Development of sustained release/long acting products for TB

2020年，1000万人患上结核病，150万人死于结核病，这是世界上第一个 十多年来结核病死亡人数上升的时间。1，2世界大约四分之一的人口患有潜伏性结核病 感染(LTBI)，有可能重新激活。这些数十亿人充当着无时无刻不存在的 新的结核病病例，与正在进行的传播事件无关3.对于LTBI患者，最大的风险因素是 罹患结核病是艾滋病毒的混合感染。艾滋病毒感染使潜伏的结核病重新激活的风险增加20倍。此外， 结核病是导致艾滋病毒阳性者死亡的主要原因。因此，开发LTBI治疗方法至关重要 与艾滋病毒治疗相适应。4短程、以利福霉素为基础的、3个月或4个月的潜伏结核病感染 治疗方案优先推荐为6个月或9个月的异烟肼单一疗法。5单一药物 使用四个月的利福平或利福平方案进行LTBI治疗，如果持续服用，已被证明是有效的。 8虽然利福布汀尚未在治疗潜伏性结核病的随机试验中进行研究，但它已经降低了 药物-药物相互作用，使其比其他药物更适合于治疗结核分枝杆菌/艾滋病毒混合感染 9-13不遵守药物疗法会产生严重的后果，并可能导致 14、15长效(LA)肠外用药的疗效及耐药性分析 提供持续药物释放数周或数月的制剂有可能减少剂量。 这样的频率使得只注射一次或几次药物制剂就足以治疗LTBI。 这将极大地提高治疗依从性和治疗效果。最近，我们开发了 基于原位成型植入技术的抗结核药物利福平长效制剂的研制 (RFB-ISFI)。RFB-ISFI是可注射的，皮下注射后形成植入物，提供缓释 RFB连续给药16周，对小鼠结核病模型防治急性结核感染具有很好的疗效 (Kim等人，2022年)。由于ISFI聚合物的生物相容性和生物可降解性，植入物不 需要在治疗结束时取出。然而，如果不良事件，如毒性，药物相互作用， 或发生过敏反应时，可以安全地取出植入物。异烟肼制剂的释药特性 可以通过改变液体配方的组成进行操纵，并根据特定需要进行调整 一种特定的治疗方法。这一提议的科学前提是高效的RFB-ISFI配方 我们研制的药物可用于治疗短暂性脑损伤。我们的最终目标是开发一种可注射的配方，即 可以每两个月一次，每两个月一次，或不太频繁，对LTBI治疗有效， 包括接受抗逆转录病毒治疗的患者。为了实现这一目标，我们汇集了一支杰出的、多方面的 纪律调查团队，在包括非人类在内的动物模型方面拥有综合证明的专业知识 灵长类，用于研究结核病和治疗，洛杉矶药物输送系统，药代动力学(PK)分析， 临床病理学和生物统计学将协同工作，以实现以下具体目标。

In 2020, 10 million people developed tuberculosis (TB) and 1.5 million people died from TB, marking the first time TB deaths rose in over a decade.1,2 Approximately one-fourth of the world's population has a latent TB infection (LTBI) with the potential for reactivation. These billions of people serve as an ever-present source of new TB cases, independent of ongoing transmission events 3. For people with LTBI, the greatest risk factor for developing TB is HIV co-infection. HIV-infection increases the risk of latent TB reactivation by 20-fold. Further, TB is the leading cause of death of HIV positive individuals. It is thus critical to develop LTBI treatments that are compatible with HIV treatments.4 Short-course, rifamycin-based, 3- or 4-month latent TB infection treatment regimens are preferentially recommended over 6- or 9-month isoniazid monotherapy.5 A single-drug LTBI therapy with a four-month rifampin or rifabutin regimen has been show efective when taken consistently.6- 8 While rifabutin has not been studied in a randomized trial for latent TB treatment, it has reduced potential for drug-drug interactions, which makes it more suitable for treatment of Mtb/HIV coinfections compared to other rifamycins.9-13 Non-adherence to drug regimens has grave consequences and can lead to loss of therapeutic effectiveness and the development of drug resistance.14,15 Long acting (LA) parenteral drug formulations that provide sustained drug release over weeks or months have the potential to reduce dosing frequency such that only one or a few injections of the drug formulation could be sufficient for LTBI treatment. This would dramatically increase treatment compliance and efficacy of treatment16-18. Recently, we developed long-acting formulation of the anti-TB drug rifabutin (RFB) based on In Situ Forming Implant (ISFI) technology (RFB-ISFI). RFB-ISFI is injectable, forms an implant after subcutaneous injection, provides sustained release of RFB for 16 weeks, and is highly effective in mouse models of TB prevention and treatment of acute TB infection (Kim et al 2022). Due to the biocompatible and biodegradable nature of the ISFI polymer, the implant does not need to be removed at the end of treatment. However, if adverse events such as toxicity, drug-drug interactions, or an allergic response occurs, the implant can be safely removed. Drug release properties of ISFI formulations can be manipulated by changes in composition of the liquid formulation and adjusted to meet the specific needs of a given treatment. The scientific premise of this proposal is that the highly effective RFB-ISFI formulation we developed can be used for treatment of LTBI. Our ultimate goal is to develop an injectable formulation, that can be administered once every two months bi-monthly or less frequently and be effective for LTBI treatment, including patients on antiretroviral therapy. To accomplish this goal, we have assembled an outstanding, multi- disciplinary team of investigators with combined demonstrated expertise in animal models, including non-human primates, for studying TB disease and treatment, LA drug delivery systems, pharmacokinetics (PK) analysis, clinical pathology, and biostatistics that will work collaboratively to accomplish the following specific aims.