Long-acting injectable tacrolimus for chronic immunosuppression

项目总结 这种直接到第二阶段SBIR的广泛的、长期的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。两个以上的人 几十年来，他克莫司在预防器官移植排斥反应中是一种有价值的药理工具。它是 市面上有两种和一种每日一次的口服药片。口服制剂经历首过代谢和 生物利用度低且可变，进而导致患者内和患者间的高药代动力学 (Pk)可变性。他克莫司的治疗指数很窄，因此血液水平低于治疗水平(&lt；5 ng/ml) 结果是器官排斥，而超治疗水平(&gt；15 ng/ml)是有毒的。每天服用的剂量一直是 与用药不依从有关。依从性差的移植受者的医疗费用是 移植后3年，比依从性高的患者高出30,000美元。因此，报告的三个未满足 需要更高的药物依从性、更好的移植物存活率和线性PK曲线。 Auritec制药公司开发了一种皮下注射的他克莫司配方，可提供 在单次给药后30天内维持治疗血药浓度。该产品基于 关于Auritec的创新Plexis技术，该技术已在两个第一阶段试验中显示出临床概念。这个 Plexis技术与其他长效注射技术的区别在于它的药物含量高 加载、可扩展的制造工艺和更线性的释放动力学。该产品已证明是安全的。 他克莫司在一项首次人体安全性/PK研究中的持续释放，采用“探索性IND”方法。 PK建模表明，每月给药计划可以很容易地在移植受者身上维持 他克莫司血药浓度在安全有效范围内(5-15 ng/ml)。我们产品的好处包括1) 一次服药后完全坚持服药1个月；2)减少移植物排斥反应；3) 更简单的给药计划，以及；4)平稳的PK曲线，没有亚治疗或超治疗水平。人口数量 预计将从该产品中受益的是：对他克莫司有耐受性但发现它的患者 具有挑战性地坚持每天固定的时间表(如年轻患者)和/或快速代谢物 他克莫司。最终结果将是一种成本效益高的维持疗法。 这一直接到第二阶段SBIR的具体目标是执行活动以追求传统的第一阶段 IND“津贴。建议的工作包括-根据当前的良好制造进行制造 操作规范(CGMP)；符合良好实验室操作规范(GLP)的动物试验；分析方法 开发；化学、制造和控制(CMC)测试；最后，IND提交给FDA。 这些努力将导致IND批准，并允许首次人类安全测试，PK和 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 通过使其更接近临床测试，并使其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.