Assessment of Multiple Dose Administration ofGlucagon Receptor Blocker REMD477 in Type 1 Diabetes

摘要 胰岛素仍然是1型糖尿病(T1D)的主要治疗方法；然而，它与 慢性医源性高胰岛素血症和危及生命的低血糖事件。长期的胰岛素治疗是 也与继发性高脂血症有关，心血管并发症的发生率更高， 往往会更加严厉。事实上，在胰岛素中，死于心血管并发症的人是普通人的三倍。 治疗的T1D患者比普通公众更多。迫切需要一种安全、有效的附加疗法。 这减少了每日的胰岛素需求，进而将慢性高胰岛素血症的并发症降至最低。 T1D高血糖不仅与胰腺β细胞缺陷有关，还与胰升糖素的过度分泌有关 活动。在正常情况下，β细胞会分泌胰岛素，这种胰岛素会局部抑制 附近的α-Cells。然而，由于T1D患者缺乏胰岛内胰岛素、α细胞活性和胰升糖素分泌 是不受约束的，不受反对的。外源性胰岛素注射不能影响这种局部反馈 机制。因此，阻断胰高血糖素受体(GCGR)已成为一个有趣的治疗靶点。 治疗T1D。 REMD-477是一种完全人源性、高亲和力的GCGR抗体，可阻断肝脏的GCGR 并减少肝脏葡萄糖和酮类的产生。REMD-477在动物身上显示出良好的安全性 并在健康志愿者中进行了一项首次人类研究。在最近完成的Fast Track的第一阶段中，我们展示了 REMD-477对三种糖尿病动物模型的降糖作用。在快车道的第二阶段， 我们在一项小型临床研究中证明了单剂REMD-477的安全性和有效性。 基于这些有希望的临床前和临床结果，目前的IIB期SBIR努力将确定 多剂量REMD-477能否安全有效地降低高血压患者的胰岛素需求 T1D。在这项随机、双盲、赋形剂对照的2期临床试验中，我们探讨了12周 REMD-477治疗可以降低每日/平均胰岛素用量、24小时血糖浓度、HgbA1c和 低血糖事件。我们还将通过以下方法评估REMD-477对α细胞和β细胞功能的影响 分别检测胰升糖素、活性和总的胰升糖素样肽1(GLP-1)和C-肽。我们会 同时研究肝内脂肪含量、体重和生活质量的测量。 REMD-477正在被开发为T1 DM的附加疗法，以显著(&gt；50%)每天减少胰岛素 剂量，导致更好的血糖控制，更少和更温和的并发症，并改善生活质量。

ABSTRACT Insulin remains the mainstay treatment for type 1 diabetes mellitus (T1D); however, it is associated with chronic iatrogenic hyperinsulinemia and life-threatening hypoglycemia events. Long term insulin treatment is also associated with secondary hyperlipidemia, and a higher incidence of cardiovascular complications, which tend to be more severe. Indeed, death due to cardiovascular complications is three-fold higher among insulin- treated T1D patients than in the general public. There exists a critical need for a safe, effective add-on therapy that reduces daily insulin requirements and, in turn, minimizes complications of chronic hyperinsulinemia. Hyperglycemia in T1D is not only caused by deficient pancreatic β-cell, but also by exaggerated glucagon activity. Under normal circumstances, β-cells secrete insulin that locally supresses glucagon release from nearby α-cells. However, since patients with T1D lack intra-islet insulin, α-cells activity and glucagon secretion are unrestrained and unopposed. Exogenous insulin administration is unable to affect this local feedback mechanism. Consequently, glucagon receptor (GCGR) blockade has become an intriguing therapeutic target to treat T1D. REMD-477 is a fully human, high affinity, glucagon receptor (GCGR) antibody that blocks the hepatic GCGR and reduces hepatic glucose and ketone production. REMD-477 exhibited a benign safety profile in animals and in healthy volunteers in a first-in- human study. In Phase I of a recently completed Fast Track, we showed the glucose-lowering effects of REMD-477 in three animal models of diabetes. In Phase II of the Fast Track, we demonstrated the safety and efficacy of a single dose of REMD-477 in a small clinical study. Based on these promising preclinical and clinical results, the current Phase IIB SBIR effort will determine whether multiple doses of REMD-477 can safely and effectively reduce insulin requirements in patients with T1D. In this randomized, double-blind, vehicle-controlled, Phase 2 clinical trial, we explore whether 12 weeks treatment with REMD-477 can lower daily/average insulin use, 24h blood glucose concentration, HgbA1c, and hypoglycemic events. We will also assess the effect of REMD-477 on alpha- and beta-cell function by assessing glucagon and active and total glucagon-like peptide 1 (GLP-1), and c-peptide, respectively. We will also study intrahepatic lipid content, body weight, and quality of life measures. REMD-477 is being developed as 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.