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By Ajay Malik, PhD

Age-related macular degeneration (AMD) is the leading cause of vision loss and blindness in adults over 50 years age. While 90% of AMD patients have the dry-type AMD (atrophic), it is the wet AMD (exudative), driven by choroidal neovascularization (CNV), which is responsible for severe and acute vision loss in over 90% of the patients. Famous people, like the artist Georgia O’Keefe, entertainer Bob Hope and the author Henry Grunwald have coped with AMD. There are over 1.6 million people with AMD in the United States and about 200,000 people are diagnosed with wet AMD every year.

One promising approach in late-stage clinical development is the use of beta-radiation to selectively target the proliferating cells in the macular lesion. A small company 40-miles south of San Francisco called NeoVista in Newark, Calif., is at the forefront of testing an epimacular brachytherapy device in the pivotal CABERNET (CNV Secondary AMD Treated with BEta RadiatioN Epiretinal Therapy) Study. The results of this trial are expected in October 2011 (read here). The CABERNET trial is a multicenter randomized controlled study with two arms in which 495 treatment-naive patients will be randomized into a control group who will receive a regular schedule of ranibizumab (anti-VEGF Fab; Lucentis; Genentech, South San Francisco) injections (the standard of care); the patients in the second arm will receive strontium-90 beta radiation and Lucentis as needed.

The early safety and efficacy trails NVI-68 and NVI-111 showed a visual acuity gain of 10.3 letters, and three-fourths of the NVI-111 patients required no further anti-VEGF treatment. The procedure was shown to be safe in patients who were on persistent anti-VEGF therapy (MERITAGE trial)‚Äîthe data from this trial was presented by Timothy L. Jackson and colleagues at the last month’s meeting of the Association for Research in Vision and Ophthalmology (ARVO) at Fort Lauderdale (ARVO 2011 Poster: 1680/A75); a PowerPoint presentation by Dr. David Boyer on the 18-month clinical update of MERITAGE trial can be accessed here or here. With the procedure deemed safe and potentially efficacious, all eyes are now on the pivotal CABERNET trial.

Wet AMD is caused by uncontrolled proliferation of the choroidal capillaries in the outer layers of the eye. These capillaries break through the defenses of Bruch’s membrane, enter the inner layers of the globe, and begin to proliferate under the retina which is the inner most layer of the eye. These new unwanted capillaries are prone to leakage and rupture, initiating inflammation and repair response which leads to scarring and permanent loss of photoreceptor cells and vision. NeoVista’s epimacular brachytherapy system (called VIDION) exposes the macular lesion to a beta-radiation source probe containing strontium-90. This probe is delivered by a routine surgical procedure called pars plana; the lesion is exposed to the probe for about four minutes and then the probe is removed. Beta-radiation travels a very short distance; thus, the target macular lesion is exposed to 24 gray radiation, but the surrounding structures are spared‚Äî the optic nerve receives just one-tenths of the radiation compared to the macula and the cornea which are exposed to a thousand-fold less radiation‚Äîthis avoids the risks of retinopathy and cataracts, making epimacular brachytherapy an extremely safe procedure.

The approval of an anti-VEGF, ranibizumab, exactly five years ago in June 2006, was the watershed event in the management of wet-AMD. But at $2000 per treatment, ranibizumab has faced some level of push-back from insurance companies and NHS. Two months ago, NIH released the results of a comparative study showing that similar efficacy can be obtained by using Avastin (parent version of Lucentis; Avastin is MAb and Lucentis is it’s Fab version) at one-fortieth the cost compared to ranibizumab (read here and here). However, anti-VEGF therapy is not for everyone; besides injection inconveniences, the vision gains require monthly dosing and gains are often lost upon therapy discontinuance. Genentech’s MARINA trial (monthly ranibizumab injections over two years) showed an average of 10 letter vision improvement, but subsequent HORIZON study that followed these patient for another two years, found that the gains were down to two letters due to less frequent dosing. Epimacular brachytherapy may have an advantage over anti-VEGF monotherapy. Epimacular brachytherapy combines three approaches into one: targeted radiation to the lesion, vitrectomy which increases oxygenation (improving radiation mediated cell death via free radical formation) and also by combining with anti-VEGF, the biological mediators are targeted. In addition to CABERNET trial (in treatment-naive patients), NeoVista is also sponsoring MERLOT trial which will include patients who are already on anti-VEGF therapy. The latter will compare ranibizumab monotherapy with the combination of epimacular brachytherapy and ranibizumab (as required). Read more on NeoVista updates here.

 

More about author Ajay Malik, PhD, Cancer Biologist and Medical and Scientific Writer

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