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（T1 D）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。长期胰岛素治疗 还与继发性高脂血症有关，以及心血管并发症的发生率较高， 会变得更严重事实上，由于心血管并发症导致的死亡是胰岛素组的三倍， T1 D患者比一般人更容易接受治疗。迫切需要一种安全、有效的附加疗法 这减少了每日胰岛素需求，并反过来最大限度地减少了慢性高胰岛素血症的并发症。 T1 D高血糖症不仅是由胰岛β细胞缺乏引起的，也是由胰高血糖素过度分泌引起的 活动在正常情况下，β细胞分泌胰岛素，其局部抑制胰高血糖素从β细胞释放。 附近的α细胞。然而，由于T1 D患者缺乏胰岛内胰岛素、α细胞活性和胰高血糖素分泌， 是不受约束的，没有人反对外源性胰岛素给药不能影响这种局部反馈 机制因此，胰高血糖素受体（GCGR）阻断剂已成为一个有趣的治疗靶点 来治疗T1 D REMD-477是一种完全人源的高亲和力胰高血糖素受体（GCGR）抗体，可阻断肝脏GCGR 并减少肝葡萄糖和酮的产生。REMD-477在动物中表现出良好的安全性特征 在一项首次人体研究中，在最近完成的快速通道的第一阶段，我们展示了 REMD-477在三种糖尿病动物模型中的降糖作用。在快速通道的第二阶段， 我们在小型临床研究中证明了单剂量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，当前的IIB期SBIR工作将确定 多剂量REMD-477是否可以安全有效地减少患者的胰岛素需求 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周是否 用REMD-477治疗可以降低每日/平均胰岛素使用量、24小时血糖浓度、HgbA 1c和 低血糖事件。我们还将通过以下方式评估REMD-477对α和β细胞功能的影响： 分别评估胰高血糖素和活性和总胰高血糖素样肽1（GLP-1）以及c肽。我们将 还研究了肝内脂质含量、体重和生活质量指标。 REMD-477正在开发作为T1 DM的附加治疗，以大幅（>50%）减少每日胰岛素 剂量，导致更好的血糖控制，更少和更轻的并发症，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.