Sphingomab Mitigates the Multiple Pathologies of Age-Related Macular Degeneration

描述(申请人提供)：老年性黄斑变性(AMD)是美国主要的致盲原因，目前影响超过1500万人(1350万干性失明和160万新生血管失明)。尽管AMD导致的视力丧失很普遍，但只有少数几种疗法可以减缓AMD的进展，更没有几种疗法可以逆转视力丧失。目前受青睐的治疗方法包括Lucentis和非标签外使用阿瓦斯丁，这两种药物都针对单一生长因子VEGF，似乎通过抗渗透作用发挥其大部分有益作用，导致视网膜内和视网膜下水肿的缓解，因为实际的CNV病变并不明显内化。然而，渗出性AMD相关的视力丧失并不完全是由于CNV引起的视网膜下和视网膜内的水肿。由CNV、视网膜下纤维化、水肿和炎症共同引起的视网膜和视网膜下结构的病理破坏和重塑导致与AMD相关的视力丧失。这些视网膜损伤的多种原因并没有被现有的治疗方法所解决。有能力治疗渗出性AMD相关视力丧失的多种机制的药物，除了治疗血管渗漏外，将具有很大的价值，并可能满足与渗出性AMD相关的未得到满足的医疗需求。LPath最近开发了一种新型人源化单抗Sonepcizumab，针对具有生物活性的溶血磷脂-1-磷酸鞘氨醇(S1P)。Sonepcizumab是第一个成功创建的针对溶血磷脂的单抗。Sonepcizumab充当分子海绵，选择性地、特异性地以皮摩尔亲和力从细胞外液中吸收S1P，降低S1P的有效浓度。越来越多的证据表明，S1P可能在渗出型AMD相关的不良适应视网膜重塑的早期和晚期起作用。S1P具有明显的非血管内皮生长因子依赖的促血管生成作用。S1P还刺激多种细胞类型的迁移、增殖和存活，包括参与渗出性AMD多种不良适应过程的成纤维细胞、内皮细胞和炎症细胞。S1P还与血管内皮生长因子、成纤维细胞生长因子、PDGF、MCP-1、IL-6、IL-8等生长因子的产生和激活有关，参与渗出型AMD的发病机制。因此，抑制S1P的作用可能是治疗渗出型AMD的一种有效的治疗方法，它可能比单独使用抗血管内皮生长因子的方法有显著的优势，或者与它们协同作用，以解决最终导致AMD相关视力丧失的复杂过程和多个步骤。在LPATH的I期SBIR研究中，鼠抗S1P抗体在减少AMD小鼠模型的脉络膜新生血管以及其他血管和血管外过程方面显示出显著的疗效。为了继续第一阶段开始的研发工作，我们在此提议进行一系列第二阶段研究，以测试人源化抗体S1P的中和是否是治疗渗出性AMD的有效策略。第二阶段研究计划的第一个目标是评估Sonepcizumab的药理活性/疗效，以减少激光诱导的Cynomolgus猴子CNV模型中渗出性AMD的多种病理改变。我们将通过与抗血管内皮生长因子治疗药物Lucentis的比较和协同作用来研究Sonepcizumab不仅可以减轻新生血管和水肿，还可以减轻视网膜下纤维化和炎症。第二个目标是评估Sonepcizumab在反复玻璃体内给药后对食蟹猴的安全性。最后，将研究Sonepcizumab能够缓解AMD的多种病因的作用机制。这些第二阶段研究的成功完成将证明Sonepcizumab支持IND申报和后续临床试验的有效性和安全性。项目简介老年性黄斑变性(AMD)是美国导致失明的主要原因，目前影响着超过1500万人(1350万干性黄斑变性和160万新生血管性失明)。据估计，全世界的病例数量是这个数字的3倍。尽管AMD引起的视力丧失很普遍，但只有少数疗法，主要是基于抗血管内皮生长因子的疗法，可以减缓AMD的进展，更少的疗法可以逆转视力丧失。因此，为这种病理性新生血管发现新的治疗方法对社会极其重要。

DESCRIPTION (provided by applicant): Age-related macular degeneration (AMD) is the leading cause of blindness in the U.S. and currently affects more than 15 million people (13.5 million dry-form & 1.6 million neovascular-form). Despite the epidemic of vision loss caused by AMD, only a few therapies can slow the progression of AMD and even fewer can reverse vision loss. Currently favored therapeutic modalities include Lucentis and off-label use of Avastin, both of which target a single growth factor VEGF, and appear to exert most of their beneficial effect via an anti-permeability action resulting in resolution of intra and sub-retinal edema, as the actual CNV lesion does not markedly involute. Exudative AMD-related vision loss however, is not due solely to CNV induced sub-retinal and intra-retinal edema. Pathologic disruption and remodeling of the retinal and subretinal architecture caused collectively by CNV, sub-retinal fibrosis, edema and inflammation results in the loss of visual acuity associated with AMD. These multiple causes of retinal injury are not addressed by available treatments. Agents having the ability to treat the multiple mechanisms which underlie exudative AMD-related vision loss, beyond just treating vascular leakage, would be of great value and are likely to fulfill the unmet medical need associated with exudative AMD. Lpath has recently developed Sonepcizumab, a novel humanized monoclonal antibody directed against the bioactive lysophospholipid, sphingosine-1-phosphate (S1P). Sonepcizumab represents the first successfully created monoclonal antibody against a lysophospholipid. Sonepcizumab acts as a molecular sponge to selectively and specifically with picomolar affinity, absorb S1P from the extracellular fluid, lowering the effective concentration of S1P. Growing evidence suggests that S1P could contribute to both the early and late stages of maladaptive retinal remodeling associated with exudative AMD. S1P has a pronounced non-VEGF dependent pro-angiogenic effect. S1P also stimulates migration, proliferation and survival of multiple cell types, including fibroblasts and endothelial and inflammatory cells that participate in the multiple maladaptive processes of exudative AMD. S1P is also linked to the production and activation of VEGF, FGF, PDGF MCP-1, IL-6, IL-8 and other growth factors implicated in the pathogenesis of exudative AMD. Inhibiting the action of S1P could therefore be an effective therapeutic treatment for exudative AMD that may offer significant advantages over exclusively anti-VEGF approaches or act synergistically with them to address the complex processes and multiple steps that ultimately lead to AMD associated visual loss. In Lpath's Phase I SBIR studies, the murine anti-S1P antibody demonstrated profound efficacy to reduce choroidal neovascularization as well as other vascular and extravascular processes of AMD in a murine model. In continuation of the R&D efforts initiated in Phase I, we hereby propose as series of Phase II studies to test whether neutralization of S1P with the humanized antibody, Sonepcizumab, is an effective strategy for the treatment of exudative AMD. The first goal of the Phase II research plan is to evaluate the pharmacological activity/efficacy of Sonepcizumab to reduce the multiple pathologies of exudative AMD in a laser-induced Cynomolgus monkey model of CNV. We will investigate the ability of Sonepcizumab to mitigate not only neovascularization and edema but also sub-retinal fibrosis and inflammation in comparison and synergistically with Lucentis, an anti-VEGF therapy. The second goal is to assess the safety of Sonepcizumab after repeat intravitreous administration to Cynomolgus monkeys. Finally, the mechanism of action by which Sonepcizumab is able to mitigate the multiple etiologies of AMD will be investigated. The successful completion of these Phase II studies will demonstrate the efficacy and safety profiles of Sonepcizumab to support an IND filing and subsequent clinical trials. Project Narrative Age-related macular degeneration (AMD) is the leading cause of blindness in the U.S. and currently affects more than 15 million people (13.5 million dry-form & 1.6 million neovascular-form). There are estimated to be 3 times this many cases worldwide. Despite the epidemic of vision loss caused by AMD, only a few therapies, mostly anti-VEGF based, can slow the progression of AMD and even fewer can reverse vision loss. Discovering new treatments for this form of pathologic neovascularization is therefore extremely important to society.