Targeted Lymphoablation as an alternative to HSCT to cure T1D

靶向淋巴消融作为 HSCT 的替代疗法来治疗 T1D

• 批准号: 10484003
• 负责人: Theresa Deisher
• 金额: $ 66.77万
• 依托单位: AVM BIOTECHNOLOGY, LLC
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-20 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10484003
• 关键词: Adoption; Adult; Affect; Age; Animal Model; Antigens; Autoimmune Diseases; Autoimmunity; Biotechnology; Blood Glucose; Businesses; CD3 Antigens; Cause of Death; Cells; Childhood; Clinical; Clinical Trials; Clinical Trials Design; Communities; Companions; Cytotoxic T-Lymphocytes; Data; Dexamethasone; Diabetes Mellitus; Disease remission; Dose; Drug Industry; Excipients; Excision; FDA approved; Florida; Formulation; Glucocorticoids; Grant; Health; Healthcare; Healthcare Systems; Hematopoietic Stem Cell Transplantation; Human; Immune system; Immunologics; Immunosuppression; Immunosuppressive Agents; Immunotherapeutic agent; Immunotherapy; Impairment; Inbred NOD Mice; Individual; Insulin; Insulin-Dependent Diabetes Mellitus; Intravenous; Leadership; Length; Longevity; Lymphocyte; Malignant lymphoid neoplasm; Marketing; Medical; Modeling; Monoclonal Antibody HuM291; Mus; Non obese; Oral; Patients; Pharmacology; Phase; Placebo Control; Population; Prediabetes syndrome; Procedures; Process; Production; Program Development; Randomized; Refractory; Regimen; Relapse; Risk; Safety; Scientist; Small Business Innovation Research Grant; Solid; Testing; Therapeutic; Time; Toxic effect; Toxicology; Translating; Treatment Protocols; Universities; anti-CD20; autoreactivity; base; chemotherapy; clinical development; combinatorial; cost estimate; design; diabetic; drug development; early onset; efficacy study; experience; experimental study; immunoregulation; innovation; insight; insulin dependent diabetes mellitus onset; novel; novel strategies; novel therapeutic intervention; pre-clinical; preclinical study; preclinical trial; prevent; restoration; rituximab; sodium phosphate; symptom management

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.

项目摘要 胰岛素是唯一经批准的1型糖尿病（T1D）治疗的治疗 需要针对小儿和成年患者提供明确的治疗。在美国，糖尿病目前影响14％ 所有年龄段的人口，也是第七大死亡原因，估计每一欧元的成本为2370亿美元 一年进入医疗保健系统。医学界已将T1D视为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。但是，只有造血干细胞 重置有毒化疗的免疫系统后的移植（HSCT），到目前为止显示了暂时的 恢复胰岛素独立性。抗原特异性免疫疗法（Teplizumab）提供部分 只有5-6％的患者表现出两年胰岛素独立性，治疗益处。 AVM生物技术 （AVM）正在基于新型免疫调节公式（AVM0703）开发一种新方法 动员“增压”天然杀手T细胞，以安全去除负责的自动反应性淋巴细胞 T1D。第一阶段活动的结果表明，单独管理的AVM0703可以预防45％的糖尿病，或 在T1D的NOD模型中，在55％的小鼠中，将其发作降低了20-31周。 AVM0703可能代表保险箱 根据临床前鼠标数据，50％的患者的独立治疗选择，提供预期 胰岛素独立的窗口为3 - 30年。如果出现缓解，AVM0703的安全性将允许 Reptititive剂量最多为8次，该反传递难治性FDA目前批准了正在进行的临床试验 淋巴恶性肿瘤（NCT04329728）。对于未显示缓解的患者，AVM0703有望加强 其他免疫疗法允许更广泛的T1D患者实现胰岛素独立性，例如 用teplizumab（抗CD3）组合治疗。这个SBIR II期项目已被设计为 随机，安慰剂对照的多中心临床前试验以获取可用的固体数据 AVM0703的毒理学信息和诸如Teplizumab之类的潜在伴侣的毒理学信息将加快IND 批准并为临床试验铺平道路。 AIM 1中的活动将指示进行临床前剂量 - 在三种情况下，在NOD小鼠中发现和机制研究：糖尿病前，新发育和建立 糖尿病。 AIM 1的结果将用于确定要在关键效率中使用的AVM0703剂量 在目标2和3中逆转新发糖尿病和已建立的糖尿病的研究。 在项目结束时提起。