Commercialization of iSONEP, a Humanized Monoclonal Antibody Against the Bioactiv

描述(由申请人提供)：渗出性(或湿性)AMD(年龄相关性黄斑变性)是导致美国老年人严重视力丧失和失明的主要原因。虽然Lucentis(R)和阿瓦斯丁(R)的非标签使用--湿性AMD的明确市场领先者--在一段时间内改善了一些患者的视力，但它们并不代表完整的解决方案。这两种药物都针对单一的生长因子，血管内皮生长因子，似乎通过抗渗透作用发挥了大部分的有益作用，导致视网膜水肿的消退，但潜在的脉络膜新生血管(CNV)病变并未明显消退，这种慢性疾病通常会继续发展。越来越多的证据表明，生物活性脂质S1P可能在与湿性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，以及其他几种血管内皮生长因子所没有的作用。例如，S1P刺激成纤维细胞、内皮细胞、周细胞和炎症细胞的迁移、增殖和存活--这些细胞参与了渗出性AMD的多种适应不良过程。因此，抑制S1P的作用可能是一种新颖而有效的治疗湿性AMD的方法，它可能比单独使用抗血管内皮生长因子的方法(或与它们协同作用)具有显著的优势，以解决最终导致视力丧失的复杂过程和多个步骤。LPATH的iSONEP候选药物是一种针对S1P的人源化单抗。ISONEP起到分子海绵的作用，选择性地从细胞外液中吸收S1P，降低S1P的有效浓度。抗S1P单抗已在几种湿性AMD动物模型中显示出有效性；此外，iSONEP对小鼠、兔子、非人类灵长类动物和人类都有很好的耐受性。LPATH最近完成了湿性AMD患者的第一阶段临床试验，根据初步数据(未经审计)，该试验显示出令人鼓舞的迹象，表明生物效应对疾病的关键参数产生了影响。在单剂iSONEP后，大多数患者表现出改善，包括视网膜水肿和相关视网膜厚度显著减少，潜在的CNV病变完全消退(血管内皮生长因子抑制剂很少做到这一点)，RPE脱离几乎完全消失(血管内皮生长因子抑制剂通常不能做到这一点)。大多数患者以前接受过多次抗血管内皮生长因子治疗，但反应不佳，这表明iSONEP可能具有独立于这些治疗的效果。这项建议的具体目标是进行(I)第一阶段临床试验，以评估iSONEP与Lucentis联合使用的剂量和安全性，并支持动物毒理学和生物分布研究；(Ii)第二阶段临床试验，以评估联合疗法的疗效；以及(Iii)几项非临床动物试验，以评估iSONEP在湿性AMD以外的其他应用，如糖尿病视网膜病变、干性AMD和PVR，在这些领域存在重大的未得到满足的医疗需求。这些目标的成功将证明iSONEP有可能影响湿性AMD(可能还有其他眼部疾病)的多种潜在病理，从而为一种复杂和致残的疾病提供更完整的解决方案。 与公共健康相关渗出性(或湿性)AMD(老年性黄斑变性)是美国老年人严重视力丧失和失明的主要原因。虽然Lucentis(R)和阿瓦斯丁(R)的非标签使用--湿性AMD的明确市场领先者--在一段时间内改善了一些患者的视力，但它们并不代表完整的解决方案。LPath的创新候选药物iSONEP针对的是一种生物活性脂质S1P，可能代表下一代湿性AMD治疗方法，以及潜在地解决其他致残性眼病，如糖尿病视网膜病变、干性AMD和增殖性玻璃体视网膜病变。

DESCRIPTION (provided by applicant): Exudative (or wet) AMD (age-related macular degeneration) is the leading cause of severe vision loss and blindness among older Americans. While Lucentis(r) and off-label use of Avastin(r)-the clear market leaders in wet AMD- improve vision in some patients for a period of time, they do not represent the complete solution. Both of these drugs target a single growth factor, VEGF, and appear to exert most of their beneficial effect via an anti-permeability action resulting in resolution of retinal edema, but the underlying choroidal neovascular (CNV) lesion does not markedly involute, and the chronic disease typically continues to progress. Growing evidence suggests that the bioactive lipid S1P could contribute to both the early and late stages of maladaptive retinal remodeling associated with wet AMD. S1P has a pronounced non-VEGF-dependent pro-angiogenic effect and several other effects not exhibited by VEGF. For example, S1P stimulates migration, proliferation and survival of fibroblasts, endothelial cells, pericytes and inflammatory cells- the same cells that participate in the multiple maladaptive processes of exudative AMD. Thus, inhibiting the action of S1P could be a novel and effective therapeutic treatment for wet 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 visual loss. Lpath's iSONEP drug candidate is a humanized monoclonal antibody directed against S1P. iSONEP acts as a molecular sponge to selectively absorb S1P from the extracellular fluid, lowering the effective concentration of S1P. Anti-S1P mAbs have demonstrated efficacy in several animal models of wet AMD; moreover, iSONEP is well tolerated by mice, rabbits, non-human primates, and humans alike. Lpath has recently completed a Phase I clinical trial in wet AMD patients, and, based on preliminary data (unaudited), the trial showed encouraging signs of biological effect on key parameters of disease. After a single dose of iSONEP, a majority of patients exhibited improvement, including marked reduction in retinal edema and related retinal thickness, complete regression of the underlying CNV lesion (which the VEGF inhibitors rarely do), and near-complete resolution of RPE detachment (which the VEGF inhibitors normally do not do). Most patients had previously received multiple anti-VEGF treatments, but were not responding well, suggesting that iSONEP may have effects that are independent of these treatments. The specific aims of this proposal are to conduct (i) a Phase I lead-in clinical trial to assess dosing and safety of iSONEP in combination with Lucentis, with supporting toxicological and bio-distribution studies in animals, (ii) a Phase II clinical trial to assess the efficacy of the combination therapy, and (iii) several nonclinical animal studies to assess additional applications of iSONEP beyond wet AMD, like diabetic retinopathy, dry AMD and PVR, where there are significant unmet medical needs. Success with these aims will demonstrate iSONEP's potential to affect the multiple underlying pathologies of wet AMD (and perhaps other ocular conditions) and thereby provide a more-complete solution to a complex and disabling disease. PUBLIC HEALTH RELEVANCE Exudative (or wet) AMD (age-related macular degeneration) is the leading cause of severe vision loss and blindness among older Americans. While Lucentis(r) and off-label use of Avastin(r)-the clear market leaders in wet AMD-improve vision in some patients for a period of time, they do not represent the complete solution. Lpath's innovative drug candidate, iSONEP, targets a bioactive lipid, S1P, and may represent the next generation of wet-AMD treatments, as well as potentially addressing other disabling ocular disorders such as diabetic retinopathy, dry AMD and proliferative vitreoretinopathy.