Long-acting injectable tacrolimus for chronic immunosuppression

长效注射用他克莫司治疗慢性免疫抑制

基本信息

批准号：
10662560
负责人：
Sarjan Shah
金额：
$ 102.36万
依托单位：
AURITEC PHARMACEUTICALS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-08 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10662560
关键词：
Acquired Immunodeficiency Syndrome Address Adherence Adolescent Animal Model Animal Testing Animals Antiviral Agents Area Biological Assay Biological Availability Biometry Blood Blood drug level result Calcineurin inhibitor Chemistry Chronic Clinical Clinical Research Clinical Trials Cytomegalovirus Retinitis Data Development Devices Documentation Dose Drug Delivery Systems Drug Kinetics Drug Monitoring Effectiveness Ensure Environment Exhibits FDA approved Formulation Goals Good Manufacturing Process Graft Rejection Graft Survival Immunosuppression Infrastructure Injectable Intellectual Property Kinetics Laws Legal patent Leukocyte Adherence Inhibition Test Maintenance Therapy Manufactured Materials Medical Care Costs Metabolism Oral Oral Administration Organ Outcome Patients Performance Pharmaceutical Preparations Pharmacologic Substance Phase Polymer Chemistry Population Preparation Procedures Prophylactic treatment Regulatory Affairs Reporting Research Research Personnel Risk Safety Schedule Shapes Sheep Small Business Innovation Research Grant Tacrolimus Technology Testing Therapeutic Therapeutic Index Toxic effect Toxicology Transplant Recipients Transplant Surgeon Transplantation Treatment Efficacy Treatment-related toxicity Universities Validation Virginia Work analytical method care outcomes compliance behavior cost effective drug development experience first-in-human good laboratory practice improved innovation interpatient variability manufacture manufacturing process manufacturing scale-up medication compliance medication nonadherence meetings method development organ transplant recipient organ transplant rejection patient variability pharmacokinetic model pharmacologic phase I trial pill post-transplant pre-Investigational New Drug meeting pre-clinical preclinical development product development research clinical testing safety and feasibility safety testing subcutaneous tool

项目摘要

PROJECT SUMMARY The broad, long-term goal of this Direct to Phase II SBIR is to improve immunosuppression outcomes in organ transplant recipients by developing a long-acting injectable calcineurin inhibitor (CNI). For more than two decades, tacrolimus is a valuable pharmacological tool in the prophylaxis of organ transplant rejection. It is commercially available as twice and once-daily oral pills. Oral formulations undergo first-pass metabolism and suffer from low and variable bioavailability which in turn leads to high intra- and inter- patient pharmacokinetic (PK) variability. Tacrolimus has a narrow therapeutic index, hence sub-therapeutic blood levels (<5 ng/ml) results in organ rejection whereas supra-therapeutic levels (>15 ng/ml) are toxic. Daily dosing has been associated with medication non-adherence. The medical costs transplant recipients with poor adherence are ~$30,000 higher than patients with high adherence at 3 years post-transplant. Thus, the three reported unmet needs are higher medication adherence, better outcomes of graft survival, and linear PK profile. Auritec Pharmaceuticals has developed a subcutaneous injectable formulation of tacrolimus that provides consistent therapeutic blood levels of the drug for 30 days after a single administration. The product is based on Auritec’s innovative Plexis technology that has shown clinical proof of concept in two Phase 1 trials. The Plexis technology is differentiated from other long-acting injectable technologies in terms of its high drug loading, scalable manufacturing process, and more linear release kinetics. The product has demonstrated safe and sustained release of tacrolimus in a first-in-human safety/PK study using the “exploratory IND” approach. PK modeling shows that a monthly dosing schedule can be readily achieved in transplant recipients to maintain tacrolimus blood levels in the safe and efficacious range (5-15 ng/ml). The benefits of our product include 1) complete medication adherence for 1 month after one administration; 2) fewer episodes of graft rejections; 3) simpler dosing schedule, and; 4) a smooth PK profile without sub- or supra-therapeutic levels. The populations anticipated to benefit from the product are: Patients who have demonstrated tolerability to tacrolimus but find it challenging to adhere to a daily fixed schedule (such as younger patients) and/or rapid metabolizers of tacrolimus. The end result will be a cost-effective maintenance therapy for maintenance therapy. The specific aims of this Direct to Phase II SBIR are to perform activities in pursuit of a “traditional Phase 1 IND” allowance. The proposed work includes - manufacturing in accordance with current Good Manufacturing Practices (cGMP); animal testing in compliance with Good Laboratory Practices (GLP); analytical method development; Chemistry, Manufacturing and Controls (CMC) testing; and finally, IND submission to the FDA. These efforts will result in an IND approval and allow for the first-in-human testing of safety, PK, and preliminary efficacy in transplant recipients. Successful completion of this work will further de-risk the product by bringing it closer to clinical testing and making it attractive to investors.

项目概要该直接进入 II 期 SBIR 的广泛、长期目标是改善器官的免疫抑制结果通过开发一种长效可注射钙调神经磷酸酶抑制剂（CNI）来治疗移植受者的两种以上。几十年来，他克莫司一直是预防器官移植排斥反应的重要药理学工具。商业上可买到的每日两次和一次口服药丸口服制剂经历首过代谢和生物利用度低且变化多端，进而导致患者体内和患者间的药代动力学较高 (PK) 变异性。他克莫司的治疗指数较窄，因此血药浓度低于治疗水平 (<5 ng/ml)。导致器官排斥，而每日剂量（>15 ng/ml）是有毒的。与药物不依从性相关的移植受者的医疗费用是依从性差的。移植后 3 年，比高依从性患者高出约 30,000 美元，因此，三人报告未达到要求。需求是更高的药物依从性、更好的移植物存活结果和线性 PK 曲线。 Auritec Pharmaceuticals 开发了一种他克莫司皮下注射制剂，可提供单次给药后 30 天内药物的治疗血液浓度保持一致。 Auritec 的创新 Plexis 技术已在两项 1 期试验中显示出临床概念证明。 Plexis技术与其他长效注射技术的区别在于其高药物浓度该产品已被证明是安全的。以及在首次人体安全/药代动力学研究中使用“探索性 IND”方法持续释放他克莫司。 PK 模型表明，移植受者可以轻松实现每月给药方案，以维持他克莫司的血液浓度处于安全有效的范围内（5-15 ng/ml），我们产品的优点包括 1)。一次给药后完全坚持用药 1 个月；2) 移植物排斥反应较少；3) 更简单的给药方案，以及；4) 平滑的 PK 曲线，没有低于或高于治疗水平。预计将从该产品中受益的是：已表现出对他克莫司耐受但发现它的患者难以遵守每日固定时间表（例如年轻患者）和/或快速代谢者最终结果将是一种具有成本效益的维持治疗。直接进入第二阶段 SBIR 的具体目标是开展活动以实现“传统的第一阶段拟议的工作包括 - 根据现行良好制造标准进行制造。规范（cGMP）；符合良好实验室规范（GLP）的动物测试；开发；化学、制造和控制（CMC）测试；最后，向 FDA 提交 IND。这些将导致 IND 批准工作，并允许首次进行人体安全性、PK 和这项工作的成功完成将进一步降低该产品的风险。使其更接近临床测试并使其对投资者有吸引力。