could potentially increase the success rate of ocriplasmin to at least 50%, pharmacologically induced vitreolysis cannot provide, at present, the answer for all cases, Haller said.

“There will still be a need for surgery. Ocriplasmin won’t entirely replace vitrectomy,” she said.

“What we have learned so far is that 74% of the patients, according to the study data, don’t have a solution from ocriplasmin. In my view, it would be interesting to offer it as first-line treatment, and if it doesn’t work, do surgery. The problem is cost because we might end up in many cases with the double financial burden of injection and surgery in patients where ocriplasmin doesn’t work,” Ruiz Moreno said.

VMT in AMD and DME

Phase 2 clinical trials have evaluated the effects of enzymatic vitreolysis vs. sham injection in VMT concomitant with age-related macular degeneration and diabetic macular edema.

“Releasing the vitreous earlier could potentially benefit the natural course of these diseases,” Haller said. “The phase 2 trials have shown that ocriplasmin injections were well tolerated.” – by Michela Cimberle

• References:
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• Albert J. Augustin, MD, professor and chairman of the Department of Ophthalmology, Klinikum Karlsruhe, Karlsruhe, Germany, can be reached at albertjaugustin@googlemail.com.
• Julia A. Haller, MD, ophthalmologist-in-chief at the Wills Eye Institute and professor and chair of the department of ophthalmology at Thomas Jefferson University, Philadelphia, U.S.A., can be reached at jhaller@willseye.org.
• José Maria Ruiz Moreno, MD, professor of ophthalmology at the University Castilla La Mancha and head of the retina unit at Vissum Corporation, Alicante, Spain, can be reached at josemaria.ruiz@uclm.es.
• Peter Stalmans, MD, PhD, professor of ophthalmology at Leuven University Hospital, Belgium, can be reached at peter.stalmans@uzleuven.be.

Disclosures: Augustin is a consultant to Alcon. Haller is a consultant to Thrombo-Genics. Ruiz Moreno is on the advisory board of Alcon-Novartis. Stalmans is a consultant to Alcon and holds a research grant from ThromboGenics.

What other options are there?

A different approach to surgical management

Interface disorders have a pathological vitreous attachment that, in 30% of cases, is very firm and does not easily respond to mechanical removal. Long operating sessions, working for 10 to 20 minutes near the macula, carry a high risk of causing both mechanical and phototoxic damage. For these cases where standard techniques do not work, I developed hydrolifting. After triamcinolone-assisted removal of as much vitreous as possible, I inject a current of fluid, directed away from the fovea, that gently lifts the sides of the residual attached cortical vitreous. The fluid slowly detaches all vitreous adhesions and suction or forceps can then be used for removal, causing no trauma to the macula. I use for hydrolifting the new controlled reflux system of the Alcon Constellation, but the current of fluid can also be created with a 2-cc syringe using a soft-tip flute needle. I have also created a new device that regulates the reflux of the flow and avoids the potential damage to the retina that may be caused by the impact of the fluid current.

Another option involves Jetrea (ocriplasmin, ThromboGenics), but as an aid to surgery rather than a standalone procedure. The investigation protocol we have proposed to Alcon involves the injection of ocriplasmin 24 hours prior to surgery. This should give the drug sufficient time to loosen the adhesion, making standard vitrectomy easier, faster and less traumatic. Our study is going to involve initially 250 cases with different interface pathologies. If the combined procedure proves successful, it will represent a safer, more effective new option for those 30% of patients who had to undergo vitrectomy with a high risk of complications. We expect that complication rate might drop to 3% to 4%.

Athanasios Nikolakopoulos, MD, is chairman of ophthalmology, Papanikolaou Hospital, Thessaloniki, Greece. Nikolakopoulos has no relevant financial disclosures.

A different approach to non-surgical management

Pars plana vitrectomy, or PPV, has been for many years the treatment of choice for symptomatic vitreomacular adhesion. However, the cost, risks and inconvenience of PPV have driven the development of alternatives. Pharmacological vitreolysis is an attractive concept. Ocriplasmin has raised expectations, but the well-conducted phase 3 trials show that some patients fail to respond, and there is ongoing work to refine case selection to enhance the success rate.

We recently reported a retrospective case series of patients treated with a single, intravitreal injection of perfluoropropane (C3F8) gas. We included 15 eyes with symptomatic vitreomacular traction, either idiopathic or associated with DME, or neovascular age-related macular degeneration. Perfluoropropane gas (Arceole) was injected intravitreally through the pars plana using a 27-gauge needle. Complete resolution of vitreomacular traction was achieved in 40% of the eyes at 1 month and in 60% at 6 months. Eyes with smaller areas of adhesion were more likely to respond. Complete restoration of normal foveal contour was observed on spectral-domain optical coherence tomography in 80% of those with release of vitreomacular traction. No serious complications occurred.

Our study was limited by the small number of patients, and a larger study would be required to assess the safety and efficacy of this technique. However, our findings suggest that pneumatic release of vitreomacular traction may be a safe, simple and effective alternative to PPV in selected cases. In addition, intravitreal gas has the advantage of being readily available, low-cost and minimally invasive. However, until a large study is completed to validate our preliminary findings, observation, ocriplasmin and PPV remain management options.

Tim Jackson, PhD, FRCOphth, is a consultant ophthalmic surgeon and senior lecturer, King’s College London, UK. Jackson has no relevant financial disclosures.