Targeting galectin-3 to overcome insulin resistance in type 2 diabetes

靶向 Galectin-3 克服 2 型糖尿病的胰岛素抵抗

基本信息

批准号：
10758803
负责人：
HAFIZ AHMED
金额：
$ 181.05万
依托单位：
GLYCOMANTRA, INC.
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-22 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10758803
关键词：
Affinity Agreement Animal Experiments Animal Model Animals Apoptosis Area B-Lymphocytes Binding Biological Biological Markers Biological Products Biological Response Modifier Therapy Blood Capital Carbohydrates Cells Chinese Hamster Ovary Cell Clinical Trials Critical Pathways Cyclic GMP Diabetes Mellitus Dose Engineering Extracellular Matrix FDA approved Fatty acid glycerol esters Frequencies Funding Future Galectin 3 Genes Goals High Fat Diet Home Human Immune Industry Inflammation Inflammatory Insulin Insulin Receptor Insulin Resistance Knowledge Lectin Licensing Ligands Liver Macrophage Measures Mediating Modeling Molecular Muscle Non-Insulin-Dependent Diabetes Mellitus Obesity Organ Outcome Outcome Study Patients Pharmaceutical Preparations Pharmacologic Substance Phase Phase I Clinical Trials Positioning Attribute Process Production Proteins Receptor Signaling Regulation Research Resolution Running Source Subcutaneous Injections Suspensions Technology Therapeutic Time Toxicology Training Transfection Translating Work antagonist cell bank clinical development design diet-induced obesity dietary drug candidate drug development experimental study fasting glucose first-in-human glucose tolerance impaired glucose tolerance improved insight insulin sensitivity insulin signaling insulin tolerance islet manufacture manufacturing process nanomolar novel pharmacokinetics and pharmacodynamics phase 1 study preclinical study primary endpoint product development restoration scale up subcutaneous technological innovation

项目摘要

Project Summary/Abstract Obesity-mediated insulin resistance is a hallmark of type 2 diabetes (T2D), which accounts for ~90% of all diabetes. Despite many drugs that are available to treat T2D, there is no FDA-approved drug that directly works on the insulin receptor (IR) to overcome insulin resistance. Recent studies show that galectin-3 (Gal3) can bind directly to the IR and inhibit downstream IR signaling causing insulin resistance and impaired glucose tolerance in obesity-induced T2D. Our scientific premise is that we have developed a very potent Gal3 antagonist, TFD100, from a natural dietary source. The primary objective of this Phase II proposal is to complete the preclinical studies required for our IND submission to the FDA to enable the initiation of a first–in– human Phase 1 clinical trial. Successful completion of our proposed aims will achieve a significant value inflection point for the company, positioning us well for either partnering or a capital raise. The proposed research embodies technological innovation in two areas: 1) This will be the first FDA- approved biologic therapeutics based on a natural carbohydrate compound; 2) TFD100’s picomolar affinity to Gal3 has many advantages including overcoming the common saturation issue related to antigenicity. An anticipated corollary benefit of the proposed studies includes the elucidation of novel lectin-mediated molecular mechanisms of cell-cell or cell-extracellular matrix (ECM) interactions that modulate IR signaling in T2D. This knowledge will be fundamental to opening-up new carbohydrate-based approaches to T2D treatments. We have successfully completed Phase 1 studies. In studies with cells, Gal3 inhibited IR/IRS-1 activation, which was reversed by TFD100. In high fat diet (HFD) animal model, TFD100 treatment significantly improved glucose tolerance and insulin tolerance compared to the vehicle-treated animals. After analyzing our results, we are excited to continue our drug development. TFD100 is a biologic drug and we believe that TFD100 will likely be distributed as a solution in the prefilled cartridge to be taken by T2D patients at home similar to non- invasive SC injection of insulin or Ozempic. To enhance the scientific rigor, we plan to ascertain SC administered TFD100’s ability to treat T2D in HFD model, and to complete relevant IND-enabling experiments in the following specific aims: 1) Determine PK/PD of TFD100; 2) Ascertain efficacy of SC administered TFD100 to treat HFD induced obesity, insulin resistance and T2D, and 3) GLP production of TFD100 for future toxicology studies. The proposed activities will be either performed by expert contractual collaborators or will be guided by an exceptional consultant team with specialized industry expertise in biologics product development, regulation, and clinical development. The outcomes of these studies will lead to the submission of IND to the FDA followed by a Phase 1 clinical trial.

项目概要/摘要肥胖介导的胰岛素抵抗是 2 型糖尿病 (T2D) 的一个标志，约占所有糖尿病患者的 90% 尽管有许多药物可用于治疗 T2D，但尚无 FDA 批准的直接药物。最近的研究表明半乳糖凝集素 3 (Gal3) 通过作用于胰岛素受体 (IR) 来克服胰岛素抵抗。可直接与 IR 结合并抑制下游 IR 信号传导，导致胰岛素抵抗和血糖受损我们的科学前提是我们已经开发出一种非常有效的 Gal3。拮抗剂 TFD100，来自天然饮食来源该 II 期提案的主要目标是完成我们向 FDA 提交 IND 所需的临床前研究，以便启动首个- 人类一期临床试验的成功完成我们提出的目标将实现显着的价值。公司的拐点，使我们处于合作或融资的有利位置。拟议的研究体现了两个领域的技术创新：1）这将是第一个 FDA- 基于天然碳水化合物化合物的批准生物疗法；2) TFD100 的皮摩尔亲和力； Gal3 具有许多优点，包括克服与抗原性相关的常见饱和问题。拟议研究的预期必然结果包括阐明新型凝集素介导的分子调节 T2D 中 IR 信号传导的细胞-细胞或细胞-细胞外基质 (ECM) 相互作用的机制。知识对于开辟新的基于碳水化合物的 T2D 治疗方法至关重要。我们已经成功完成了第一阶段的细胞研究，Gal3 抑制 IR/IRS-1 激活， TFD100 可逆转这种情况，在高脂肪饮食 (HFD) 动物模型中，TFD100 治疗显着改善。与媒介物治疗的动物相比，葡萄糖耐量和胰岛素耐量在分析我们的结果后，我们很高兴继续我们的药物开发，TFD100 是一种生物药物，我们相信 TFD100 将会。可能会以预装药筒中的溶液形式分发，供 T2D 患者在家服用，类似于非药物侵入性SC注射胰岛素或Ozempic 为了提高科学性，我们计划确定SC。赋予 TFD100 在 HFD 模型中治疗 T2D 的能力，并完成相关的 IND 实验实现以下具体目标：1) 确定 TFD100 的 PK/PD；2) 确定 SC 给药的功效； TFD100 用于治疗 HFD 引起的肥胖、胰岛素抵抗和 T2D，以及 3) TFD100 的 GLP 生产用于治疗未来的毒理学研究将由专家合同合作者进行。或将由具有生物制剂产品专业行业知识的杰出顾问团队指导这些研究的结果将导致提交。向 FDA 提交 IND，然后进行 1 期临床试验。