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

 描述(由申请人提供)：(快速通道)胰岛素仍然是1型糖尿病(T1D)的主要治疗方法，通常也是唯一的治疗方法。然而，它与慢性医源性高胰岛素血症、继发性高脂血症、较高的心血管并发症发生率和严重性以及危及生命的低血糖事件有关。在接受胰岛素治疗的T1D患者中，因心血管并发症而导致的死亡率(2.7%，vs.0.9%)高于普通人群[3]。需要一种有效的补充疗法来减少每天的胰岛素剂量，并将其并发症降至最低。REMD-477是一种完全人类的、高亲和力的胰高血糖素受体(GCGR)抗体，它可以阻断肝脏的GCGR，减少肝脏葡萄糖/酮的产生。REMD-477可恢复2型糖尿病(T2D)动物模型的正常血糖，并在少数T1D小鼠模型中显示出初步但有前景的降糖作用。在一项首次人类研究中，REMD-477在动物和健康志愿者身上显示出良好的安全性。由于过度活跃的胰高血糖素作用在T1D和T2D中都是常见的发现，一种强大的GCGR阻滞剂，如REMD-477，代表了一种有前景的新策略。在该项目的第一阶段，将在T1D的两个动物模型中彻底评估REMD-477的降糖效果，包括化学物质(链脲佐菌素)诱导的大鼠模型和未经胰岛素治疗的自身免疫性非肥胖型糖尿病(NOD)小鼠模型。动物研究将由德克萨斯州达拉斯大学西南医学中心试金石糖尿病中心的罗杰·昂格尔博士指导。在第二阶段，将对20名T1D患者进行为期4天的随机、双盲、载体对照的临床研究，以定量评估在保持标准化的餐后和吸收后血糖控制的同时胰岛素需求量的减少。这项研究将由科长Sam Klein博士指导。他是密苏里州圣路易斯市洗涤大学医学院的老年医学与营养科学教授。小型企业REMD Inc.为该项目的第一阶段和第二阶段提供研究材料、进行激素和代谢物分析，并协调整个项目管理和支持职责。REMD-477预计将是治疗T1 DM的一种附加疗法，大幅(&gt；50%)减少胰岛素的每日剂量，导致更好的血糖控制，更少和更温和的并发症，以及改善生活质量。

 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.