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Principal Investigator: Ann Cornwall Collier
Organization: UNIVERSITY OF WASHINGTON
Fiscal Year: 2020
Award: $771,303
Funding agency: National Institute of Allergy and Infectious Diseases
The Targeted Long-acting Combination Antiretroviral Therapy (TLC-ART) Program has discovered a novel
platform that can stabilize insoluble and soluble antiretroviral drugs together in a nanosuspension which
provides long-acting (LA) plasma and cell concentrations in pre-clinical studies. The lead formulation (called
TLC-ART 101) combines three FDA-approved drugs (active pharmaceutical ingredients, APIs) that are
available generically lopinavir (LPV), ritonavir (RTV) and tenofovir (TFV). While TLC-ART 101 may not be
developed as a commercial product, substantial pre-clinical data exists and the program has received
favorable regulatory pathway guidance from the FDA. TLC-ART 101 is years ahead of other TLC-ART
formulations in development. In this application, we propose a first-in-human, hypothesis-driven, clinical trial to
provide human data about this novel, next generation, LA drug-combination platform technology. The trial will
address multiple questions about the human pharmacokinetics (PK) and safety of this new platform. The
project will be managed by an experienced, multi-disciplinary Study Leadership Team. The clinical trial will
conducted by the staff at the UW AIDS Clinical Trials Unit (a Division of AIDS-approved research site affiliated
with the AIDS Clinical Trials Group), overseen by an independent Data Monitoring Committee, and monitored
by independent monitors. The proposed trial is an open-label, single-arm study with a pharmacologically-
guided dose and duration adaptive design. The trial's hypothesis is that the TLC-ART drug-combination
nanoparticle platform is safe and able to transform the PK of three short-acting generic and physically diverse
antiretroviral drugs to create a LA concentration-time course in human plasma and cells. The primary
objectives of the clinical trial are: 1) To characterize the plasma concentration-time course and PK of a single
dose of the three APIs of TLC-ART 101 (LPV, RTV, and TFV) administered by sub-cutaneous injection, and 2)
To characterize the safety and tolerability of a single subcutaneous injection of TLC-ART 101. The trial also
has 4 exploratory mechanistic objectives that will provide information about the cell-targeting characteristics of
TLC-ART 101 (meaning intracellular blood and lymphoid cells have equal or higher API concentrations than
plasma), as well as exploring whether there are sex differences in the PK parameters of the 3 APIs. Twelve to
16 healthy persons without HIV will be enrolled in dose cohorts of 4, monitored carefully for safety, and
undergo intensive PK sampling (18 timepoints over 35 days) for plasma API concentrations using a sensitive,
validated assay done under GLP. Intracellular API and TFV-diphosphate concentrations from blood
mononuclear cells and lymph node mononuclear cells (in a subset) will be compared to plasma concentrations
to address the cell-targeting characteristics of the platform technology. The 3-year proposal includes major
milestones and a timeline that will be closely monitored to ensure success of this innovative clinical trial. These
human data will form a basis to develop more potent highly active LA antiviral combinations with this platform.
Terms: <AACTG><ACTG><AIDS><AIDS Virus><AIDS clinical trial group><Acquired Immune Deficiency><Acquired Immune Deficiency Syndrome><Acquired Immune Deficiency Syndrome Virus><Acquired Immuno-Deficiency Syndrome><Acquired Immunodeficiency Syndrome><Acquired Immunodeficiency Syndrome Virus><Acquired Immunologic Deficiency Syndrome><Address><Anti-Retroviral Agents><Antiproteases><Antiretroviral Agents><Antiviral Agents><Antiviral Drugs><Antivirals><Assay><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Bioassay><Biologic Assays><Biological Assay><Blood><Blood Cells><Blood Plasma><Blood Plasma Cell><Blood Reticuloendothelial System><Cell Body><Cells><Characteristics><Clinical><Clinical Data><Clinical Research><Clinical Study><Clinical Trials><Clinical Trials Data Monitoring Committees><Clinical Trials Unit><Combination Drug Therapy><Communication><Complex><Data><Data Bases><Data Monitoring Committees><Data and Safety Monitoring Boards><Databases><Development><Differences between sexes><Differs between sexes><Diphosphates><Dose><Drug Combinations><Drug Kinetics><Drugs><Endopeptidase Inhibitors><Enrollment><Ensure><Excipients><FDA approved><Formulation><Funding><Future><HIV><History><Hour><Human><Human Immunodeficiency Viruses><Hydrogen Oxide><IRB><IRBs><Injectable><Institutional Review Boards><Investigational Drugs><Investigational New Drugs><Kaletra><Kinetics><LAV-HTLV-III><Lead><Leadership><Lipids><Liposomal><Liposomes><Lopinavir><Lopinavir/Ritonavir><Lymph Node Reticuloendothelial System><Lymph node proper><Lymphadenopathy-Associated Virus><Lymphatic Tissue><Lymphatic nodes><Lymphoid Cell><Lymphoid Tissue><Medical center><Medication><Modeling><Modern Man><Monitor><Mononuclear><NIH><National Institutes of Health><Nucleotides><Oral><PBMC><Participant><Pb element><Peptidase Inhibitors><Peptide Hydrolase Inhibitors><Peptide Peptidohydrolase Inhibitors><Performance><Peripheral Blood Cell><Peripheral Blood Mononuclear Cell><Persons><Pharmaceutic Preparations><Pharmaceutical Agent><Pharmaceutical Preparations><Pharmaceuticals><Pharmacokinetics><Pharmacologic Substance><Pharmacological Substance><Pharmacology><Physiology><Plasma><Plasma Cells><Plasma Serum><Plasmacytes><Polychemotherapy><Pre-Clinical Model><Preclinical Models><Protease Antagonists><Protease Inhibitor><Proteinase Inhibitors><Pyrophosphates><Recording of previous events><Regulatory Pathway><Research><Reticuloendothelial System, Serum, Plasma><Reverse Transcriptase Inhibitors><Safety><Safety Monitoring Boards><Sampling><Services><Sex Differences><Sexual differences><Site><Subcutaneous Injections><Suspension substance><Suspensions><Technology><Tenofovir><Testing><Time><TimeLine><Translational Research><Translational Science><United States National Institutes of Health><Universities><Viread><Virus-HIV><Washington><Water><Woman><acquired immunodeficiency syndrome clinical trial group><anti-retroviral><anti-retroviral therapy><anti-retroviral treatment><anti-viral agents><anti-viral drugs><anti-virals><antiretroviral><antiretroviral therapy><antiretroviral treatment><arm><base><cohort><combination chemotherapy><combination pharmacotherapy><combined drug therapy><data base><design><designing><developmental><drug/agent><enroll><experience><first in man><first-in-human><heavy metal Pb><heavy metal lead><human data><human study><innovate><innovation><innovative><lipid nanoparticle><lymph gland><lymph nodes><lymphnodes><men><men's><multidisciplinary><nano particle><nano-sized particle><nanoparticle><nanosized particle><next generation><non-human primate><nonhuman primate><novel><open label><open label study><plasmocyte><pre-clinical><pre-clinical study><preclinical><preclinical study><programs><response><sex-dependent differences><sex-related differences><sex-specific differences><statistics><success><translation research>