Sphingomab Mitigates the Multiple Pathologies of Age-Related Macular Degeneration

描述（由申请人提供）：年龄相关性黄斑变性 (AMD) 是美国失明的主要原因，目前影响超过 1500 万人（1350 万人为干性黄斑变性，160 万人为新生血管性黄斑变性）。尽管 AMD 导致视力丧失的情况很普遍，但只有少数疗法可以减缓 AMD 的进展，而能够逆转视力丧失的疗法就更少了。目前受欢迎的治疗方式包括 Lucentis 和标签外使用 Avastin，两者都针对单一生长因子 VEGF，并且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消退，因为实际的 CNV 病变并未明显消退。然而，渗出性 AMD 相关的视力丧失不仅仅由 CNV 引起的视网膜下和视网膜内水肿所致。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性破坏和重塑导致与 AMD 相关的视力丧失。现有的治疗方法无法解决视网膜损伤的多种原因。除了治疗血管渗漏之外，能够治疗渗出性 AMD 相关视力丧失的多种机制的药物将具有很大的价值，并且可能满足与渗出性 AMD 相关的未满足的医疗需求。 Lpath 最近开发了 Sonepcizumab，这是一种针对生物活性溶血磷脂、1-磷酸鞘氨醇 (S1P) 的新型人源化单克隆抗体。 Sonepcizumab 代表了第一个成功制造的抗溶血磷脂的单克隆抗体。 Sonepcizumab 作为分子海绵，以皮摩尔亲和力选择性、特异性地吸收细胞外液中的 S1P，降低 S1P 的有效浓度。越来越多的证据表明，S1P 可能导致与渗出性 AMD 相关的适应不良视网膜重塑的早期和晚期阶段。 S1P 具有显着的非 VEGF 依赖性促血管生成作用。 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 多种适应不良过程的成纤维细胞、内皮细胞和炎症细胞。 S1P 还与 VEGF、FGF、PDGF MCP-1、IL-6、IL-8 和其他与渗出性 AMD 发病机制有关的生长因子的产生和激活有关。因此，抑制 S1P 的作用可能是渗出性 AMD 的有效治疗方法，与单纯抗 VEGF 方法相比，它可能具有显着的优势，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，小鼠抗 S1P 抗体在小鼠模型中显示出对减少脉络膜新生血管以及 AMD 其他血管和血管外过程的深远功效。为了继续第一阶段启动的研发工作，我们特此提出一系列第二阶段研究，以测试用人源化抗体 Sonepcizumab 中和 S1P 是否是治疗渗出性 AMD 的有效策略。 II 期研究计划的第一个目标是评估 Sonepcizumab 在激光诱导的食蟹猴 CNV 模型中减少渗出性 AMD 的多种病理的药理活性/功效。我们将研究 Sonepcizumab 与 Lucentis（一种抗 VEGF 疗法）的比较和协同作用，不仅可以减轻新生血管形成和水肿，还可以减轻视网膜下纤维化和炎症。第二个目标是评估 Sonepcizumab 对食蟹猴重复玻璃体内给药后的安全性。最后，将研究 Sonepcizumab 能够减轻 AMD 多种病因的作用机制。这些 II 期研究的成功完成将证明 Sonepcizumab 的有效性和安全性，以支持 IND 申请和后续临床试验。项目叙述 年龄相关性黄斑变性 (AMD) 是美国失明的主要原因，目前影响超过 1500 万人（1350 万人为干性黄斑变性，160 万人为新生血管性黄斑变性）。据估计，全球病例数是这个数字的三倍。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 VEGF 的药物）可以减缓 AMD 的进展，而能够逆转视力丧失的疗法就更少了。因此，发现这种形式的病理性新生血管形成的新疗法对社会极其重要。

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.