Commercialization of iSONEP, a Humanized Monoclonal Antibody Against the Bioactiv

iSONEP（一种针对 Bioactiv 的人源化单克隆抗体）的商业化

• 批准号: 7926379
• 负责人: Roger A Sabbadini
• 金额: $ 300万
• 依托单位: LPATH THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2013-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7926379
• 关键词: Address; Affect; Age related macular degeneration; American; Animal Disease Models; Animal Model; Animals; Area; Avastin; Biodistribution; Biological; Biological Preservation; Blindness; Blood Vessels; Cells; Choroid; Chronic Disease; Clinical; Clinical Research; Clinical Trials; Combined Modality Therapy; Complement; Complex; Data; Development; Diabetic Retinopathy; Disease; Disease model; Dose; Drug Delivery Systems; Drug Formulations; Endothelial Cells; Exhibits; Extracellular Fluid; Exudative age-related macular degeneration; Eye; Fibroblasts; Fibrosis; Fluorescein Angiography; Funding; Future; Grant; Growth; Growth Factor; Human; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Label; Lead; Lesion; Lipids; Lucentis; Malignant Neoplasms; Marketing; Medical; Molecular; Mus; Optical Coherence Tomography; Oryctolagus cuniculus; Pathogenesis; Pathologic Neovascularization; Pathology; Patients; Pericytes; Permeability; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Porifera; Process; Proliferative Vitreoretinopathy; Proteins; Public Health; Publishing; Request for Applications; Research; Research Methodology; Resolution; Retina; Retinal; Retinal Edemas; Safety; Small Business Innovation Research Grant; Solutions; Staging; Structure; Therapeutic; Therapeutic Agents; Thick; Time; Vascular Endothelial Growth Factors; Vision; Visual; Work; age group; angiogenesis; base; bevacizumab; commercialization; design; disabling disease; drug candidate; efficacy trial; experience; humanized monoclonal antibodies; improved; inhibitor/antagonist; innovation; macrophage; macula; migration; neovascular; next generation; nonhuman primate; novel; payment; phase 2 study; programs; promoter; public health relevance; safety study; sphingosine 1-phosphate; success

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.

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）的标签外使用-湿性AMD的明确市场领导者-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。这两种药物都靶向单一的生长因子VEGF，并且似乎通过抗渗透作用发挥其大部分有益作用，导致视网膜水肿消退，但潜在的脉络膜新生血管（CNV）病变并不明显渐开线，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S1 P可能有助于与湿性AMD相关的适应不良视网膜重塑的早期和晚期阶段。S1 P具有显著的非VEGF依赖性促血管生成作用和VEGF未表现出的几种其他作用。例如，S1 P刺激成纤维细胞、内皮细胞、周细胞和炎性细胞的迁移、增殖和存活，这些细胞参与渗出性AMD的多种适应不良过程。因此，抑制S1 P的作用可能是湿性AMD的一种新的有效治疗方法，其可能比专门的抗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候选药物是针对S1 P的人源化单克隆抗体。iSONEP作为分子海绵从细胞外液中选择性吸收S1 P，降低S1 P的有效浓度。抗S1 P mAb已在几种湿性AMD动物模型中证明了疗效;此外，iSONEP在小鼠、兔、非人灵长类动物和人类中耐受性良好。Lpath最近在湿性AMD患者中完成了一项I期临床试验，根据初步数据（未经审计），该试验显示了对疾病关键参数的生物学效应的令人鼓舞的迹象。iSONEP单次给药后，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，基础CNV病变完全消退（VEGF抑制剂很少这样做），以及RPE脱离接近完全消退（VEGF抑制剂通常不会这样做）。大多数患者之前接受过多种抗VEGF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。本提案的具体目的是进行（i）I期导入临床试验，以评估iSONEP与Lucentis联合给药的剂量和安全性，并支持动物毒理学和生物分布研究，（ii）II期临床试验，以评估联合治疗的疗效，以及（iii）几项非临床动物研究，以评估iSONEP在湿性AMD之外的其他应用，如糖尿病视网膜病变，干性AMD和PVR，其中存在显著未满足的医疗需求。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（以及可能的其他眼部疾病），从而为复杂和致残性疾病提供更完整的解决方案。 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）的标签外使用-湿性AMD的明确市场领导者-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。Lpath的创新候选药物iSONEP靶向生物活性脂质S1 P，可能代表下一代湿性AMD治疗，并可能解决其他致残性眼部疾病，如糖尿病视网膜病变，干性AMD和增殖性玻璃体视网膜病变。