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

口服可溶纸条（ODS）作为潜伏性结核病治疗的新儿科和成人给药方式

• 批准号: 10760389
• 负责人: EDWARD G MALISKI
• 金额: $ 27.35万
• 依托单位: OAK THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10760389
• 关键词: Address; Adherence; Adolescent; Adolescent and Young Adult; Adult; Affect; Africa; Antibiotics; Biotechnology; COVID-19; Caregivers; Cause of Death; Cessation of life; Child; Childhood; China; Choking; Clinical; Communicable Diseases; Deglutition Disorders; Development; Disease; Doctor of Philosophy; Dose; Drug Formulations; Drug Kinetics; Drug resistance; Drug resistance in tuberculosis; Elderly; Encapsulated; Experimental Designs; Exposure to; Extreme drug resistant tuberculosis; Film; Formulation; Foundations; Future; Goals; HIV; HIV Seropositivity; Health; Human; Hygiene; In Vitro; India; Infant; Legal patent; Life; Light; Liquid substance; London; Low income; Masks; Measures; Medical; Modeling; Multidrug-Resistant Tuberculosis; Newly Diagnosed; Oral; Oral cavity; Patients; Persons; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Polymers; Population; Preparation; Preventive treatment; Privacy; Property; Provider; Rattus; Recommendation; Reference Standards; Refrigeration; Regimen; Research Personnel; Resource-limited setting; Resources; Rifampicin resistance; Rifampin; Sampling; Schools; Small Business Innovation Research Grant; Source; South Africa; Tablets; Taste Perception; Technology; Test Result; Testing; Therapeutic; Therapeutic Equivalency; Treatment Protocols; Tropical Medicine; Tuberculosis; United States National Institutes of Health; Water; Woman; aged; antimicrobial drug; barrier to care; capsule; caregiver education; comorbidity; comparative; compliance behavior; cost; design; falls; global health; human study; improved; in vivo; in vivo evaluation; innovative technologies; isoniazid; lead candidate; learning materials; men; mortality; nanoparticle; nervous system disorder; novel; pediatric patients; physical property; prevention service; rifapentine; social stigma; socioeconomics; standard care; tablet formulation; treatment adherence; treatment services; tuberculosis drugs; tuberculosis treatment

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.

项目摘要 结核病（TB）仍然是全球传染病的主要死亡率之一。在2021年 估计有640万人被新诊断为全球结核病，大约有1060万人病了，1.4 百万因该病死亡。在死于这种疾病的患者中，有54％是男性，女性32％，14％为 年龄<15岁的儿童。结核病也是感染艾滋病毒的人的主要死亡原因，死亡187,000人 由于艾滋病毒阳性患者在2021年（WHO，2022年）。艾滋病毒感染者平均19 与没有艾滋病毒的患者相比，发展活性结核病的可能性高，大约有1个艾滋病毒死亡人数 是由于结核病。此外，最近归因于资源转移的结核病案例有所增加 Covid 19。 在中国，印度和南非，结核病将大约有200,000名死亡的项目 在2020年至2024年之间。虽然结核病是一种可治疗且健康的疾病，但治疗抗菌病患者 毒品仍然受到挑战。该方案的持续时间非常长（最小6个月），加上 吞咽困难的现象，尤其是在儿科和老年患者中 - 是缺乏根本原因之一 耐心的依从性。结果，疾病进一步传播和更严重的问题， 耐药性。在全球范围内，估计有484,000人产生了利福平抗性或多种耐药性结核病 （RR/MDR-TB）在2018年。治疗最耐药的结核病的费用约为513,000美元 高于治疗非抗药性结核病的平均成本18,000美元。 Oak Therapeutics正在开发一项技术，该技术允许通过口服分散来提供挽救生命的结核病药物 条（ODS）。 ODS方法解决了与平板电脑当前交付相关的许多问题， 胶囊或液体，特别是在婴儿和小孩使用时。在此提案中，橡木疗法 专有技术将用于创建异念珠菌的两种不同的固定剂量（1个儿科和1成人） 利福丁（INH-RPT）多药ODS，目的是简化治疗的管理，改善 患者/护理人员隐私，最终成功治疗潜在结核病。在AIM 1橡木治疗学计划 开发利福丁RPT-ods。尽管效率很高，但在长期存在的情况下，RPT不稳定 暴露于水分，热量或直射光。因此，RPT和INH将被封装以最大程度地减少负面 这些环境条件对RPT-OD的稳定性以及使其可口的影响。在AIM 2中， 使用实验设计策略，Oak Therapeutics将确定多饮用的适当条件 配方和所得INH-RPT OD将对体内的生物等效片剂进行测试 在AIM 3中进行的药代动力学研究。一阶段的成功完成将奠定 第二阶段，将重点介绍ODS的包装设计，提供者和照顾者培训的策略以及 小儿依从性的教学材料和措施。然后，提交包（505（b）（2））将是 为谁和美国FDA审查和批准做好准备。