Assessment of the glucagon receptor blocker REMD-477 on insulin requirements in type 1 diabetes

胰高血糖素受体阻滞剂 REMD-477 对 1 型糖尿病胰岛素需求的评估

• 批准号: 9041432
• 负责人: Samuel Klein
• 金额: $ 22.47万
• 依托单位: REMD BIOTHERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9041432
• 关键词: Adverse event; Affinity; Alkaline Phosphatase; Animal Model; Animals; Antibodies; Autoimmune Process; Benign; Bilirubin; Biological Assay; Blocking Antibodies; Blood; Blood Glucose; Businesses; C-Peptide; Cardiovascular system; Chemicals; Chronic; Clinical Research; Diabetes Mellitus; Dose; Double-Blind Method; Electrocardiogram; Event; General Population; Geriatrics; Glucagon; Glucagon Receptor; Glucose; Glycosylated hemoglobin A; Hepatic; Hormonal Change; Hormones; Human; Hyperglycemia; Hyperinsulinism; Hyperlipidemia; Hypoglycemia; Inbred NOD Mice; Incidence; Infusion procedures; Injection of therapeutic agent; Inpatients; Insulin; Insulin-Dependent Diabetes Mellitus; Intravenous; Investigational Drugs; Ketones; Life; Liver; Medical center; Metabolic; Modeling; Monitor; Mus; Non obese; Non-Insulin-Dependent Diabetes Mellitus; Nutritional Science; Outpatients; Pancreas; Patients; Phase; Placebos; Production; Quality of life; Randomized; Rattus; Reporting; Research; Residual state; Safety; Secondary to; Serious Adverse Event; Severities; Staining method; Stains; Streptozocin; Subcutaneous Injections; Texas; Tissues; Transaminases; Universities; blood glucose regulation; blood lipid; clinical efficacy; diabetic; diabetic patient; diabetic rat; follow-up; glucagon-like peptide 1; glucose output; glycemic control; healthy volunteer; human study; improved; insulin secretion; liver function; medical schools; mortality; mouse model; non-diabetic; novel strategies; public health relevance; subcutaneous; total measurement Bilirubin; type I diabetic

 DESCRIPTION (provided by applicant): (Fast-Track) Insulin remains the primary, and often the only, treatment for type 1 diabetes mellitus (T1D). However it is associated with chronic iatrogenic hyperinsulinemia, secondary hyperlipidemia, higher incidence and severity of cardiovascular complications, and life-threatening hypoglycemia events. A higher mortality (2.7%,vs. 0.9%) due to cardiovascular complications were reported in insulin-treated T1D patients, versus the general public [3]. An effective add-on therapy is needed to reduce daily insulin doses and to minimize its complications. REMD-477 is a fully human, high affinity, glucagon receptor (GCGR) antibody, that blocks the hepatic GCGR and reduces hepatic glucose/ketone production. REMD-477 restores euglycemia in animal models of type 2 diabetes mellitus (T2D), and shows preliminary but promising glucose-lowering effect in a few T1D mouse models. REMD-477 demonstrated a benign safety profile in animals, and in healthy volunteers in a first-in- human study. Since the overactive glucagon action is a common finding in both T1D and T2D, a robust GCGR blocker, such as REMD-477, represents a promising novel strategy. In Phase I of this project, the glucose-lowering effects of REMD-477 will be thoroughly evaluated in 2 animal models of T1D, including a chemical (streptozotocin)-induced model in rats; and an autoimmune, non-obese diabetic (NOD) model in mice, both without insulin treatment. The animal studies will be directed by Dr. Roger Unger, at the Touchstone Diabetes Center, University of Texas Southwestern Medical Center, Dallas, TX. In Phase II, a randomized, double-blind, vehicle-controlled, 4-day, in-patient, clinical study will be conducted i 20 patients with T1D, to quantitatively assess the reduction in insulin requirements while maintaining standardized postprandial and postabsorptive glycemic control. The study will be directed by Dr. Sam Klein, Chief, Div. of Geriatrics & Nutritional Sciences, at the Washing University School of Medicine, St. Louis, MO. The small business, REMD Inc., provides research materials, performs the hormone and metabolite assays, and coordinates the overall project management and supportive duties, for both Phase I and II of this project. REMD-477 is projected to be an add-on therapy for T1DM, to substantially (>50%) reduce insulin daily doses, leading to better glucose control, fewer and milder complications, and an improved quality of life.

 描述（由适用提供）：（快速轨道）胰岛素仍然是主要的，通常是唯一的1型糖尿病治疗方法（T1D）。然而，它与慢性医源性高胰岛素血症，继发性高脂血症，心血管并发症的发病率和严重程度更高以及威胁生命的低血糖事件有关。在胰岛素治疗的T1D患者中，由于心血管并发症而导致的死亡率较高（2.7％，比0.9％），与公众相比[3]。需要有效的附加疗法来减少每日胰岛素剂量并最大程度地减少其并发症。 REMD-477是一种完全人类的高亲和力，胰高血糖素受体（GCGR）抗体，可阻断肝GCGR并减少肝素葡萄糖/酮的产生。 REMD-477在2型糖尿病（T2D）的动物模型中恢复了葡萄糖，并在一些T1D小鼠模型中显示出初步但有希望的降糖作用。 REMD-477在人类研究中表现出了动物和健康志愿者的良性安全性。由于过度活跃的胶合作用是T1D和T2D中的一个普遍发现，因此稳健的GCGR阻滞剂（例如REMD-477）代表了一种有望的新颖策略。在该项目的第一阶段，将在2种T1D动物模型中对REMD-477的降糖作用进行彻底评估，包括大鼠的化学（链唑霉素）诱导的模型。以及小鼠中的自身免疫性，非肥胖糖尿病（NOD）模型，均无需胰岛素治疗。动物研究将由德克萨斯州达拉斯西南医学中心的Touchstone糖尿病中心Roger Unger博士指导。在第二阶段，将进行一项随机，双盲，媒介物对照，4天，住院，临床研究，I 20例T1D患者，以定量评估胰岛素需求的减少，同时保持标准的餐后和后吸收性血糖控制。这项研究将由Div。密苏里州圣路易斯洗车大学医学院的老年医学和营养科学。小型企业Remd Inc.提供研究材料，执行Horsene和代谢物测定法，并为该项目的第一阶段和II期协调整体项目管理和支持职责。 REMD-477预计是T1DM的附加疗法，大大减少胰岛素每日剂量，从而可以更好地控制葡萄糖，更少和米勒并发症以及改善的生活质量。