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）AMD（与年龄相关的黄斑变性）是老年美国人严重视力丧失和失明的主要原因。虽然Lucentis（R）和标签不使用Avastin（R） - 在一段时间内，在某些患者的潮湿AMD中，明确的市场领导者改善了视力，但它们并不代表完整的解决方案。这两种药物都靶向单个生长因子，VEGF，并且似乎通过抗渗透性作用发挥其大部分有益作用，从而导致视网膜水肿解决，但是潜在的脉络膜新生血管（CNV）病变并未明显地散发出明显的侵入，并且慢性疾病通常会继续前进。越来越多的证据表明，生物活性脂质S1P可能有助于与湿AMD相关的不良视网膜重塑的早期和晚期。 S1P具有明显的非VEGF依赖性促血管生成效应，而VEGF没有表现出的其他几种作用。例如，S1P刺激成纤维细胞，内皮细胞，周细胞和炎性细胞的迁移，增殖和存活 - 参与透明度AMD的多个不良适应过程的相同细胞。因此，抑制S1P的作用可能是对湿AMD的新型且有效的治疗治疗方法，它可能比仅具有抗VEGF方法（或与之协同作用）具有显着优势，以解决最终导致视觉损失的复杂过程和多个步骤。 LPATH的ISONEP候选药物是针对S1P的人源化单克隆抗体。 ISONEP充当分子海绵，从细胞外液中选择性吸收S1P，从而降低了S1P的有效浓度。抗S1p mAb在几种湿AMD的动物模型中表现出功效。此外，ISONEP的容忍度很好，兔子，非人类灵长类动物和人类都可以耐受。 LPATH最近在湿AMD患者中完成了I期临床试验，并且根据初步数据（未经审计），该试验表明了对疾病关键参数的生物学影响的令人鼓舞的迹象。单剂量ISONEP之后，大多数患者表现出改善，包括明显减少视网膜水肿和相关厚度，对基本CNV病变的完全消退（VEGF抑制剂很少DO），以及RPE脱离的几乎完整的分辨率（VEVGF抑制剂（正常情况下）是veVGF抑制剂。大多数患者以前曾接受过多种抗VEGF治疗，但反应不佳，表明ISONEP可能具有与这些治疗无关的作用。 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和PVR，有很大的未满足医疗需求。这些目标的成功将证明ISONEP会影响湿AMD的多种潜在病理（也许还有其他眼部条件），从而为复杂而残疾的疾病提供了更完整的解决方案。 公共卫生相关性的渗出症（或湿）AMD（与年龄相关的黄斑变性）是老年美国人严重视力丧失和失明的主要原因。虽然Lucentis（R）和标签外使用Avastin（R） - 在一段时间内，在某些患者中，湿AMD-Improve视力的明确市场领导者并不代表完整的解决方案。 LPATH的创新药物ISONEP靶向生物活性脂质S1P，可能代表下一代的湿AMD治疗，并有可能解决其他残疾的眼部疾病，例如糖尿病性视网膜病，干燥的AMD和增殖性玻璃质疾病。