A Once-Weekly Oral Tacrolimus-Prednisone Fixed-Dose Combination Therapy for Post-Transplant Maintenance Immunosuppressive Therapy

实体器官移植是不可逆转的器官衰竭后一种非常成功的干预形式， 在美国，每年大约进行3.5万例移植手术。充分抑制免疫系统 是移植物存活所必需的，每天一到两次用钙调神经磷酸酶抑制剂进行免疫抑制治疗。 他克莫司是预防同种异体移植排斥反应的核心。他克莫司的免疫抑制作用显著 药学挑战，包括高度可变的药代动力学和狭窄的治疗指数，其中 每天给药一次或两次会导致血液浓度达到峰值，从而导致毒性和低谷 这可能会导致移植排斥反应。此外，尽管坚持免疫抑制治疗对移植物至关重要 移植受者的存活率和不粘附率很高，所有固体器官的平均存活率约为23%。 移植类型，其中肾移植的发生率最高(36%)。不遵守是最有问题的 在青春期和成年期，这也是免疫系统最活跃和 器官排斥的生物学风险。 Lyndra已经开发出一种新的口服给药技术，它可以提供更长的治疗药物水平 很少用药。该技术基于一种连续给药的胃滞留剂型 进入胃，然后通过下胃肠道排出体外。Lyndra剂型已经生产出来 在cGMP下，目前正在进行多项临床试验。在大型动物身上的研究表明持续给药 释放和胃滞留一周或更长时间。来自多项研究的人类临床数据显示， 安全概况和持续的药物输送。 这项拟议的研究是Lyndra和纽约大学朗格尼移植研究所的合作项目。我们的目标 正在开发一种每周一次的口服他克莫司-泼尼松固定剂量组合，用于维持性治疗 肾移植受者之前在日常治疗中稳定下来。每周一次的他克莫司-泼尼松 通过(1)通过维持他克莫司的低谷浓度来提供更安全、更有效的治疗，使患者受益 在治疗范围内减少峰谷变化；(2)减少总剂量和副作用；(3) 显著提高对长期维持免疫抑制疗法的依从性。Lyndra有 通过演示他克莫司和强的松胶囊，确立了这一概念的技术可行性， 在模拟胃条件下的稳定性和控释。 这个直接到第二阶段的SBIR方案的目标是开发和制造他克莫司-泼尼松 1期临床试验的剂型，并为开发 产品。拟议的工作包括支持IND的药物开发和GMP制造 临床用品以及最终提交IND的监管和临床规划活动 美国食品和药物管理局进行首例人类临床试验。 Lyndra Inc.保密第1页

Solid organ transplantation is a highly successful form of intervention following irreversible organ failure, with approximately 35,000 transplants performed annually in the US. Adequate suppression of the immune system is required for graft survival, and once- or twice-daily immunosuppressive therapy with the calcineurin inhibitor tacrolimus is central to allograft rejection prevention. Immunosuppression with tacrolimus presents significant pharmaceutical challenges, including highly variable pharmacokinetics and a narrow therapeutic index, where once- or twice-daily administration results in peaks in blood concentration which contribute to toxicity and troughs which can lead to graft rejection. In addition, while adherence to immunosuppressive therapy is critical to graft survival, non-adherence rates among transplant recipients are high, averaging about 23% across all solid organ transplant types, with highest rates (36%) observed for kidney transplants. Non-adherence is most problematic during adolescence and young adulthood, which is also the time of maximal immune system activity and biological risk for organ rejection. Lyndra has developed a novel oral drug delivery technology that provides extended therapeutic drug levels with infrequent dosing. The technology is based on a gastric residence dosage form that delivers drug continuously to the stomach and then exits the body through the lower GI tract. Lyndra dosage forms have been manufactured under cGMP and are currently in multiple clinical trials. Studies in large animals demonstrate continuous drug release and gastric retention for one week or more. Human clinical data from multiple studies show an excellent safety profile and sustained drug delivery. The proposed research is a collaboration between Lyndra and the NYU Langone Transplant Institute. Our goal is to develop a once-weekly oral tacrolimus-prednisone fixed-dose combination for maintenance therapy in kidney transplant recipients previously stabilized on daily therapy. Once-weekly tacrolimus-prednisone may benefit patients by (1) providing a safer, more effective therapy by maintaining trough tacrolimus concentrations within the therapeutic range with reduced peak-trough variation, (2) reducing total dose and side effects, and (3) substantially improving adherence to long-term maintenance immunosuppressive therapy. Lyndra has established technical feasibility of this concept by demonstrating tacrolimus and prednisone encapsulation, stability and controlled release under simulated gastric conditions. The objective of this Direct-to-Phase II SBIR proposal is to develop and manufacture a tacrolimus-prednisone dosage form for a Phase 1 clinical trial and to lay the clinical and regulatory groundwork for development of the product. The proposed work includes IND-enabling pharmaceutical development and GMP manufacturing of clinical supplies along with regulatory and clinical planning activities that culminate in the submission of an IND to the US FDA for a first-in-human clinical trial. Lyndra Inc Confidential Page 1