CAPTAIN: Choroidal Neovascularization Assessment by Pattern Electroretinography After Ranibizumab in Naive Age-related Macular Degeneration Patients

1. Background 1.1 Pathophysiology Age-related macular degeneration (AMD) is a progressive disease that causes irreversible visual impairment and blindness in nearly 50 million people globally 1. 2. Current estimates of patients affected with AMD are higher than those affected by Alzheimer's disease 1.3 Although geographic atrophy and neovascularization represent the advanced forms of AMD, neovascular AMD is the more aggressive form and accounts for almost 90% of blindness from this disease. It is characterized by choroidal neovascularization (CNV) which is the development of abnormal blood vessels underneath the retina. Current treatments such as photodynamic therapy (PDT) and intravitreal pegaptanib are designed to limit further visual loss, but these are only marginally effective 4-6.

1.2 Treatment of on-label naive AMD patients Recent randomized clinical trials (Marina, Anchor) have conclusively demonstrated that continued intravitreal therapy with ranibizumab in patients with subfoveal CNV from AMD leads to stabilization of vision in over 90% of patients and improvement in vision in at least a third of the patients and has led to the approval of ranibizumab (0.5 mg) for the treatment of neovascular AMD. Naive patients will be used in this study to determine if an improvement by ERG can be determined in those without prior therapy.

1.3 Electroretinography(ERG) Effects Of Ranibizumab Therapy AMD trials are typically designed to address visual acuity outcomes but not designed to evaluate retinal function outcomes. Global and macular retinal indices as measured by electroretinography (ERG) are key indicators of retinal health which have largely been ignored in clinical trials.

1.4 Non-Clinical Experience With Ranibizumab 1.4.1 Nonclinical Pharmacokinetics The pharmacokinetics of ranibizumab have been investigated in rabbits and cynomolgus monkeys following intravitreal and intravenous administration. In both species, following intravitreal administration, ranibizumab was cleared from the vitreous humor with a half life of 2-3 days. Following single intravitreal administration to cynomolgus monkeys, retinal concentrations of ranibizumab were approximately one third of vitreous concentrations and declined in parallel with vitreous concentrations. In humans, the intravitreal half-life of ranibizumab is estimated to be 7-8 days. Repeated intravitreal injections of ranibizumab can lead to detectable antibodies in serum in rabbits and cynomolgus monkeys.

1.4.2 Nonclinical Toxicology A series of nonclinical studies of ranibizumab administered by intravitreal injection to cynomolgus monkeys have been performed (details regarding study design and results can be found in the Investigator Brochure).