Phase II trial of extended release exenatide (Bydureon) and teplizumab in patients with new onset Type 1 Diabetes.

在了解1型糖尿病(T1D)的免疫学机制方面取得了很大进展，但 这些进展并没有转化为治疗这种疾病的新疗法。最近“成功”的试验结果 表现出胰岛素分泌的短暂改善，但持续改善并不一致 看到了。这一提议的基础是，免疫疗法的成功开发需要解决 代谢障碍也是如此。这项R34规划拨款是为了设计和完成行政和 启动随机II期临床试验以比较替普利单抗组合所需的其他任务 (一种非FCR结合的抗CD3单抗)与拜度瑞隆(缓释埃塞那肽)单独应用于两种药物的患者 伴新发的T1D。替普利单抗已在4个随机对照临床试验中被证明可以改善C- 新发和新发T1D患者的多肽反应。在之前的研究中，我们已经确定 与临床反应相关的免疫学机制，涉及CD8+T细胞的调节 车厢。此外，我们发现，这种药物会导致T细胞迁移到肠道，并获得 监管职能。GLP-1受体激动剂Bydureon被批准用于治疗T2D。其作用机制 动作靶点T1D功能障碍的特点。它抑制胰高血糖素水平，减缓胃排空，刺激 胰岛素释放，并已被假定为刺激β细胞复制。它也可能有抗炎作用。 效果。短期服用艾塞那肽已被证明具有显著的效果，可降低餐后血糖 短途旅行。拟议试验的主要终点是测试替普利单抗+ 在诱导临床缓解(定义为HbA1c&lt；7.0%)方面，Bydureon比任何一种药物都更有效 胰岛素用量：0.25U/kg/d：这些参数是根据ADA的护理标准选择的 之前的临床试验。次要终点包括C-肽反应的比较 治疗臂、胰岛素非依赖性缓解的频率和血糖漂移。的一个重要部分 建议的研究是在我们之前的研究和与ITN合作的基础上进行的，以 确定免疫反应的基础。我们将扩大我们对在 临床应答者与糖尿病抗原特异性CD_8~+T细胞及β细胞比率的变化 杀戮。此外，我们还将检验微生物群调节替普利珠单抗反应的新假设。 我们在人源化小鼠身上的研究表明了这一点。这项临床试验方案是独一无二的，因为它 第一个涉及两个相关的疾病机制。它还使用以下测量结果作为端点 有可能被广泛接受，并使治疗方法的开发能够改善临床状况 对病人来说。

There have been great advances in understanding the immunologic mechanisms of Type 1 diabetes (T1D) but these advances have not translated into new therapies for the disease. The results of recent “successful” trials have shown transient improvement in insulin secretion but sustained improvement has not been uniformly seen. The basis for this proposal is that the successful development of an immune therapy requires addressing the metabolic impairment as well. This R34 planning grant is to design and complete the administrative and other tasks needed to commence a randomized Phase II clinical trial to compare the combination of teplizumab (a non-FcR binding anti-CD3 mAb) with Bydureon (extended release exenatide) to either drug alone in patients with new onset T1D. Teplizumab has been shown, in 4 randomized controlled clinical trials, to improve C- peptide responses in patients with new and recent onset T1D. In previous studies, we have identified immunologic mechanisms that are associated with clinical responses, involving modulation of the CD8+ T cell compartment. In addition, we found that the drug causes migration of T cells to the gut and acquisition of regulatory function. Bydureon, the GLP-1 receptor agonist, is approved for treatment of T2D. Its mechanisms of action target dysfunctional features of T1D. It inhibits glucagon levels, slows gastric emptying, stimulates insulin release, and has been postulated to stimulate beta cell replication. It also may have anti-inflammatory effects. Short term use of exenatide has been shown to have dramatic effects reducing post-prandial glucose excursions. The primary endpoint of the proposed trial is to test whether the combination of teplizumab + Bydureon is more effective than either drug alone in inducing clinical remission defined as a HbA1c< 7.0% and insulin use < 0.25U/kg/d: These parameters were chosen based on ADA standards of care the analysis of previous clinical trials. The secondary endpoints including a comparison of C-peptide responses in the treatment arms, the frequency of insulin independent remissions, and glycemic excursion. An important part of the proposed studies is to build on our previous studies and those from collaborative work with the ITN to identify the basis for immunologic responses. We will expand our studies of the gene signatures found in clinical responders and the changes in diabetes antigen specific CD8+ T cells as well as the rates of β cell killing. In addition, we will test the novel hypothesis that the microbiome modulates responses to teplizumab which has been suggested by our studies in humanized mice. This clinical trial proposal is unique because it is the first that addresses two relevant disease mechanisms. It also uses, as endpoints, measurements that are likely to be widely accepted and enable the development of treatments that will improve the clinical condition for patients.