Long-acting injectable tacrolimus for chronic immunosuppression

项目摘要 这一直接进入II期SBIR的广泛、长期目标是改善器官移植中的免疫抑制结局。 通过开发长效注射钙调磷酸酶抑制剂（CNI）来治疗移植受体。了两个多 几十年来，他克莫司是预防器官移植排斥反应的有价值的药理学工具。是 市售的每日两次和每日一次的口服丸剂。口服制剂经历首过代谢， 这又导致高患者内和患者间药代动力学 (PK)可变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，而超治疗水平（>15 ng/ml）是有毒的。每日剂量已 与药物不依从有关。依从性差的移植受者的医疗费用是 移植后3年，比高依从性患者高约30，000美元。因此，三个报告未得到满足的 需要更高的药物依从性、更好的移植物存活结果和线性PK特征。 Auritec Pharmaceuticals开发了一种他克莫司皮下注射制剂， 单次给药后30天内药物的治疗血药浓度保持一致。该产品基于 Auritec的创新Plexis技术已在两项1期试验中证明了其概念的临床证明。的 Plexis技术与其他长效注射技术的区别在于其高药物浓度， 负载、可扩展的制造工艺和更线性的释放动力学。该产品已被证明安全 和缓释他克莫司在首次人体安全性/PK研究中使用“探索性IND”方法。 PK建模显示，在移植受者中可以容易地实现每月给药方案，以维持 他克莫司血药浓度在安全有效范围内（5-15 ng/ml）。我们产品的优点包括1） 一次给药后1个月内完全药物依从性; 2）移植物排斥反应发生率更低; 3） 更简单的给药方案，和; 4）平稳的PK曲线，没有低于或高于治疗水平。人口 预期受益于该产品的是：已证明对他克莫司耐受但发现 难以坚持每日固定时间表（如年轻患者）和/或快速代谢者 他克莫司。最终的结果将是一个具有成本效益的维持治疗的维持治疗。 本直接进入第II阶段SBIR的具体目标是开展活动，以实现“传统的第1阶段 IND”津贴。拟议的工作包括-按照现行药品生产质量管理规范生产 规范（cGMP）;符合药物非临床研究质量管理规范（GLP）的动物试验;分析方法 开发;化学、制造和控制（CMC）测试;最后，向FDA提交IND。 这些努力将导致IND批准，并允许首次在人体内进行安全性，PK和 对移植受者的初步疗效。这项工作的成功完成将进一步降低产品的风险 使其更接近临床试验，并对投资者具有吸引力。

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.