Choosing the Right Patients for Ocriplasmin

Subgroup analyses from the Phase III trials provide clear guidance for succeeding with the first nonsurgical treatment for symptomatic VMA.

Choosing the Right Patients for Ocriplasmin

Subgroup analyses from the Phase III trials provide clear guidance for succeeding with the first nonsurgical treatment for symptomatic VMA.


As the first FDA-approved pharmacologic treatment for symptomatic vitreomacular adhesion (VMA), ocriplasmin ( Jetrea, ThromboGenics) is a true breakthrough. Relieving VMA and the complications caused by related traction with an injection was a previously unavailable option and is often a more attractive treatment strategy for both doctors and patients, whose only options had been vitrectomy or hoping for an acceptable outcome with observation. Ocriplasmin changes how patients with symptomatic VMA can be managed. It gives those who would have required surgery a chance to avoid it, and offers those who aren’t candidates for surgery, a chance to regain clear vision.

The ocriplasmin molecule is a bioengineered, truncated form of human serine protease plasmin (Figure 1). Its properties make it capable of liquefying the vitreous and separating it from the retina, both of which are necessary to successfully release VMA (Figures 2 and 3). FDA approval of ocriplasmin was based on the results of two multicenter, randomized, double-blind, Phase III clinical trials (MIVI-TRUST) that compared a single 125-μg intravitreal injection of ocriplasmin (n=464) with a placebo injection (n=188) in patients with symptomatic VMA.1 The primary end point was resolution of VMA at day 28, which was achieved in 26.5% of ocriplasmin-injected eyes and in 10.1% of placebo-injected eyes (P<0.001). Among the secondary end points was nonsurgical closure of macular hole at 28 days, which was achieved in 40.6% of ocriplasmin-injected eyes and in 10.6% of placebo-injected eyes (P<0.001). In the trials, ocriplasmin was generally well-tolerated. Most adverse events were mild and transient.


Figure 1. The ocriplasmin molecule is a truncated form of human serine protease plasmin. It is produced using recombinant DNA technology.

Understanding of Results Requires a Closer Look

Mitchell S. Fineman, MD, associate surgeon at Wills Eye Institute and associate professor of Ophthalmology at Jefferson Medical School of Thomas Jefferson University Hospital in Philadelphia, was the principal investigator at Wills in the ocriplasmin trials. In the first several months after its FDA approval, he used the new treatment on seven patients. For now, he considers it only for patients he expects would achieve the best outcomes based on the clinical trial data. That information is found in the subgroup analyses, he said. “It’s important to look at the breakdown of the numbers. The 26.5% success rate for resolution of VMA and the 40.6% success rate for macular hole closure represent all patients in the trial. For specific groups of patients, the rates were much higher. The size of the adhesions and the size of the macular holes were key predictors of the success of ocriplasmin. VMA resolved in 33.6% of patients whose adhesions were ≤ 1,500 μm. Only 10.3% of adhesions larger than 1,500 μm resolved. In patients with macular hole who didn’t undergo vitrectomy, if the hole was larger than 250 μm the closure rate was 24.6%. However, if the hole was ≤ 250 μm the closure rate jumped to 58.3%.”


Figure 2. Ocriplasmin used in the treating of vitreomacular adhesion.

Dr. Fineman also emphasized the results of another prespecified analysis in the trial, ocriplasmin’s performance in the presence vs. the absence of an epiretinal membrane (ERM). Among patients treated with ocriplasmin who did not have an ERM, 37.4% had nonsurgical resolution of VMA compared with 14.3% in the placebo group (odds ratio, 3.79; 95% CI, 2.09 to 7.22; P<0.001). Among patients treated with ocriplasmin who had an ERM, resolution of VMA occurred in 8.7% compared with 1.5% in the placebo group (odds ratio, 6.20; 95% CI, 0.93 to 265.068; P=0.046).

“The stratified data clearly show that patients with focal areas of VMA and patients with smaller versus larger macular holes do better,” Dr. Fineman said. “Therefore, when I am evaluating patients, I look for those characteristics in order to achieve the best outcomes. In addition, patients with ERMs are not good ocriplasmin candidates. This makes sense intuitively as well. Even if we could cleave the VMA with ocriplasmin, the membrane might still be compromising vision and surgery would be needed to remedy it.”

MIVI-TRUST Enrollment Criteria

The following inclusion and exclusion criteria were utilized in the Phase III MIVI-TRUST clinical trials of ocriplasmin ( Jetrea) for the treatment of vitreomacular adhesion and macular holes:


■ At least 18 years of age

■ Presence of focal vitreomacular adhesion (i.e., central vitreal adhesion within 6 mm OCT field surrounded by elevation of the posterior vitreous cortex) that in the opinion of the investigator is related to decreased visual function (e.g., metamorphopsia, decreased visual acuity or other visual complaint)


■ Any evidence of proliferative retinopathy (including proliferative diabetic retinopathy or other ischemic retinopathy involving vitreoretinal vascular proliferation) or exudative AMD or retinal vein occlusion in the study eye

■ Any vitreous hemorrhage or other vitreous opacification that precludes either of the following: visualization of the posterior pole by visual inspection or adequate assessment of the macula by either OCT and/or fluorescein angiogram in the study eye

■ Macular hole diameter > 400 μm in the study eye

■ Aphakia in the study eye

■ High myopia (more than 8D) in the study eye (unless prior cataract extraction or refractive surgery makes refraction assessment unreliable for myopia severity approximation, in which case axial length >28 mm is an exclusion)

Is Ocriplasmin Changing the VMA Treatment Paradigm?

The availability of ocriplasmin has changed Dr. Fineman’s management of VMA patients the most in regard to whom he chooses to treat rather than observe. “In the past, I would have preferred observation over surgery for patients if their visual acuity wasn’t very poor, even if they were bothered by their visual symptoms. Now, I’m more likely to use ocriplasmin in those cases. It’s shifted the ratio toward more reward and less risk.” Ocriplasmin has changed his approach in another way, too. “It’s been my experience that 50% of patients with a stage 1 macular hole being pulled on by the vitreous progress to a full-thickness or stage 2 hole. The problem is I wouldn’t know which 50% would progress and which 50% would spontaneously release. In this situation, I see ocriplasmin as a good option that lies between surgery and observation. I strongly consider using it for stage 1 holes with traction to prevent the conversion to a stage 2 hole and further vision loss.”

In five of the seven patients Dr. Fineman treated with ocriplasmin in the months following its approval, VMA resolved with no further treatment (Figures 4 and 5). The other two patients, both of whom had macular holes, subsequently underwent vitrectomy. One of those patients had a stage 2 hole with traction on one of the flaps, which converted to a stage 3 hole following treatment with ocriplasmin (Figures 6 and 7). “Ocriplasmin released the traction but didn’t close the hole,” he explained. “The treatment worked in the sense that I didn’t have to alleviate the traction during surgery.”

George A. Williams, MD, professor and chair of the Department of Ophthalmology at Oakland University William Beaumont School of Medicine, is also limiting his initial use of ocriplasmin to eyes with the best prognoses according to the Phase III trial results — focal adhesions with no ERM and small early-stage holes (Figures 8-10). “I’m using it in those specific situations, which are a subset of the cases in which I would have recommended surgery in the past,” he said. “The trials showed the injection works best for early small macular holes, so I tell those patients they should have surgery relatively soon or we can try ocriplasmin, which gives them an approximately 60% chance of being able to avoid surgery. And, as was seen in the trials, if the treatment doesn’t have the desired outcome, the probability of a successful surgery isn’t diminished.”

Dr. Williams added that he also discusses ocriplasmin with patients who have had persistent VMA but don’t want to have surgery because their visual symptoms are bothersome but tolerable. For example, “One of my patients had chronic symptomatic VMA for more than a year but was averse to surgery. She was, however, willing to try ocriplasmin, which we did and it was successful.”

Four of Dr. Williams’ first five ocriplasmin patients experienced successful outcomes, he said. “Vitrectomy for VMA has a high success rate, but success comes at the price of the risks of the surgery itself and the recovery time, which often includes the need for a gas or air bubble and head positioning, so it’s not a trivial undertaking. We all have limited experience with ocriplasmin, but so far mine has been positive in that I’ve been able to avoid taking most patients I have treated to the OR.” Dr. Williams also noted that in his first three successful ocriplasmin cases, VMA resolved within the first week post-injection. “In the MIVI-TRUST trials,” he said, “VMA resolved in 70% of the treated eyes by seven days.”


Figure 3. Vitreomacular adhesion diagnosed using OCT.


Figure 4. Left eye with focal VMA prior to treatment with ocriplasmin.


Figure 5. Left eye with resolution of focal VMA following a ocriplasmin injection.


Figure 6. Right eye with a stage 2 macular hole and traction before treatment with ocriplasmin.


Figure 7. Right eye three days after ocriplasmin injection. Traction on the stage 2 hole released, leading to a stage 3 hole.


Figure 8. Pre-ocriplasmin OCT of a stage 2 macular hole in a 64-year-old patient with progressive visual loss and metamorphopsia for 1 month. Visual acuity was 20/150.


Figure 9. One week post-injection, visual acuity improved to 20/60.


Figure 10. One month post-injection, visual acuity improved to 20/40.

The first patient Jay S. Duker, MD, chairman of the Department of Ophthalmology at the Tufts University School of Medicine and ophthalmologist-in-chief at Tufts Medical Center in Boston, treated with ocriplasmin outside the clinical trials was a 79-year-old female with bilateral vitreomacular traction (VMT). Her visual acuity was 20/40 in the right eye and 20/60 in left eye. She underwent ocriplasmin injection in the left eye and returned one day later with symptoms of flashing lights and decreased vision. Her acuity had dropped to 20/100. By one week after treatment, the VMT had resolved, and her new symptoms were gone. Vision had returned to baseline, and the subretinal fluid had decreased. At 2 months after treatment, she was 20/50 with mild persistent subretinal fluid.


“In the past, I would have preferred observation over surgery for patients if their visual acuity wasn’t very poor, even if they were bothered by their visual symptoms. Now, I’m more likely to use ocirplasmin in those cases. It’s shifted the ratio toward more reward and less risk.”

—Mitchell S. Fineman, MD

Take-Home Points from the Ocriplasmin Phase III Trials

■ Success depends on appropriate patient selection — focal vitreomacular adhesions, small early-stage macular holes, no epiretinal membrane.

■ Most patients experience worsening symptoms, i.e., flashes, floaters and/or reduced vision, before they improve.

■ If ocriplasmin does not induce the release of the vitreomacular adhesion within a month after injection, it likely will not.

■ Vitrectomy is not precluded for patients who do not achieve posterior vitreous detachment with ocriplasmin.

■ Also, prior to use, ocriplasmin must be stored in a freezer at or below -4°F (-20°C) in its original package. At room temperature, it thaws within a few minutes.

– Mitchell S. Fineman, MD

Currently, Dr. Duker is reserving the use of ocriplasmin for patients on whom he plans to perform surgery. That includes all macular hole patients as long as they have a small or medium-size hole (<250 μm or 250-400 μm) and persistent vitreomacular traction, meaning the hyaloid is still attached to the hole. “If they agree and the injection works, that’s terrific,” he said. “If it doesn’t work, we can proceed with surgery.” Further explaining his approach, he continued, “I prefer to use the term vitreomacular traction because that’s what we are really treating with ocriplasmin. The approved indication — symptomatic VMA — is essentially a new term. VMA is a common finding on OCT, but often it’s not causing any problems. Interestingly, the labeled indication for ocriplasmin in Europe is VMT.”

Dr. Duker doesn’t plan to use ocriplasmin for larger macular holes or vitreomacular adhesions broader than 1,500 μm unless new evidence is presented to suggest it works in those situations. “I may consider using it for mild to moderate traction (too mild to go to the operating room) when I personally have more experience with it and some post-approval studies are made available,” he said.

Educate Patients About What to Expect

Doctors using ocriplasmin say it’s crucial to ensure patients understand they may experience flashes, floaters and/or decreased vision following the injection. These symptoms indicate the treatment is working by creating a posterior vitreous detachment. “Symptoms are subjective, so not every ocriplasmin patient may notice them, but the majority of my patients have experienced them at some level,” Dr. Williams said. According to Dr. Fineman, most of his patients noticed the symptoms within a few days of treatment and some had them persist for 2-3 weeks. “Some people have a significant response and it can be disconcerting for them,” he said. “One of my patients described what she experienced as ‘like a war going on.’ In general, these symptoms come and go in the first few weeks, but clearly we need to give patients fair warning.”

Potential for Use in Other Vitreo-retinopathies

While the general approach to using ocriplasmin in clinical practice at this time is conservative, doctors are eager to see whether further study and experience lead to an expansion of its use. Areas of inquiry will likely include whether repeat or higher doses of the drug could be safe and more effective and how it might perform in conjunction with other treatments such as anti-VEGF agents for conditions in which VMA or retinal traction are believed to play a role. Ocriplasmin may also have potential as a surgical adjunct whereby a preoperative injection might weaken adhesions to make complex procedures easier or reduce complications. More precise delivery methods could also emerge. “Ultimately what we care about is maximizing patients’ vision and minimizing their risk and costs,” Dr. Duker said. “We are able to accomplish those goals with ocriplasmin in many cases and perhaps we will be building on that in the future.” ■


1. Stalmans P, Benz MS, Gandorfer A, et al.Enzymatic vitreolysis with ocriplasmin for vitreomacular traction and macular holes. N Engl J Med 2012;367:606-615.