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）是美国老年人严重视力丧失和失明的主要原因。虽然Lucentis(r)和Avastin(r)——湿性AMD的市场领导者——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生长因子VEGF，并且似乎通过抗渗透性作用发挥其大部分有益作用，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，并且慢性疾病通常继续进展。越来越多的证据表明，生物活性脂质S1P可能有助于湿性AMD相关的早期和晚期的不适应视网膜重塑。S1P具有明显的非VEGF依赖性促血管生成作用和VEGF未表现出的其他几种作用。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的多个不适应过程。因此，抑制S1P的作用可能是一种新的有效治疗湿性AMD的方法，可能比单独的抗vegf方法（或与它们协同作用）提供显著的优势，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的人源化单克隆抗体。iSONEP作为分子海绵，选择性地从细胞外液中吸收S1P，降低S1P的有效浓度。抗s1p单克隆抗体在几种湿性AMD动物模型中显示出疗效；此外，iSONEP对小鼠、兔子、非人类灵长类动物和人类都有良好的耐受性。Lpath最近完成了一项针对湿性AMD患者的I期临床试验，根据初步数据（未经审核），该试验在疾病的关键参数上显示出令人鼓舞的生物学效应迹象。单剂量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的显著减少，潜在CNV病变的完全消退（VEGF抑制剂很少做到），RPE脱离的几乎完全解决（VEGF抑制剂通常不会做到）。大多数患者先前接受过多种抗vegf治疗，但效果不佳，这表明iSONEP可能具有独立于这些治疗的作用。该提案的具体目标是进行(i)一项i期先导临床试验，以评估iSONEP与Lucentis联合使用的剂量和安全性，并在动物中进行支持毒理学和生物分布研究；（ii）一项ii期临床试验，以评估联合治疗的疗效；（iii）几项非临床动物研究，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。有大量医疗需求未得到满足的地方。这些目标的成功将证明iSONEP有潜力影响湿性AMD的多种潜在病理（可能还有其他眼部疾病），从而为复杂和致残的疾病提供更完整的解决方案。

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.