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Principal Investigator: Alessandro Grattoni
Organization: METHODIST HOSPITAL RESEARCH INSTITUTE
Fiscal Year: 2024
Award: $816,407
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY/ABSTRACT
Maternal mortality and AIDS are among the leading causes of death in reproductive-age women globally due to
unintended pregnancy and the disproportionate burden of HIV infection. While effective prevention methods
exist, only 21% of women have access to modern contraceptives and adherence to HIV PrEP regimen is poor
in many HIV-endemic regions. Multipurpose prevention technologies (MPT) aim to synchronize contraceptive
delivery with HIV PrEP, offering a patient-centered approach to provide dual coverage to sexually active women
in a single product. A long-acting unified delivery product that can be administered in a discreet manner could
reduce stigma around contraceptives and HIV PrEP, thereby improving uptake and adherence to combination
prevention products. Our goal is to develop a long-acting delivery implant of etonogestrel (ENG) and islatravir
(ISL) drugamer with an unprecedented 2-year release duration for pregnancy and HIV prevention that eliminates
further need of adherence. A new subcutaneous nanofluidic multipurpose implant (NanoMPI) will be brought
together with a new polymeric prodrug technology termed “drugamer”, to achieve this innovative product
candidate that delivers ultra-long acting ENG+ISL drug dosing durations. The NanoMPI leverages a nanofluidic
membrane with nanochannels and a single drugamer reservoir to achieve zero-order release kinetics through
passive diffusion without pumping mechanisms, permitting discreet, user-independent dosing. Key product
attributes will include drug stabilization on the multi-year timeframe, minimized early- and late-stage burst release
and pharmacokinetic (PK) tailing, zero-order drug release kinetics tailored to the individual drug PK/PD
(pharmacodynamic) requirements, user-independent dosing, and retrievability. The project is structured around
3 specific aims: 1) to develop optimized ENG-ISL drugamer formulations that stabilize the drugs and exhibit the
desired zero order release profiles, in concert with the optimization of the NanoMPI device for 2-year sustained
release; 2) to assess pharmacokinetics, tolerability, and safety of the lead ENG-ISL NanoMPI device for 2 years
in pigtail macaques; and 3) to evaluate contraception and HIV PrEP efficacy of ENG-ISL NanoMPI in pigtail
macaques via repeated low-dose vaginal challenge and develop a PK/PD model. We will use a milestone-driven
research approach to advance the ENG-ISL NanoMPI technology towards the ultimate goal of clinical translation,
leveraging the interdisciplinary team’s experience in drugamer technology, drug delivery, pre-clinical and clinical
HIV prevention studies, and hormonal contraceptive and antiretroviral pharmacology. Importantly, the NanoMPI
addresses user preferences for a dual prevention product, discretion and longer dosing duration. Successful
completion will generate a versatile MPT platform that could be adopted for other drug combinations and
preventative strategies.
Terms: <3-keto-desogestrel><3-ketodesogestrel><3-oxo desogestrel><3-oxodesogestrel><AIDS><AIDS Virus><AIDS prevention><Acquired Immune Deficiency><Acquired Immune Deficiency Syndrome><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome><Acquired Immunodeficiency Syndrome Virus><Address><Adherence><Adopted><Age><Anti-Retroviral Agents><Body Tissues><Cause of Death><Clinical><Cold Chains><Common Rat Strains><Contraception><Contraceptive Agents><Contraceptive methods><Contraceptives><Corlutina><Corluvite><Cyclogest><Dapivirine><Developing Countries><Developing Nations><Diffusion><Dose><Drug Combinations><Drug Delivery><Drug Delivery Systems><Drug Kinetics><Drug Precursors><Drug Stability><Drugs><Etonogestrel><Exhibits><FDA approved><Fertility Control><Formulation><Future><Gestagenic Agents><Gestagens><Gestation><Gestiron><Gestone><Goals><HIV><HIV Infections><HIV Prevention><HIV anti-retroviral><HIV/AIDS prevention><HTLV-III Infections><HTLV-III-LAV Infections><Health><High Risk Woman><Hormonal><Human><Human Immunodeficiency Viruses><Human T-Lymphotropic Virus Type III Infections><Implanon><Implant><Individual><Inhibition of Fertilization><Ion Channel><Ionic Channels><Kinetics><LAV-HTLV-III><LMIC><Lead><Less-Developed Countries><Less-Developed Nations><Lipo-Lutin><Luteohormone><Lutocyclin><Lutocylin M><Lutogyl><Lutromone><Lymphadenopathy-Associated Virus><M nemestrina><M. nemestrina><Macaca nemestrina><Maternal Mortality><Medication><Membrane><Membrane Channels><Methods><Modern Man><Modernization><Oral><PBMC><Pb element><Peripheral Blood Mononuclear Cell><Pharmaceutical Preparations><Pharmacodynamics><Pharmacokinetics><Pharmacology><Pigtail Macaque><Pigtail Monkey><Polymers><Position><Positioning Attribute><PrEP><Pregnancy><Preventative strategy><Prevention><Prevention strategy><Preventive><Preventive strategy><Pro-Drugs><Prodrugs><Progestagenic Agents><Progestasert><Progestational Agents><Progestational Compounds><Progestational Hormones><Progesterone Agents><Progestins><Progestogel><Progestogens><Progestol><Progeston><Prolidon><Proluton><Pump><Rat><Rats Mammals><Rattus><Recommendation><Regimen><Research><Resistance><Retrieval><Risk><SHIV><Safety><Scanning Electron Microscopy><Stigmatization><Structure><Syngesterone><TMC120 R147681><TMC120-R147681><Tail><Technology><Testing><Therapeutic Progestin><Third-World Countries><Third-World Nations><Tissues><Under-Developed Countries><Under-Developed Nations><Unplanned pregnancy><Utrogestan><Vagina><Vaginal Ring><Viral Diseases><Virus Diseases><Virus-HIV><Woman><Work><World Health Organization><ages><anti-retroviral><at-risk females><at-risk women><biomedical implant><clinical development><clinical translation><clinically translatable><contraceptive efficacy><design><designing><determine efficacy><developing country><developing nation><diffused><diffuses><diffusing><diffusions><drug release kinetics><drug release rate><drug/agent><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><evaluate efficacy><examine efficacy><experience><females at high risk><heavy metal Pb><heavy metal lead><high risk females><hormonal contraception><hormonal contraceptive><hydrophilicity><implant device><implantable device><implantation><improved><indwelling device><innovate><innovation><innovative><intravaginal ring><low and middle-income countries><maternal death><membrane structure><nano fluidic><nanochannel><nanofluidic><next generation><non-human primate><nonhuman primate><patient centered><patient oriented><pharmacodynamic model><pig-tailed macaque><pill><polymer><polymeric><pre-clinical><pre-exposure prophylaxis><preclinical><preference><pregnancy prevention><prevention of pregnancy><prophylactic><public health relevance><reproductive><resistant><response><sexual and reproductive health><sexually active><simian HIV><simian human immunodeficiency virus><social stigma><stigma><subcutaneous><subdermal><technology platform><technology system><unintended pregnancy><uptake><viral infection><viral transmission><virus infection><virus transmission><virus-induced disease><women at high risk>