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

每周一次口服他克莫司-泼尼松固定剂量联合疗法用于移植后维持免疫抑制治疗

• 批准号: 9908525
• 负责人: Stephen ZALE
• 金额: $ 100万
• 依托单位: LYNDRA THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-02 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9908525
• 关键词: Address; Adherence; Adolescence; Adolescent and Young Adult; Adrenal Cortex Hormones; Agreement; Alcohols; Animal Model; Animals; Biological; Blood; Calcineurin inhibitor; Canis familiaris; Chronic; Clinical; Clinical Data; Clinical Investigator; Clinical Protocols; Clinical Trials; Collaborations; Combined Modality Therapy; Consent Forms; Cyclic GMP; Development; Development Plans; Documentation; Dosage Forms; Dose; Drug Delivery Systems; Drug Evaluation; Drug Kinetics; Ethics Committees; Evaluation; Fasting; Formulation; Goals; Government; Graft Rejection; Graft Survival; Human; Immune system; Immunosuppression; Institutes; Intervention; Kidney; Kidney Transplantation; Lead; Life; Lower Gastrointestinal Tract; Maintenance; Maintenance Therapy; Manufactured Supplies; Oral; Oral Administration; Organ; Organ Transplantation; Organ failure; PPP3CA gene; Pamphlets; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phase I Clinical Trials; Phase Ib Trial; Plasma; Prednisone; Preparation; Prevention; Process; Research; Research Design; Risk; Safety; Small Business Innovation Research Grant; Solid; Stomach; Tacrolimus; Technology; Therapeutic; Therapeutic Index; Therapeutic immunosuppression; Time; Toxic effect; Transplant Recipients; Transplantation; Variant; Work; allograft rejection; allotransplant; base; clinical candidate; clinical development; controlled release; design; drug release kinetics; effective therapy; first-in-human; gastric retention; high risk population; improved; improved outcome; meetings; novel; novel strategies; phase I trial; post-transplant; pre-clinical; preclinical development; product development; research clinical testing; residence; side effect; volunteer; young adult

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

实体器官移植是不可逆器官衰竭后非常成功的干预形式， 每年在美国进行大约35，000例移植手术。充分抑制免疫系统 是移植物存活所必需的，并且每天一次或两次使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关键。他克莫司的免疫抑制作用 制药挑战，包括高度可变的药代动力学和狭窄的治疗指数， 每天一次或两次给药导致血药浓度的峰值， 这会导致移植排斥此外，虽然坚持免疫抑制治疗对移植至关重要 移植受者的存活率和非依从性率很高，在所有实体器官中平均约为23 移植类型中，肾移植的比率最高（36%）。不遵守是最成问题的 在青春期和青年期，这也是最大的免疫系统活动的时间， 器官排斥的生物学风险。 Lyndra开发了一种新的口服药物递送技术， 不频繁给药。该技术是基于胃驻留剂型，提供药物不断 然后通过下消化道排出体外。Lyndra剂型已经生产 目前正在进行多项临床试验。在大型动物中的研究表明， 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， 安全性和持续给药。 这项拟议中的研究是Lyndra和纽约大学Langone移植研究所之间的合作。我们的目标 是开发一种每周一次的口服他克莫司-泼尼松固定剂量组合，用于维持治疗， 肾移植受者以前稳定的日常治疗。每周一次他克莫司-泼尼松可能 通过（1）维持他克莫司谷浓度，提供更安全、更有效的治疗， 在治疗范围内，峰谷变化减少，（2）减少总剂量和副作用，和（3） 显著提高对长期维持免疫抑制治疗的依从性。林德拉已经 通过证明他克莫司和泼尼松的包封而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制释放。 本直接进入II期SBIR提案的目的是开发和生产他克莫司-泼尼松 剂型的1期临床试验，并奠定临床和监管基础的发展， 产品拟议的工作包括IND支持的药物开发和GMP制造 临床供应沿着监管和临床规划活动，最终提交IND 进行首次人体临床试验 Lyndra Inc机密第1页