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.
Public Health Relevance Statement: PROJECT NARRATIVE Globally, an estimated of 2 billion people including 45 million children (0 through 9 years) and 217 million adolescents and young adults (AYA; 10 through 24 years) carry latent TB. Current formulations for treatment of pediatric TB, adolescents and adults with comorbidities (e.g. HIV, dysphagia) pose significant caregiver and patient-related barriers to treatment adherence, especially in low income settings. With this application, Oak Therapeutics aims to develop oral dispersing strips (ODS) containing the WHO recommended fixed dose of Isoniazid-Rifapentine TB therapy, designed specifically for improving treatment adherence throughout the affected population.
Project Terms: Water; Hydrogen Oxide; Woman; rifapentine; Measures; Privacy; Care Givers; Caregivers; falls; Film; improved; Clinical; Encapsulated; Phase; Medical; Adolescent Youth; juvenile; juvenile human; Adolescent; MDR Tuberculosis; MDR-TB; Multi-Drug Resistant Tuberculosis; MultiDrug Resistance Tuberculosis; multidrug-resistant TB; Multidrug-Resistant Tuberculosis; Buccal Cavity; Buccal Cavity Head and Neck; Cavitas Oris; Mouth; Oral cavity; pediatric; Childhood; Therapeutic; fluid; liquid; Liquid substance; Exposure to; Life; antimicrobial drug; anti-microbial agent; anti-microbial drug; antimicrobial agent; Oral; Source; Test Result; Drug Formulations; innovative technologies; physical property; novel; prevention service; Modeling; Sampling; Property; social stigma; stigma; Provider; Pharmaceutical Agent; Pharmaceuticals; Pharmacological Substance; pharmaceutical; Pharmacologic Substance; Patient Compliance; patient adherence; patient cooperation; therapy compliance; therapy cooperation; treatment compliance; compliance behavior; Low income; Address; Dose; global health; Adherence; Doctor of Philosophy; Ph.D.; PhD; caregiver education; Caregiver instruction; care giver education; care giver instruction; care giver training; caregiver training; in vivo; Newly Diagnosed; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Preparation; preparations; socioeconomics; socio-economic; socio-economically; socioeconomically; Development; developmental; Extreme drug resistant tuberculosis; Extremely drug resistant tuberculosis; XDR-TB; XDR-Tuberculosis; extensively drug resistant TB; extensively drug resistant tuberculosis; cost; designing; design; Drug Resistance Tuberculosis; Drug Resistant TB; Drug Resistant Tuberculosis; TB drug resistance; drug resistance in TB; drug resistant in tuberculosis; Drug resistance in tuberculosis; nano particle; nano-sized particle; nanosized particle; nanoparticle; Rifampicin resistant; Rifampin resistance; Rifampin resistant; resistance to rifampicin; resistance to rifampin; resistant to rifampicin; resistant to rifampin; Rifampicin resistance; human study; Population; aged; comparative; Antitubercular Drugs; TB drugs; anti-TB drugs; anti-tuberculosis drugs; antituberculosis drugs; tuberculosis drugs; TB therapy; TB treatment; tuberculosis therapy; tuberculosis treatment; standard treatment; standard care; treatment adherence; tablet formulation; Regimen; Adolescent and Young Adult; child patients; pediatric patients; class material; course material; curricular material; instructional materials; learning materials; Formulation; Preventative treatment; Preventive treatment; treatment services; barrier to health care; barrier to healthcare; barrier to treatment; obstacle to care; obstacle to healthcare; barrier to care; lead candidate; in vivo testing; in vivo evaluation; COVID19; CV-19; CV19; corona virus disease 2019; coronavirus disease 2019; coronavirus disease-19; coronavirus infectious disease-19; COVID-19; Resource-limited setting; Low-resource area; Low-resource community; Low-resource environment; Low-resource region; Low-resource setting; Resource-constrained area; Resource-constrained community; Resource-constrained environment; Resource-constrained region; Resource-constrained setting; Resource-limited area; Resource-limited community; Resource-limited environment; Resource-limited region; Resource-poor area; Resource-poor community; Resource-poor environment; Resource-poor region; Resource-poor setting; 21+ years old; Adult Human; adulthood; Adult; Affect; Africa; advanced age; elders; geriatric; late life; later life; older adult; older person; senior citizen; Elderly; Antibiotic Agents; Antibiotic Drugs; Miscellaneous Antibiotic; Antibiotics; Biotechnology; Biotech; capsule; Capsules; Cause of Death; Pharmaceutical Chemistry; Medicinal Chemistry; Pharmaceutic Chemistry; Child; 0-11 years old; Child Youth; Children (0-21); kids; youngster; China; Mainland China; Choking; Communicable Diseases; Infectious Disease Pathway; Infectious Diseases; Infectious Disorder; comorbidity; co-morbid; co-morbidity; Cessation of life; Death; Deglutition Disorders; Dysphagia; Swallowing Disorders; Disease; Disorder; Drug resistance; drug resistant; resistance to Drug; resistant to Drug; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Experimental Designs; Foundations; Future; Goals; Health; HIV; AIDS Virus; Acquired Immune Deficiency Syndrome Virus; Acquired Immunodeficiency Syndrome Virus; Human Immunodeficiency Viruses; LAV-HTLV-III; Lymphadenopathy-Associated Virus; Virus-HIV; HIV Seropositivity; Anti-HIV Positivity; HIV Positive; HIV Positivity; HIV Seroconversion; HIV antibody positive; HTLV-III Seroconversion; HTLV-III Seropositivity; Human; Modern Man; Hygiene; In Vitro; India; Infant; isoniazid; Isonicotinic Acid Hydrazide; Light; Photoradiation; London; Masks; men; mortality; Persons; United States National Institutes of Health; NIH; National Institutes of Health; nervous system disorder; Nervous System Diseases; Neurologic Disorders; Neurological Disorders; neurological disease; Legal patent; Patents; Patients; Drug Kinetics; Pharmacokinetics; Polymers; polymer; polymeric; Rattus; Common Rat Strains; Rat; Rats Mammals; Recommendation; Reference Standards; Refrigeration; Research Personnel; Investigators; Researchers; Resources; Research Resources; Rifampin; Benemycin; Rifadin; Rifampicin; Rimactane; Schools; South Africa; Tablets; Taste Perception; Gustation; Taste; gustatory perception; gustatory processing; gustatory response; taste processing; taste response; Technology; Testing; Therapeutic Equivalency; Bioequivalence; Clinical Equivalency; Generic Equivalency; drug bioequivalence; drug bioequivalent; Treatment Protocols; Treatment Regimen; Treatment Schedule; Tropical Medicine; Tuberculosis; M tuberculosis infection; M. tb infection; M. tuberculosis infection; M.tb infection; M.tuberculosis infection; MTB infection; Mycobacterium tuberculosis (MTB) infection; Mycobacterium tuberculosis infection; TB infection; disseminated TB; disseminated tuberculosis; infection due to Mycobacterium tuberculosis; tuberculosis infection; tuberculous spondyloarthropathy
