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Chemical Vitreous Manipulation May Represent New Frontier in the Treatment of Retinal Disease of Wet AMD
Ocriplasmin, a bioengineered truncated form of the human plasmin molecule, has proved effective in providing resolution of vitreomacular adhesion (VMA) and improving visual acuity and function when compared with placebo injection in two large phase 3 studies.
Pravin U. Dugel, MD, presented the pooled data from MIVI-6 and MIVI-7 during the Institut de Microcirurgia Ocular Trends in Surgical and Medical Retina Meeting in Barcelona.1 Dr. Dugel said that 26.5% of patients achieved the primary endpoint of pharmacologic VMA resolution at day 28 after one injection of ocriplasmin, with approximately 75% of these patients experiencing resolution within 1 week of injection. Enrollement criteria for the trials did not exclude patients with epiretinal membrane (ERM). “If you look at patients who did not have an ERM with one injection alone, 37.4% achieved this end goal of resolution of VMA. If you look at patients with an ERM, 8.7% had resolution of VMA, which is also statistically significant.”
Toward the secondary endpoints, 13.4% of patients achieved complete posterior vitreous detachment (PVD) and 23.7% and almost 10% gained two or three lines of vision or more, respectively. Over 40% of patients with full-thickness macular hole had closure after a single injection. For macular holes smaller than 250 µm, however, this increased to almost 60%, said Dr. Dugel. Visual function was also favorable in the groups that received ocriplasmin injection. The safety profile of ocriplasmin was favorable in both phase 3 studies, according to Dr. Dugel.
Although the mechanisms of PVD appear simple, the process is complicated, requiring the steps of liquefaction and separation of the vitreous from the retina to be synchronized, said Dr. Dugel. Abnormal VMA and subsequent partial PVD can lead to vitreomacular traction (VMT) syndrome, resulting in metamorphopsia and decreased vision. Many patients with VMA, however, present with relatively good visual acuity. “For these patients, we just watch and wait, because the risk/benefit ratio of vitrectomy, currently the only treatment available, will be too large,” said Dr. Dugel. “However, these patients come to our office unhappy and leave our office unhappy."
VMT syndrome is implicated in a variety of retinal diseases, including macular hole, neovascular age-related macular degeneration (AMD), diabetic macular edema (DME), retinal vein occlusions (RVO), and vitreopapillary sydrome, said Dr. Dugel. Improved imaging may allow for earlier detection of VMA. “Chemical vitreous manipulation has the potential to have a major effect on clinical practice,” he concluded.
- Dugel PU. A single injection of ocriplasmin for the treatment of symptomatic vitreomacular adhesion (sMVA): results of phase III MIVI-TRUST program. Paper presented at: Trends in Surgical and Medical Retina. June 3-4, 2011; Barcelona.
Updated Classification System Proposed for DME
An updated classification system may be warranted for DME, as the terms focal and diffuse macular edema do not appear to be relevant to the treatment response with either laser alone or in combination with anti-vascular endothelial growth factor (VEGF) therapy, according to Neil M. Bressler, MD, who presented at the 11th Euretina Congress in London.1
Dr. Bressler acknowledged the widely accepted idea that focal edema responds best to laser, and that diffuse edema has a worse natural course and responds best to steroids. However, he said, the definition of focal and diffuse edema has not been substantiated in the literature, nor is there agreement on the term clinically significant macular edema. Further, these terms may no longer be relevant in the era of optical coherence tomography (OCT) and anti-VEGF therapies, said Dr. Bressler.
“The Early Treatment for Diabetic Retinopathy Study determined that laser was superior to no treatment regardless of the source of leakage on fluorescein angiography (FA), and the DRCR.net trial comparing ranibizumab (Lucentis, Genentech) plus prompt or deferred laser, or triamcinolone plus prompt laser for DME, did not identify outcome differences with laser or anti-VEGF therapy based on the classification of the edema by the ophthalmologist at onset,” Dr. Bressler said.
Dr. Bressler said that the proposed new classification system for DME would include the location of the edema (whether it is central-involved, pericentral inner-involved, or pericentral outer-involved DME); the amount of edema (mean thickness, volume and/or logOCT by subfield, plus total volume of all nine subfields); and absence or presence of vitreoretinal interface abnormalities.
“Reclassification of DME will of course await further tests in clinical trials and then its acceptance in clinical practice,” he said.
- Bressler NM. Proposed update of classification of diabetic macular edema. Paper presented at: 11th Euretina Congress; May 26-28, 2011; London.
Novartis Gains European Commission Approval for Ranibizumab to Treat Vision Loss due to Macular Edema Secondary to RVO
The European Commission has approved the use of ranibizumab to treat patients with visual impairment due to macular edema secondary to RVO. The approval makes ranibizumab the first anti-VEGF therapy licensed for the treatment of both branch and central RVO (BRVO or CRVO) in the European Union. Ranibizumab is approved by the European Commission for wet AMD and for the treatment of visual impairment due to DME.
The approval of ranibizumab came after data were released from two phase 3 studies in patients with BRVO (BRAVO) and CRVO (CRUISE).1,2 The BRAVO trial data showed that patients with BRVO experienced a mean gain from baseline of 18.3 letters in visual acuity at month 6 with monthly ranibizumab injections, compared with a gain of 7.3 letters with current standard practice (laser). In the trial, approximately 60% of BRVO patients treated with monthly ranibizumab gained at least 15 letters of visual acuity at 6 months, compared with 29% of patients treated with current standard of care.
In the CRUISE trial, patients with CRVO experienced a mean gain from baseline of 14.9 letters at month 6 with monthly ranibizumab injections, compared with a gain of 0.8 letters with current standard practice (observation). In the trial, approximately 48% of CRVO patients treated with monthly ranibizumab gained at least 15 letters of visual acuity at 6 months compared with 17% of patients treated with current standard of care.
Safety data from the BRAVO and CRUISE trials were similar to previous studies with ranibizumab in patients with wet AMD and visual impairment due to DME, and no new adverse events were reported. At 6 months, the most common ocular adverse events that occurred in the ranibizumab-treated patients included conjunctival hemorrhage (48%) and eye pain (17%), according to Novartis.
"This is an important step forward in the management of patients with RVO because the disease is difficult to treat with few available options," Ian Pearce, Consultant Ophthalmologist, Royal Liverpool University Hospital, said in a Novartis news release. "Laser treatment can provide partial improvement for BRVO patients but many do not regain their vision. Laser treatment for patients with CRVO is not considered effective and prognosis is worse than that for BRVO."
Ranibizumab was developed by Genentech and Novartis. Genentech has the commercial rights to ranibizumab in the United States, where ranibizumab is also approved for the treatment of macular edema following RVO. Novartis has exclusive rights in the rest of the world. Ranibizumab is already approved for RVO in the United States.
- Campochiaro PA, Heier JS, Feiner L, et al; BRAVO Investigators. Ranibizumab for macular edema following branch retinal vein occlusion: six-month primary end point results of a phase III study. Ophthalmology. 2010;117(6):1102-1112.e1. Epub 2010 Apr 15.
- Brown DM, Campochiaro PA, Singh RP, et al; CRUISE Investigators. Ranibizumab for macular edema following central retinal vein occlusion: six-month primary end point results of a phase III study. Ophthalmology. 2010;117(6):1124-1133.e1. Epub 2010 Apr 9.
VEGF Trap-Eye Submitted for EU Marketing Authorization for Treatment of Wet AMD
Regeneron Pharmaceuticals, Inc. (Tarrytown, NY) announced that its partner Bayer HealthCare AG (Leverkusen, Germany) has submitted an application for marketing authorization in Europe for aflibercept (VEGF Trap-Eye, Regeneron) for the treatment of neovascular wet AMD.
Regeneron and Bayer HealthCare are collaborating on the global development of aflibercept for the treatment of wet AMD, CRVO, DME, and myopic choroidal neovascularization (mCNV), according to a company news release. Regeneron submitted a Biologics License Application (BLA) to the US Food and Drug Administration (FDA) for marketing approval in wet AMD in the United States in February 2011 and received a Priority Review designation.
The aflibercept submission is based on the positive results from two randomized, double-masked, phase 3 clinical trials—the North American Regeneron-sponsored VIEW 1 study and the international Bayer HealthCare-sponsored VIEW 2 study. Both randomized, double-masked phase 3 clinical trials showed that, in patients with wet AMD, all regimens of aflibercept, including aflibercept dosed every 2 months, achieved the primary endpoint compared with ranibizumab dosed every month.
In VIEW 1, 96% of patients receiving aflibercept 0.5 mg monthly, 95% of patients receiving aflibercept 2.0 mg monthly, and 95% of patients receiving aflibercept 2.0 mg every 2 months achieved maintenance of vision compared with 94% of patients receiving ranibizumab 0.5 mg every month. In VIEW 2, 96% of patients receiving aflibercept 0.5 mg monthly, 96% of patients receiving aflibercept 2.0 mg monthly, and 96% of patients receiving aflibercept 2.0 mg every 2 months achieved maintenance of vision compared with 94% of patients receiving ranibizumab 0.5 mg every month.
A generally favorable safety profile was observed for both aflibercept and ranibizumab. The ocular adverse events were balanced across all treatment groups in both studies. There were no notable differences in non-ocular adverse events among the study arms.
Bayer HealthCare will market aflibercept outside the United States, where the companies will share equally the profits from any future sales of aflibercept. Regeneron maintains exclusive rights to aflibercept in the United States.
NICE Recommends Dexamethasone Intravitreal Implant as RVO Treatment
The National Institute for Health and Clinical Excellence (NICE) has recommended the dexamethasone 0.7 mg intravitreal implant (Ozurdex, Allergan, Inc.) for the treatment of macular edema due to CRVO and BRVO, according to an Allergan news release.
"The decision announced today represents the first NICE recommendation for a licensed treatment for macular edema associated with RVO, and with it NICE has made available to retinal specialists and their patients an important treatment for this potentially devastating condition," Douglas D. Ingram, Executive Vice President, President, Allergan, Europe, Africa and the Middle East, said in a news release. "We look forward to working with retinal specialists, hospitals and commissioning groups in the UK to support the National Health Service in rapidly adopting this cost effective solution to maximize patient benefits and to minimize premature vision loss as a result of RVO."
The efficacy of the dexamethasone intravitreal implant was assessed in two 6-month, prospective, double-masked, parallel-group studies in which 1,267 patients with macular edema due to either BRVO or CRVO were randomized to receive either the dexamethasone intravitreal implant or sham. Clinically significant improvement in vision of 15 letters or more was seen after 2 months in up to 30% of patients with macular edema due to RVO following just one injection of the dexamethasone intravitreal implant, according to Allergan. The most frequently reported adverse reactions in patients who received the dexamethasone intravitreal implant were increased intraocular pressure (24%) and conjunctival haemorrhage (14.7%).
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