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

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

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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.

项目摘要直接直接进入第二阶段SBIR的广泛的长期目标是改善器官的免疫抑制结果通过开发长效注射钙调神经蛋白抑制剂（CNI）的移植受者。超过两个十年来，他克莫司是预防器官移植排斥反应的宝贵药物工具。这是商业上可作为两次和每天一次的口服药丸。口服公式经历了第一频道的代谢和患有低和可变的生物利用度，进而导致患者间和患者间药代动力学（PK）可变性。他克莫司有一个狭窄的治疗指数，因此是亚治疗水平（<5 ng/ml）有器官排斥的结果，而上治疗水平（> 15 ng/ml）有毒。每天给与药物不遵守有关。依从性较差的医疗费用移植接受者是移植后3年的患者高约30,000美元。那三个报告未得到满足需求是较高的药物依从性，更好的移植物存活率和线性PK剖面。 Auritec Pharmaceuticals已开发出一种可乐的皮下注射式，可提供单个给药后30天的药物的治疗血液水平一致。该产品是基于的关于Auritec的创新丛集技术，该技术在两阶段试验中显示了临床概念证明。这从高级药物方面负载，可扩展的制造过程以及更多线性释放动力学。该产品证明了安全并使用“探索性IND”方法在人类的第一个安全/PK研究中持续释放他克莫司。 PK建模表明，可以在移植者中很容易实现每月的给药时间表以维护他克莫司血液水平在安全有效范围内（5-15 ng/ml）。我们产品的好处包括1）一个政府后1个月的完全依从性； 2）移植拒绝的发作较少； 3）更简单的给药时间表； 4）平滑的PK轮廓，没有子或超及治疗水平。人口预计会从产品中受益的是：表现出对克莫司的耐受性但发现的患者具有挑战性地遵守每日固定时间表（例如年轻患者）和/或快速代谢物克莫司。最终结果将是一种具有成本效益的维护治疗，用于维护治疗。直接对第二阶段SBIR的具体目的是为了追求“传统阶段1 Ind”津贴。拟议的工作包括 - 根据当前良好的制造业制造实践（CGMP）；符合良好实验室实践（GLP）的动物测试；分析方法发展;化学，制造和控制（CMC）测试；最后，IND提交给FDA。这些努力将获得IND的批准，并允许对安全，PK和移植受者的初步效率。成功完成这项工作将进一步降低产品的风险通过使其更接近临床测试并使其对投资者有吸引力。