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

项目总结 结核病(TB)仍然是全世界传染病死亡的主要来源之一。2021年和 据估计，全球有640万人新诊断出结核病，约1060万人因此患病，140万人 有100万人死于这种疾病。在死于这种疾病的人中，54%是男性，32%是女性，14%是 15岁的儿童。结核病也是艾滋病毒感染者的主要死因，有187,000人死亡 由于2021年艾滋病毒阳性者中的结核病(世卫组织，2022年)。艾滋病毒携带者的平均年龄为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病例 是由结核病引起的。此外，最近结核病病例有所增加，原因是资源被转用于 一个模型，由伦敦卫生和热带医学院的研究人员开发， 预计中国、印度和南非将有大约20万人死于结核病 在2020至2024年间。虽然结核病是一种可治疗和治愈的疾病，但抗菌药物对患者的治疗 毒品仍然具有挑战性。超长的养生期(分钟)。6个月)，与 吞咽困难现象--尤其是在儿科和老年患者中--是缺乏的根本原因之一 坚持不懈的精神。结果，疾病进一步蔓延，出现了更严重的问题， 抗药性。在全球，估计有484,000人患上了对利福平耐药或耐多药结核病 (RR/耐多药结核病)在2018年。治疗耐药性最强的结核病的费用约为51.3万美元，这一点值得注意 高于治疗非耐药结核病的平均成本18,000美元。 橡树治疗公司正在开发一种技术，可以通过口服分散剂来提供救命的结核病药物 条带(Ods)。消耗臭氧层物质方法解决了与当前通过片剂递送相关的许多问题， 胶囊，或液体，尤指婴幼儿使用时。在这项提案中，橡树治疗公司的 专利技术将被用来创造两种不同的固定剂量的异烟肼(1名儿童和1名成人)- 利福喷丁(INH-RPT)多药消耗臭氧层物质，目的是简化治疗管理，改善 患者/护理者隐私，并最终成功治疗潜伏性结核病。在AIM 1中，橡树治疗公司计划 开发利福喷丁RPT-ods。尽管有效，但RPT在长期存在的情况下并不稳定 暴露在潮湿、高温或直射光线下。因此，RPT和INH将被封装，以最大限度地减少负面影响 这些环境条件对RPT-ods的稳定性以及使其适口性的影响。在目标2中， 利用试验设计策略，橡树治疗公司将确定适用于多种药物的条件 该制剂和由此得到的异烟肼-RPT-ODS将在体内与生物等效片制剂进行对比测试 将在目标3进行的药代动力学研究。第一阶段的成功完成将为 第二阶段，重点是消耗臭氧层物质的包装设计、提供者和护理者培训战略以及 儿科依从性的教材和措施。然后，提交包(505(B)(2))将被 准备供世卫组织和美国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.