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Novel agent resolves vitreomacular traction, closes macular holes
Enzymatic vitreolysis with ocriplasmin dissolves laminin and fibronectin, which bind the vitreous to the retina.
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A single intravitreal injection of a biologic agent effectively resolved vitreomacular traction and closed macular holes without surgery, according to a study.
Based on results from the Microplasmin for Intravitreous Injection-Traction Release without Surgical Treatment (MIVI-TRUST) clinical trials, the U.S. Food and Drug Administration’s Dermatologic and Ophthalmic Drugs Advisory Committee unanimously recommended approval of a 125-µg dose of ocriplasmin (ThromboGenics) for the treatment of vitreomacular adhesion.
“The endpoint in the study was one that has never been used for any approval before: OCT-documented evidence of release of vitreomacular traction, an anatomic OCT-determined endpoint. All of that is brand new,” Julia A. Haller, MD, OSN Retina/Vitreous Board Member, said in a subsequent interview.
Julia A. Haller
If the FDA approves ocriplasmin, then retina specialists would have the first nonsurgical treatment for vitreomacular adhesion; vitrectomy is the only current treatment for vitreomacular traction and macular holes.
“This was particularly exciting because it was an entirely new disease that has never been approached before pharmacologically,” Haller said. “In effect, we would be doing a pharmacologic vitrectomy rather than a surgical vitrectomy, with fewer associated risks.”
Enzymatic vitreolysis with ocriplasmin liquefies the vitreous and dissolves laminin and fibronectin, which bind the vitreous to the retina.
Results of the MIVI-TRUST clinical trials were published in The New England Journal of Medicine.
Study design and endpoints
In two multicenter, randomized, double-masked, placebo-controlled phase 3 trials, 652 eyes were examined: 464 eyes received a single intravitreal injection of 125 µg of ocriplasmin, and 188 eyes received placebo. Patients were assessed at baseline, on the day of injection, and at 7, 14, 28, 90 and 180 days after injection.
Inclusion criteria were age older than 18 years, evidence of focal vitreomacular adhesion based on optical coherence tomography, and ETDRS best corrected visual acuity of 20/25 or less in the study eye and 20/800 or more in the non-study eye.
The primary endpoint was percentage of eyes with nonsurgical resolution of vitreomacular adhesion at 28 days. Secondary endpoints included percentage of eyes with total posterior vitreous detachment at 28 days, closure of macular holes, need for vitrectomy, and gains of three or more lines of BCVA.
Nonsurgical resolution
At 28 days, the percentage of patients with nonsurgical resolution of vitreomacular adhesion was significantly higher with ocriplasmin than with placebo in both trials. Overall, vitreomacular adhesion resolved in 26.5% of eyes treated with ocriplasmin and 10.1% of eyes in the placebo group (P < .001).
Total posterior vitreous detachment at 28 days was seen in 13.4% of eyes injected with ocriplasmin compared with 3.7% of eyes injected with placebo (P < .001).
Nonsurgical closure of macular holes was seen in 40.6% of ocriplasmin eyes and 10.6% of placebo eyes (P < .001).
“They are the ones for whom surgery would have been the most daunting just because of the gas bubble and the face-down positioning that would be required,” Haller said.
At 6 months, 17.7% of patients in the ocriplasmin group and 26.6% of patients in the placebo group underwent vitrectomy.
BCVA, quality of life, adverse events
BCVA improved by three or more lines in 12.3% of ocriplasmin eyes and 6.4% of placebo eyes.
National Eye Institute Visual Functioning Questionnaire-25 quality-of-life scores improved 6.1 points in the ocriplasmin group and 2.1 points in the placebo group (P = .006).
Data showed that 68.4% of eyes in the ocriplasmin group and 53.5% of eyes in the placebo group had ocular adverse events such as vitreous floaters, photopsia, injection-related eye pain or conjunctival hemorrhage.
Placebo eyes had slightly more serious ocular adverse events than ocriplasmin eyes, Haller and colleagues said.
“There were some adverse events, but there were actually more overall in the placebo-treated group than in the drug-treated group. This was because more in the placebo-treated group needed to go on to surgery,” Haller said. – by Matt Hasson
Reference:
- Stalmans P, Benz MS, Gandorfer A, et al; MIVI-TRUST Study Group. Enzymatic vitreolysis with ocriplasmin for vitreomacular traction and macular holes. N Engl J Med. 2012;367(7):606-615.
For more information:
- Julia A. Haller, MD, can be reached at Wills Eye Institute, 840 Walnut St., Philadelphia, PA 19107-5109; 215-928-3073; fax: 215-928-3853; email: jhaller@willseye.org.
- Disclosure: Haller served as a consultant for ThromboGenics and chaired the monitoring and safety committee for the phase 3 clinical trials.
Perspective
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Pravin U. Dugel, MD
Ocriplasmin will immediately fill an unmet need in patients who complain of decreased vision and metamorphopsia but have fairly good visual acuity (around 20/30 or 20/40). Currently, the only options are observation or surgical intervention. We often and appropriately choose observation. However, long-term follow-up of these patients has shown that a majority develop permanent structural changes resulting in permanent loss of vision. A pharmaceutical option with a more favorable risk-benefit ratio would fill this unmet need.
Ocriplasmin (ThromboGenics) will have an immediate role in patients with macular hole. If a patient presented to me with a small to moderate macular hole (less than 250 µm), with a single injection I would be able to offer the patient a 60% chance of closure of the hole without the risk of surgical intervention. Moreover, even if the ocriplasmin injection failed, studies have shown that the success rate with subsequent surgery would be no less. Excellent studies from Europe have shown that vitreomacular traction may have important implications in the formation of neovascular degeneration. Other studies have shown that vitreomacular traction may have an equally important impact on the development of diabetic macular edema, branch retinal vein occlusion and central retinal vein occlusion. Indeed, ocriplasmin may offer an entirely different and powerful element in combination therapy in the treatment of these important diseases.
The safety profile of ocriplasmin is excellent and has a long, consistent track record. Therefore, I predict that once we have access to this drug, many more indications and combinations will be discovered.
Finally, remember that all the studies thus far have been done with a single injection of ocriplasmin. Studies need to be undertaken to see if sequential injections will yield better results. We tend to inject in the mid-vitreous or anterior vitreous cavity as a matter of safety. If ocriplasmin can be delivered to the problem area with a novel injection device, then the success rate would be even higher. In summary, ocriplasmin offers the retina physician access to an entirely new domain of drugs. It offers the promise of filling an unmet need and enhancing combination treatment for a number of important diseases we treat on a daily basis.
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