Oral Dissolvable Strips (ODS) as new pediatric and adult delivery mode of therapy for latent tuberculosis

项目摘要 结核病仍然是全世界传染病死亡的主要原因之一。2021年， 据估计，全球有640万人新诊断患有结核病，约1060万人因此患病，140万人死于结核病。 百万人死于这种疾病。在死于这种疾病的人中，54%是男性，32%是女性，14%是女性。 15岁以下儿童。结核病也是艾滋病毒感染者死亡的主要原因，有187，000人死亡 2021年艾滋病毒阳性者中因结核病死亡的人数（世卫组织，2022）。艾滋病毒感染者平均年龄为19岁， 患活动性结核病的可能性是未感染艾滋病毒的人的两倍，约三分之一的艾滋病毒死亡 都是因为肺结核此外，最近结核病病例增加，原因是资源被转用于 COVID 19.伦敦卫生和热带医学学院的研究人员开发了一种模型， 预计在中国、印度和南非， 在2020年到2024年之间。虽然结核病是一种可治疗和可治愈的疾病， 毒品仍然具有挑战性。该方案持续时间非常长（至少6个月）， 吞咽困难的现象-特别是在儿科和老年患者中-是缺乏的根本原因之一 患者的依从性。因此，疾病进一步蔓延，问题更加严重， 耐药性在全球范围内，估计有484，000人患上了耐利福平或耐多药结核病 (RR/MDR-TB）。治疗耐药性最强的结核病的费用约为513，000美元， 高于治疗非耐药结核病的平均费用18，000美元。 Oak Therapeutics正在开发一种技术，可以通过口服分散来提供挽救生命的结核病药物。 条带（ODS）。ODS方法解决了与目前片剂递送相关的许多问题， 胶囊或液体，特别是婴儿和小孩使用时。在这项提案中，Oak Therapeutics 专利技术将用于生产两种不同的固定剂量（1种儿童和1种成人）的异烟肼- 利福喷丁（INH-RPT）多药ODS，目的是简化治疗给药，改善 患者/护理人员隐私，并最终成功治疗潜伏性结核病。在目标1橡树治疗计划， 开发利福喷丁RPT-ODS。尽管是有效的，但RPT在长期存在的情况下并不稳定。 暴露于湿气、热或直射光。因此，RPT和INH将被封装，以最大限度地减少 这些环境条件对RPT-ODS稳定性的影响以及使其可口。在目标2中， 使用实验设计策略，Oak Therapeutics将确定多药治疗的适当条件。 制剂和所得INH-RPT ODS将在体内试验中对照生物等效片剂制剂进行检测。 在目标3中进行药代动力学研究。第一阶段的成功完成将为 a第二阶段将侧重于ODS的包装设计、提供者和护理人员培训战略， 儿科依从性的指导材料和措施。然后，提交分组（505（B）（2））将被 准备供WHO和US FDA审查和批准。

PROJECT SUMMARY Tuberculosis (TB) remains one of the major sources of mortality from infectious diseases worldwide. In 2021 an estimated 6.4 million were newly diagnosed with TB globally, approximately 10.6 million fell ill from it, and 1.4 million died from the disease. Of those who died from the disease, 54% were men, 32% women, and 14% were children aged <15 years. TB is also a leading cause of death for people infected with HIV, with 187,000 deaths due to tuberculosis among HIV-positive people in 2021 (WHO, 2022). People living with HIV are on average 19 times more likely to develop active TB disease than people without HIV, and approximately 1 in 3 HIV deaths are due to TB. Furthermore, there is a recent increase in TB cases attributable to resources being diverted for COVID 19. One model, developed by researchers at the London School of Hygiene and Tropical Medicine, projects that there will be around 200,000 additional deaths from TB across China, India, and South Africa between 2020 and 2024. While TB is a treatable and curable disease, the treatment of patients with antimicrobial drugs remains challenging. The extraordinarily long duration of the regimen (min. 6 months), combined with the phenomenon of dysphagia – especially in pediatric and geriatric patients – is one of the root causes for the lack of patient adherence. As a result, there is further spreading of the disease and an even more serious problem, drug resistance. Globally, an estimated 484,000 people developed rifampin resistant or multidrug-resistant TB (RR/MDR-TB) in 2018. Costs for treating the most drug resistant form of TB are around $513,000, significantly higher than the average cost of $18,000 for treating nonresistant TB. Oak Therapeutics is developing a technology that allows life-saving TB drugs to be delivered via Oral Dispersing Strips (ODS). The ODS approach solves many of the problems associated with current delivery by tablets, capsules, or liquids, especially when used by infants and small children. In this proposal, Oak Therapeutics’ proprietary technology will be used to create two distinct fixed doses (1 pediatric and 1 adult) of Isoniazid- Rifapentine (INH-RPT) multi-drug ODS, with the goal of simplifying therapy administration, improving patient/caregiver privacy and ultimately successfully treating latent TB. In Aim 1 Oak Therapeutics plans to develop Rifapentine RPT-ODS. Despite being efficacious, RPT is not stable in the presence of long-term exposure to moisture, heat or direct light. As such, RPT and INH will be encapsulated to minimize the negative effects of these environmental conditions on the stability of RPT-ODS as well as to make it palatable. In Aim 2, using experimental design strategy, Oak Therapeutics will determine appropriate conditions for multidrug formulation and the resulting INH-RPT ODS will be tested against bioequivalent tablets formulation in an in vivo pharmacokinetic study to be performed in Aim 3. The successful completion of Phase I will lay the foundation of a Phase II that will focus on the packaging design for the ODS, strategy for provider and caregiver training and instructional materials and measures for pediatric adherence. Then, a submission packet (505 (b)(2)) will be prepared for WHO and US FDA review and approval.