EyeWorld Asia-Pacific March 2011 Issue

37 EW NEWS & OPINION March 2011 MYRROR on myopic CNV by Chiles Aedam R. Samaniego EyeWorld Asia-Pacific Senior Staff Writer Phase III trial investigates treatment for a potentially blinding complication of pathologic myopia M yopia is so common that your average myope is not likely to consider it a serious problem, generally thinking of the condition as an inconvenience and not something that could cause serious disability. And yet, the condition said to affect around 40% of adult populations in Asia has a pathologic form that is the seventh leading cause of legal blindness in the US, the fifth and fourth in Europe, and the second in China and Japan, according to Kyoko Ohno, MD, Associate Professor, Department of Ophthalmology and Visual Science, Tokyo Medical and Dental University, Tokyo, Japan. Pathologic myopia, usually (though not always) defined as myopia of greater than 6.0 D and an axial eye length of greater than 26.5 mm, affects up to 10% of adult populations in Asia. The condition, experts say, puts patients at risk for potentially blinding myopic choroidal neovascularization (mCNV). At the moment, there is no well-established treatment for mCNV, but in January, Bayer HealthCare (Warrendale, Pa., USA/Leverkusen, Germany) and Regeneron (Tarrytown, NY, USA) announced a Phase III clinical trial in collaboration with the Singapore Eye Research Institute (SERI, National University of Singapore, Singapore) investigating the efficacy and safety of VEGF Trap-Eye (aflibercept ophthalmic solution) in patients with the condition. The study, called MYRROR, has already started in Japan, and is set to begin at sites in other parts of Asia, including Singapore, China, Korea, and Taiwan. Pathologic myopia & mCNV In an earlier study conducted in the town of Hisayama, Japan, 5.4% of a population of 1,890 was found to have pathologic myopia; 0.3% had mCNV. Assuming that these statistics are representative of the rest of the country, Dr. Ohno estimated that about 3.8 million people in Japan would have pathologic myopia; around 200,000 would have mCNV. In Singapore, about 9.1% have pathologic myopia (defined as a spherical equivalent of greater than –5.0 D), according to Saw Seang Mei, MD, Assistant Director, SERI. She said that the rate tends to be higher in cities than in rural areas. While there does appear to be a genetic predilection, with Chinese people having higher rates than either Indians or Malays in Singapore, environmental and behavioral factors may be the major determinants. The pathophysiology is initiated mechanically, according to Gemmy Cheung, MD, Consultant, Vitreo-Retina Service, Singapore National Eye Centre (SNEC), Singapore. The increase in length of the eyeball stretches and thins the retina, resulting in structural damage such as lacquer cracks—mechanical fissures in the retinal pigment epithelium– Bruch’s membrane–choriocapillaris complex. Higher degrees of myopia are thus associated with greater structural damage, with damage seen in only about 1% of patients with less than 3 D of myopia, but in more than 50% of patients with greater than 9 D of myopia. CNV develops as a pathologic response to this damage, and the risk increases with higher degrees of myopia: a patient with an axial length of greater than 26.5 mm has an up to 5.2% risk of developing mCNV; cumulatively, said Dr. Cheung, this risk goes up to 10% in 10 years. Pathologic myopia is the primary cause of CNV in the young, said Dr. Ohno. Because of this, and because it can lead to blindness, better therapy, they all agreed, is “urgently necessary”. Current treatment options, they said, offer only limited benefits: laser photocoagulation and surgical excision may only extend the area of scarring, while photodynamic therapy leads to limited improvement; anti- VEGF therapy may be effective, but is currently off-label for mCNV. Moreover, while studies have generally shown current monoclonal antibody anti-VEGF therapies bevacizumab (Avastin, Genentech, South San Francisco, Calif., USA) and ranibizumab (Lucentis, Genentech, South San Francisco, Calif., USA) to be safe, some experts have their reservations regarding their use. VEGF Trap-Eye, having already met its primary efficacy endpoints in a Phase III trial for CNV secondary to neovascular age-related macular degeneration (wet AMD), provides a promising alternative. VEGF Trap-Eye VEGF Trap-Eye is a fusion protein designed from the key domains of human VEGF receptors 1 and 2, said Todd Katz, MD, Senior Physician, Ophthalmology, Global Medical Affairs, Bayer HealthCare. This design aspect, he said, distinguishes VEGF Trap- Eye from monoclonal antibody therapies. First, because the key domains are selectively and purposefully chosen to create the fusion protein, VEGF Trap-Eye has a very high affinity for VEGF—40 to 100 times greater affinity than ranibizumab. Second, unlike monoclonal antibodies, VEGF Trap-Eye binds precisely to VEGF at a ratio of 1:1. Depending on the ratio between antibodies and VEGF molecules, ranibizumab, said Dr. Katz, typically binds two antibodies to one dimer of VEGF. Meanwhile, bevacizumab has two binding sites that are both available for binding, and has thus been found to form daisy chains of molecules, high molecular weight conglomerations of as yet unknown clinical significance. In addition to wet AMD, VEGF Trap-Eye has also been tested in large-scale clinical trials in other conditions such as diabetic macular edema and central retinal vein occlusion. “[MYRROR] will be the first trial for mCNV, and will be the first Asia-Pacific trial for VEGF Trap-Eye,” said Elke Reißig, MD, Director, Global Clinical Development Department for Neurology, Ophthalmology, Hematology and Immunology, Bayer HealthCare. Dr. Reißig serves as the Clinical Lead for the development of VEGF Trap-Eye in mCNV. MYRROR & SAILOR MYRROR is a multicenter, randomized, double-masked, sham-controlled trial to assess the efficacy, safety and tolerability of intravitreally administered VEGF Trap-Eye. The study aims to recruit 248 patients, randomized 3:1 (VEGF Trap-Eye:sham injections). The primary endpoint is mean change in best corrected visual acuity (BCVA); secondary endpoints include the percentage of patients who gain or lose lines of vision, changes in retinal thickness from baseline, changes in total mCNV lesion size, and vessel leakage as seen on angiography of the affected eye. Researchers will evaluate endpoints at 24 and 48 weeks; after 24 weeks, patients randomized to receive sham injections may be given active treatment. SERI has been appointed the reading center partner for this study, with the Singapore Advanced Imaging Laboratory for Ocular Research (SAILOR, Fusionopolis, Singapore) as the first reading center. Using a tele-ophthalmic ocular imaging platform developed at SAILOR, the imaging laboratory will read images remotely transferred from other MYRROR study sites in Asia. The study is scheduled to run until June 2013. “There remains uncertainty regarding the best methods of treatment for myopic CNV, and this new trial will go towards addressing this clinical need,” said Wong Tien Yin, MD, Director, SERI and Co-Director, SAILOR. “With this study, we hope to prove the effectiveness of VEGF Trap-Eye in combating yet another important cause of continued on page 38