A diabetes pill to replace insulin injections

该项目的总体目标是开发一种口服胰岛素替代注射胰岛素。这项工作的核心前提是，一种名为BG-148的小分子或类似分子可以口服代替注射胰岛素来帮助控制血糖。BG-148可以完全替代胰岛素注射或将胰岛素注射减少一半。为了开始临床试验来评估这一前提，必须进行正式的、受监管的毒理学计划，并且必须生产出供人使用的BG-148。这项建议的具体目标就是要解决这些障碍。第一阶段具体目标：大量生产BG-148（≈2千克）。这一目标将产生足够数量的BG-148，以完成开始人体试验所需的所有临床前研究。Aim 1还将产生分析知识，例如表征药物稳定性、特性、强度和纯度的分析方法，这将使人用BG-148的生产和完成对人进行的所有临床前研究成为可能。II期具体目标：目标2：在I型糖尿病患者中完成一项为期28天的重复给药研究。目的2将帮助确定(a) BG-148的治疗性口服剂量水平，(b) BG-148降低血糖的程度，以及(c) BG-148诱导低血糖、糖尿病酮症酸中毒或其他不良事件的可能性。这些信息将使我们能够推动和设计初步的人体试验。目标3：定义未观察到的不良反应水平（NOAEL），并得出首次人体临床试验的最大推荐起始剂量（MRSD）。目前没有足够的数据来确定重复给药BG-148时可能发生毒性的剂量水平。不知道这些剂量水平使我们无法开始人体试验。这一目标将产生临床试验所需的安全性数据。这个项目将导致鉴定出一类新的口服生物可利用分子，这种分子能够以接近胰岛素的活性降低血糖。这一发现将导致一种新的血糖控制疗法。临床工作是确定BG-148或类似分子在多大程度上能够成为有效和安全的口服治疗药物，从而减少注射胰岛素的需要的唯一方法。该项目旨在尽早达到临床阶段。

The overall goal of this program is to develop an oral replacement for injecting insulin. The central premise of this work is that a small molecule called BG-148, or similar molecules, can be taken orally in place of injecting insulin to aid in glycemic control. BG-148 could completely replace insulin injections or could reduce insulin injections by half. To begin clinical testing to evaluate this premise, a formal, regulated toxicological program must be conducted, and BG-148 must be manufactured for human use. The specific aims of this proposal are designed to address these obstacles. PHASE I SPECIFIC AIM: Make larger quantities (≈ 2 kg) of BG-148. This aim will produce sufficient amounts of BG-148 to complete all preclinical studies required to begin human testing. Aim 1 will also generate analytical knowledge, such as analytical methods to characterize the drug’s stability, identity, strength, and purity, which will enable the manufacturing of BG-148 for human use and the completion of all preclinical studies required to proceeded to humans. PHASE II SPECIFIC AIMS: AIM 2: Complete a 28-day repeat-dose study in animals with type I diabetes. Aim 2 will help define (a) the therapeutic oral dose levels of the BG-148, (b) the degree to which BG-148 is able to lower blood glucose, and (c) BG-148’s potential to induce hypoglycemia, diabetic ketoacidosis, or other adverse events. This information will allow us to power and design initial human trials. AIM 3: Define the no-observed-adverse-effect Level (NOAEL) and derive the Maximum Recommended Starting Dose (MRSD) for first-in-human clinical trials. There is currently insufficient data to determine the dose levels at which toxicity might occur in upon repeat dosing with BG-148. Not knowing these dose levels prevents us from initiating human trials. This aim will generate the required safety data to enable clinical trials. This program will lead to the identification of a new class of orally bioavailable molecule that is capable of lowering blood glucose with an activity approaching that of insulin. Such discovery would lead to a novel therapeutic for glycemic control. Clinical work represents the only method to determine the extent to which BG-148, or similar molecules, would make useful and safe oral therapeutic that are capable of reducing the need to inject insulin. This project is designed to reach this clinical stage as early as possible.