Spotlight ON TECHNOLOGY & TECHNIQUE

A Pharmaceutical Treatment for VMA

One injection of Jetrea can resolve vitreomacular adhesion without vitrectomy.

By Bill Kekevian, Associate Editor

More than 20 years in the making, the first pharmaceutical therapy for the treatment of symptomatic vitreomacular adhesion (VMA) was approved by the FDA in October following a unanimous 10-0 endorsement by an FDA advisory committee.

Ocriplasmin, formerly known as microplasmin, developed by Belgium-based ThromboGenics with a major assist from two American retina specialists, will be marketed under the brand name Jetrea.

“In the past the only management options for vitreomacular adhesion and macular holes were watchful waiting and vitrectomy,” says Peter Kaiser, MD, of the Cleveland Clinic. “With Jetrea, we now have a third option that allows us to treat patients earlier and without the need for vitrectomy (and face-down positioning) with a quick, in office, procedure.”

Risk of Vitrectomy

With vitrectomy, the risk of retinal detachment and infection is ever present, according to Julia Haller, MD, ophthalmologist-in-chief of the Wills Eye Institute, Philadelphia. Adds Dr. Kaiser, “While generally safe, vitrectomy does impact the patient’s quality of life since it requires taking time off from work, will lead to cataract acceleration in phakic patients, and is not without surgical risk.” Those risks include retinal tears, endophthalmitis and the cataract formation.

Vitrectomy typically lasts over an hour and requires the use of multiple instruments — added time and expense for the surgeon. For patients, it means all the drawbacks of major surgery: fasting the night before, preoperative adjustment to any medications, postoperative antibiotics and days of recovery.

In contrast, the recommended dose of Jetrea is 0.125 mg (0.1mL) of the diluted solution administered as a single intravitreal injection to the affected eye. Jetrea comes in a single-use vial for intravitreal injection.

Ocriplasmin, here in its molecular form, contains a recombinant protease that dissolves the proteins binding the vitreous to the macula and causing traction to induce vitreous liquification.

Jetrea’s Genesis

The pursuit of an autologous plasmin injection started in 1989 with Michael T. Trese, MD, and George Williams, MD, of Royal Oak, Mich. They were seeking a way to separate the retina from the vitreous in infants, not so much as an alterative to, but more as an adjunct to surgery. In early tests, however, the pair began to see the potential of the proteolytic enzyme.

In 2004, ThromboGenics was primarily a cardiovascular company. That company had already been researching a recombinant truncated form of plasmin enzyme, but was primarily interested in its potential for cardiovascular use. That year, ThromboGenics entered into a collaborative agreement with Drs. Trese’s and Williams’s company, NuVue, that enabled ThromboGenics to continue the development process for ocriplasmin, which had been referred to as microplasmin until then. Today, ThromboGenics refers to Jetrea as its lead product and says its focus is developing ophthalmic medicines. Alcon Laboratories purchased the international rights to the drug earlier this year.

Patient Selection

Pravin Dugel, MD, of Retinal Consultants of Arizona in Phoenix and an investigator in the ocriplasmin trials, is optimistic about the future of Jetrea and its impact on retina practice. “Jetrea provides a new dimension of therapeutic application for patients with retinal disease,” he says. “The potential for its use is enormous.”

He points out that the key to the proper use of Jetrea and success in patients lies in careful patient selection. “It is essential to understand the sub-group analyses of the two phase 3 clinical trials,” he adds. He notes these three types of patients would be candidates for Jetrea:

■Those with VMA of 1,500 μm or less, or a macular hole no larger than 250 μm. These patients had Level I evidence (based on the levels for evidence-based medicine the US Preventive Services Task Force uses) of success in the subanalysis of the MIVI-TRUST (Microplasmin for intravitreous injection-traction release without surgical treatment) trials, Dr. Dugel says. “The success rate in such patients with a single injection is approximately 40% and 60%, respectively,” he says. When the drug becomes commercially available in January, Dr. Dugel suspects this group would be the first choice of patients.

■ Those with an unfavorable vitrectomy risk-benefit ratio, but with real, debilitating VMA. An example of such a patient would be someone with 20/40 vision who is an artist. This patient population represents a large unmet need. Other factors may indicate a good chance of success with Jetrea in these patients, although direct Level I evidence may be lacking, Dr. Dugel says.

■ Those in whom Jetrea may be used as part of a combination treatment. “It is important to note that we have no scientific data yet on this group of patients regarding Jetrea,” Dr. Dugel says. “However, we do have data that vitreomacular adhesion may play an important role in many diseases that we treat on a daily basis, such as neovasular macular degeneration, branch retinal vein occlusion and diabetic macular edema. It is clear that anti-VEGF monotherapy, while very effective, is not a sustainable treatment model. The most effective and sustainable treatment model would likely be a combination treatment model … and Jetrea may have a major role here.”

If the evidence bears out this indication, Jetrea may grow to have wide application across many retinal diseases. Jetrea treatment does not rule out vitrectomy later on in refractory cases, Dr. Kaiser says. “The safety from the clinical trials was excellent, and in cases where the hole does not close with Jetrea, we still have the option of proceeding to vitrectomy with similar surgical results as those patients not receiving the drug,” he says.

How Jetrea works

Unresolved VMA has been associated with 88% of macular holes.¹ Ocriplasmin contains a recombinant protease that dissolves the proteins binding the vitreous to the macula and causing traction. It essentially induces vitreous liquification. The vitreous then separates itself from the retina. Studies showed not only did the injection induce this separation, but also managed to close macular holes.

“In vitreomacular traction (VMT), we often waited for a considerable loss of vision before proceeding to vitrectomy, leaving patients symptomatic for a long time,” Dr. Kaiser says. “Jetrea can be used on these patients at baseline with a very good chance of success in releasing the VMT.” He previously reported that a single injection of ocriplasmin can get closure of a full thickness macular hole (<400 μm in diameter) in about 40% of cases.²

The Phase 3 Study

Dr. Haller took part in the MIVI-TRUST study, led by Peter Stalmans, MD, on which the FDA based its approval.³ The phase 3 trial results showed injections of ocriplasmin were significantly more effective in resolving VMT and closing macular holes than a placebo. Of 652 eyes, 464 were treated with ocriplasmin; 26.5% showed resolution of vitreomacular adhesion within 28 days, and 40.6% achieved non-surgical closure of macular holes.³

The study also showed 68.4% of eyes treated with ocriplasmin experienced adverse ocular events, including vitreous floaters, photopsia, eye pain or conjunctival hemorrhage. These adverse events were also seen in 53.5% of eyes injected with a placebo. OM

References

1. Le Goff MM, Bishop PN. Adult vitreous structure and postnatal changes. Eye (Lond). 200;22:1214-1222.

2. Kaiser PK, Ocriplasmin for the treatment of macular holes, Presented at: Retina 2012, January 15-20, Maui, Hawaii.

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: 606-615.

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