Targeted Long-Acting Combination Antiretroviral Therapy (TLC-ART) The purpose of the University of Washington targeted long acting combination antiretroviral therapy program (UWTLC-ART) is to develop one or more safe, stable, scalable and tolerable long acting antiretroviral combinations for treatment of HIV infection in collaboration with NIH program staff. Leveraging the multidisciplinary, translational expertise and research infrastructure available at the University of Washington, this strategic drug development program integrates experts in statistics and mathematics, HIV adult and pediatric clinical trials, behavioral science, regulatory affairs, scientific and executive leadersip and business management, pharmaceutical sciences including drug targeting, delivery, metabolism and pharmacokinetics, retro virology, HIV primate models, preclinical pharmacology and toxicology, and mucosal immunology. The program has established collaborative relationships with major pharmaceutical industry and other stakeholders who can provide resources essential for the strategic development plan as well as potential future partnerships for product development. The program will also be guided by an external scientific advisory board (SAB) as well as an internal advisory group. We plan to develop three unique antiretroviral drug combination compositions/formulations, following a carefully monitored timeline. The drug combination choices are based on current antiretroviral combinations with demonstrated safety and efficacy. These drugs have known relationships between drug levels and therapeutic effect. The UWTLC-ART program utilizes a demonstrated capability to produce drug combination particles that achieve therapeutic plasma drug concentrations lasting more than seven days in a primate model. After subcutaneous injection, these compositions/formulations distribute widely throughout the lymphatic system. The program's strategic development decisions will be based on the target product profile, and will progress in accord with drug development timeline milestones. These decisions will guide prioritization of program resources to facilitate achieving the program goal. The program proposes developing three drug combinations, and will use progress on milestones, external information and the SAB to prioritize TLC-ART candidates advancing to the IND enabling studies and Phase 1 clinical trial. The program has 13 sections that are designed to interact in an integrated and collaborative way to achieve the program goal. To support the drug development, the program proposes three hypothesis-driven projects that will enhance our understanding of the distribution characteristics and safety using both pharmacokinetic/ pharmacodynamics modeling and in vivo studies. While the proposed Phase 1 clinical trial will study healthy adults, the compositions and drug development plan incorporate pediatric considerations with an eye toward future pediatric use. Although ambitious, the proposed program integrates experience and expertise, including those committed by major pharmaceutical companies to assure substantial progress in developing one or more targeted long acting antiretroviral treatments.

Public Health Relevance

Poor medication adherence and insufficient drug levels are the key to understanding HIV/AIDS disease progression. The Targeted Long-Acting Combination Antiretroviral Therapy (TLC-ART) program integrates translational medicine projects that seek to leverage advanced knowledge and a world-class interdisciplinary team of academic, NIH and industry researchers, and complementary experts to deliver three new, safe, stable, scalable, and well-tolerated antiretroviral combination treatments for HIV infection. The innovative therapeutic program draws on 13 related topics from the behavioral, technical, medical and pharmaceutical sciences to produce drug combination dosages that improve patient adherence and maximize therapeutic benefits.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project with Complex Structure Cooperative Agreement (UM1)
Project #
1UM1AI120176-01
Application #
8970537
Study Section
Special Emphasis Panel (ZAI1-JBS-A (M1))
Program Officer
Turk, Steven R
Project Start
2015-07-15
Project End
2020-06-30
Budget Start
2015-07-15
Budget End
2016-06-30
Support Year
1
Fiscal Year
2015
Total Cost
$3,528,112
Indirect Cost
$1,191,707
Name
University of Washington
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Shao, Jingwei; Kraft, John C; Li, Bowen et al. (2016) Nanodrug formulations to enhance HIV drug exposure in lymphoid tissues and cells: clinical significance and potential impact on treatment and eradication of HIV/AIDS. Nanomedicine (Lond) 11:545-64
Cherry, Allison E; Haas, Brian R; Naydenov, Alipi V et al. (2016) ST-11: A New Brain-Penetrant Microtubule-Destabilizing Agent with Therapeutic Potential for Glioblastoma Multiforme. Mol Cancer Ther 15:2018-29
Freeling, Jennifer P; Ho, Rodney J Y (2015) Antiretroviral nanoparticles: the future is now: authors' response to editorial comments. AIDS 29:863-4
Freeling, Jennifer P; Koehn, Josefin; Shu, Cuiling et al. (2015) Anti-HIV drug-combination nanoparticles enhance plasma drug exposure duration as well as triple-drug combination levels in cells within lymph nodes and blood in primates. AIDS Res Hum Retroviruses 31:107-14
Ho, Rodney J Y; Yu, Jesse; Li, Bowen et al. (2015) Systems Approach to targeted and long-acting HIV/AIDS therapy. Drug Deliv Transl Res 5:531-9
Koehn, Josefin; Ding, Yue; Freeling, Jennifer et al. (2015) A simple, efficient, and sensitive method for simultaneous detection of anti-HIV drugs atazanavir, ritonavir, and tenofovir by use of liquid chromatography-tandem mass spectrometry. Antimicrob Agents Chemother 59:6682-8
Volkin, David B; Hershenson, Susan; Ho, Rodney J Y et al. (2015) Two decades of publishing excellence in pharmaceutical biotechnology. J Pharm Sci 104:290-300
Zhang, Yitong J; Zhan, Xi; Wang, Liguo et al. (2015) pH-responsive artemisinin dimer in lipid nanoparticles are effective against human breast cancer in a xenograft model. J Pharm Sci 104:1815-24
Cross, Donna J; Garwin, Gregory G; Cline, Marcella M et al. (2015) Paclitaxel improves outcome from traumatic brain injury. Brain Res 1618:299-308
Partridge, S C; Kurland, B F; Liu, C-L et al. (2015) Tumor-induced lymph node alterations detected by MRI lymphography using gadolinium nanoparticles. Sci Rep 5:15641

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