The proposed primary indication for RTP801i-14 is the treatment of patients with neovascular (wet) Age-related Macular Degeneration (AMD or ARMD). AMD is a serious ocular disease leading to loss of central vision in the elderly. The disorder is characterized by both primary and secondary damage of macular Retinal Pigment Epithelial (RPE) cells, resulting in formation of drusen (deposits lying beneath the RPE), choroidal neovascularization (CNV), and atrophy of photoreceptors and choriocapillaris layer of the choroidea. The clinical course of the disease is divided into two stages: the early AMD stages characterized by macular drusen and late AMD stages with neovascular complications (CNV) and disciform scarring. Early forms of AMD are reported to occur in 30% of the population of 75 years and above, and late forms in 4-8% of the individuals over 70 years. The current etiopathogenic model is based on oxidative damage that negatively influences the metabolism of photoreceptors and RPE. Current therapy encompasses drug therapies, nutritive antioxidants, laser treatment, surgery and magnifying devices.
RTP801i-14 is an siRNA drug candidate designed to inhibit the expression of the hypoxia-inducible gene RTP801. We recently licensed to Pfizer our siRNA drugs inhibiting this proprietary target gene. The gene RTP801 was discovered by Quark and initially identified by its dramatic up-regulation in response to hypoxia and/or oxidative stress both in vitro and in animal models. We first reported about this novel gene in 2002. Since expression of RTP801 is rapidly upregulated in response to ischemia, hypoxia and/or oxidative stress, it represents a unique gene target that may regulate hypoxia-induced pathogenesis by a mechanism that is independent of growth factors such as VEGF. This hypoxia-inducible gene promotes neuronal cell apoptosis and the generation of reactive oxygen species in vitro. In both genetic (RTP801-knockout) and therapeutic mouse and primate models of laser-induced choroidal neovascularization (CNV), inhibition of RTP801 expression leads to inhibition or reduction of CNV and vessel leakage following intravitreal injection of RTP801i-14. RTP801i-14 significantly differentiates from the anti-VEGF drugs that are the mainstay of therapy today in that it works by a different, unique mechanism of action. We have shown that it is potentially more effective than anti-VEGF drugs in animals and because it has anti-inflammatory properties and is antiapoptotic, we believe it may offer a safer and more efficacious alternative. In pre-clinical studies, RTP 801i-14 worked in cooperation or synergism with VEGF-based drugs. It is also anti apoptotic and thus may also be useful for the treatment of dry AMD.
RTP801i-14 is in Phase II clinical study.