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Principal Investigator: John A Moss
Organization: OAK CREST INSTITUTE OF SCIENCE
Fiscal Year: 2024
Award: $886,859
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY
Pre-exposure prophylaxis (PrEP) using orally or topically delivered antiretroviral (ARV) drugs can prevent HIV
infection in susceptible, uninfected individuals. Adherence to the daily or monthly dosing regimens, however,
has emerged as a critical factor driving the clinical success of HIV PrEP. The poor adherence of some
participant groups in the ASPIRE trial of an intravaginal ring (IVR) delivering the non-nucleoside reverse
transcriptase inhibitor (NNRTI) dapivirine (DPV) indicates that multiple barriers to adherence exist, and
strategies beyond decreased dosing frequency will be required for successful implementation of an effective
non-vaccine, method to prevent HIV infection. “Long-acting” subdermal implant ARV formulations that maintain
protection for periods of 6 months, and preferably 1 year, or more may increase adherence by minimizing a
product's use demands once the initial product uptake decision is made.
We propose a resorbable subdermal implant Sustained/Extended Release Drug Delivery System (SER-DDS)
delivering a novel ARV agent from the maturation inhibitor mechanistic class. The implant will be developed
through a three-tiered formulation development process employing design, fabrication, and in vitro studies
iteratively coupled with in vivo PK, degradation, safety, and efficacy studies in three animal models. The drug is
DFH-1160005, a novel betulin-derived, 2nd generation maturation inhibitor (MI) with single-digit nanomolar
potency against HIV and a robust resistance profile. The program objectives are to develop a safe and
effective SER-DDS for HIV prevention; understand the fundamental pharmacology of sustained, systemic
DFH-1160005 delivery in the context of vaginal and rectal HIV infection, and apply rigorous methodologies to
characterize implant degradation and evaluate safety and efficacy in preclinical in vivo models. In Aim 1, we
will formulate implants, measure drug release in vitro, and conduct PK studies in rats, sheep, and rhesus
macaques. In Aim 2, we will investigate SER-DDS degradation and resorption kinetics and mechanisms in vitro
and in vivo. In Aim 3, we will evaluate lead candidate SER-DDS safety in sheep and explore efficacy and PK-
pharmacodynamic relationships in a non-human primate rectal and vaginal challenge SHIV infection model.
Terms: <AIDS Virus><AIDS prevention><Abscission><Academia><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Address><Adherence><Animal Model><Animal Models and Related Studies><Anti-Retroviral Agents><Area><Automobile Driving><Biodegradation><Biological Markers><Blood Plasma><Clinical><Clinical Trials><Collaborations><Common Rat Strains><Complex><Coupled><Dapivirine><Development><Devices><Digit><Digit structure><Dose><Drug Delivery><Drug Delivery Systems><Drug Kinetics><Drugs><EC 2.7.7.49><Early-Stage Clinical Trials><Evaluation><Excision><Extirpation><Formulation><Frequencies><Fumarates><Generations><Goals><HIV><HIV Infections><HIV Prevention><HIV/AIDS prevention><HTLV-III Infections><HTLV-III-LAV Infections><Histology><History><Human><Human Immunodeficiency Viruses><Human T-Lymphotropic Virus Type III Infections><Hydrogen Oxide><Image><Implant><In Vitro><Individual><Industry><Infection><Inflammation><Injectable><Integrase Inhibitors><Intervention><Intervention Strategies><Kinetics><Knowledge><LAV-HTLV-III><Longitudinal Studies><Lymphadenopathy-Associated Virus><M mulatta><M. mulatta><Macaca><Macaca mulatta><Macaque><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Measures><Medical><Medication><Methodology><Methods><Modeling><Modern Man><NNRTI><Nucleosides><Oral><Ovine><Ovis><PK/PD><Participant><Pharmaceutical Preparations><Pharmacodynamics><Pharmacokinetics><Pharmacology><Phase 1 Clinical Trials><Phase I Clinical Trials><Plasma><Plasma Serum><PrEP><Predisposition><Prevention><Process><Productivity><Public Health><RNA Transcriptase><RNA-Dependent DNA Polymerase><RNA-Directed DNA Polymerase><Rat><Rats Mammals><Rattus><Recording of previous events><Rectum><Regimen><Removal><Research><Resistance profile><Resistant profile><Reticuloendothelial System, Serum, Plasma><Reverse Transcriptase><Reverse Transcriptase Inhibitors><Revertase><Rhesus Macaque><Rhesus Monkey><Risk><Route><SHIV><Safety><Scientific Advances and Accomplishments><Sheep><Surgical Removal><Susceptibility><TMC120 R147681><TMC120-R147681><Techniques><Tenofovir><Topical Drug Administration><Topical application><Transmission><Vagina><Vaginal Ring><Viread><Virus-HIV><Water><administer topically><anti-retroviral><apply topically><beta-L-2',3'-dideoxy-5-fluoro-3'-thiacytidine><bio-markers><biologic marker><biomarker><comparing females and males><comparing women and men><deliver topically><design><designing><developmental><driving><drug/agent><efficacy study><emtricitabine><experience><fabrication><females compared to males><females compared with males><females versus males><females vs males><forgetting><histories><imaging><implant design><improved><in vivo><in vivo Model><inhibitor><innovate><innovation><innovative><interventional strategy><intravaginal ring><lead candidate><long-term study><longitudinal outcome studies><longterm study><metabolism measurement><metabolomics><metabonomics><model of animal><nano-molar><nanomolar><non-human primate><non-nucleoside RT inhibitors><non-nucleoside reverse transcriptase inhibitors><nonhuman primate><nonnucleoside reverse transcriptase inhibitors><novel><ovine animal model><ovine model><pharmacokinetics and pharmacodynamics><phase I protocol><pill><pre-clinical><pre-clinical development><pre-exposure prophylaxis><preclinical><preclinical development><prevent><preventing><programs><prophylactic><resection><safety study><scientific accomplishments><scientific advances><sheep model><simian HIV><simian human immunodeficiency virus><subcutaneous><subdermal><success><technology platform><technology system><topical administration><topical delivery><topical drug application><topical treatment><topically administered><topically applied><topically delivered><topically treated><transmission process><treat topically><truvada><ultrasound><uptake><women compared to men><women compared with men><women versus men><women vs men>