Targeted Lymphoablation as an alternative to HSCT to cure T1D

项目总结 由于胰岛素是1型糖尿病(T1D)唯一被批准的治疗方法，有非常大的未得到满足的医学 需要对儿童和成人患者进行彻底的治疗。在美国，糖尿病目前影响着14%的 所有年龄段的人口，它是第七大死因，估计每年造成2370亿美元的损失 向医疗保健系统捐赠一年。医学界已经确认T1D是一种自身免疫性疾病， 提出了不同的免疫治疗方法来治愈它。然而，只有造血干细胞 移植(HSCT)在使用有毒化疗重新启动免疫系统后，到目前为止显示为暂时的 恢复胰岛素的独立性。抗原特异性免疫疗法(Teplizumab)正在提供部分 治疗效果：只有5%-6%的患者表现出两年的胰岛素独立。AVM生物技术 (AVM)正在基于一种新的免疫调节配方(AVM0703)开发一种治疗T1D的新方法 动员“增强型”自然杀伤T细胞安全清除负责的自身反应淋巴细胞 T1D。第一阶段活动的结果显示，单独使用AVM0703可以预防45%的糖尿病，或 在T1D的NOD模型中，55%的小鼠将其发病推迟20-31周。AVM0703可能代表一个保险箱 根据临床前老鼠数据为50%的患者提供独立治疗选项，为他们提供预期的 胰岛素非依赖性3-30年窗口期。如果复发，AVM0703的安全配置文件将允许 重复剂量高达FDA目前批准的8倍，用于正在进行的复发难治性临床试验 淋巴系恶性肿瘤(NCT04329728)。对于没有缓解的患者，AVM0703预计会加强 其他免疫疗法允许更广泛的T1D患者实现胰岛素独立，例如， 联合应用特普利珠单抗(抗CD3)。该SBIR第二期项目被设计为 随机、安慰剂对照的多中心临床前试验，以获得可靠的数据，在现有的 AVM0703和Teplizumab等潜在辅助药物的毒理学信息将加快IND 批准并为临床试验铺平道路。目标1中的活动将被指示进行临床前剂量- NOD小鼠在糖尿病前期、新发病和已建立三种情景下的作用研究的发现和机制 糖尿病。AIM 1的结果将用于确定用于关键疗效的AVM0703剂量 在AIMS 2和AIMS 3中逆转新发糖尿病和已确诊糖尿病的研究。IND将应用 在项目结束时提交。

PROJECT SUMMARY With insulin being the only approved treatment of Type 1 Diabetes (T1D), there is a very large unmet medical need for a definitive cure for pediatric and adult patients. In the U.S., diabetes currently affects 14% of the population of all ages, and it is the seventh leading cause of death, with an estimated cost of $237 billion every year to the healthcare system. The medical community has recognized T1D as an autoimmune disease and proposed different immunotherapeutic approaches to cure it. However, only hematopoietic stem cell transplantation (HSCT) after reset of the immune system with toxic chemotherapy, has so far shown temporary restoration of insulin independence. Antigen-specific immunotherapies (Teplizumab) are offering partial therapeutic benefits with only 5-6% of the patients showing two-year insulin independence. AVM Biotechnology (AVM) is developing a new approach for T1D based on a novel immunomodulatory formulation (AVM0703) that mobilizes “Supercharged” Natural Killer T-Cells for safe removal of autoreactive lymphocytes responsible for T1D. Results from Phase I activities show that AVM0703 administered alone can prevent diabetes in 45%, or delay its onset by 20-31 weeks in 55% of mice in the NOD model of T1D. AVM0703 may represent a safe standalone curative option for 50% of the patients based on preclinical mouse data, providing them an expected window of insulin independence of 3-30 years. In case of relapse, the safety profile of AVM0703 will allow repetitive dosing up to 8 times as currently approved by the FDA for an ongoing clinical trial in relapsed refractory lymphoid malignancies (NCT04329728). For patients not showing remission, AVM0703 is expected to reinforce other immunotherapies allowing a wider range of T1D patients to achieve insulin independence, for instance, combinatorial therapy with Teplizumab (anti-CD3). This SBIR Phase II project has been designed as a randomized, placebo-controlled multi-center pre-clinical trial to obtain solid data which, with the already available toxicology information for AVM0703 and potential companion agents such as Teplizumab, will expedite IND approval and pave the way to clinical trials. Activities in Aim 1 will be directed to perform a pre-clinical dose- finding and mechanism of action study in NOD mice in three scenarios: pre-diabetic, new-onset, and established diabetes. Results from Aim 1 will be used to determine the AVM0703 dose to be used in the pivotal efficacy study for reversal of new-onset diabetes and established diabetes in Aims 2 and 3. An IND application will be filed at the end of the project.