R01AI165372

Ultra-Long Acting Transcutaneously Refillable Islatravir Nanofluidic Implant for HIV Pre-Exposure - Abstract

Long-acting (LA) pre-exposure prophylactic (PrEP) strategies offer the promise of improving adherence to therapeutic regimens for maximal HIV preventive efficacy. Key attributes of zero-order release kinetics, long-term drug delivery, user-independent dosing, therapeutic discretion, safety for chronic use, and retrievability are desirable criteria for successful widespread clinical PrEP implementation.

To date, LA PrEP strategies do not sufficiently address the aforementioned criteria. Our goal is to address these limitations by developing an ultra-long acting Islatravir (ISL) delivery implant with an unprecedented release duration of at least 2 years uninterrupted for durable and safe HIV prevention independent of user adherence.

To achieve this goal, we propose the Nanoddi, a transcutaneously refillable subcutaneous nanofluidic drug delivery implant for sustained and constant ISL release. The Nanoddi comprises a newly patented nanofluidic membrane and ports for rapid, minimally invasive transcutaneous drug refilling. Refilling is performed manually via a syringe without any complex pumps or equipment to extend implant use duration beyond 2 years.

The nanofluidic membrane uses nanochannels to control drug release through passive diffusion without pumping mechanisms, permitting discrete, long-term user-independent dosing. Unlike injectables or other LA polymeric strategies, Nanoddi avoids burst and decay release. Zero-order release kinetics is achieved independent of physiological conditions, regardless of interindividual heterogeneity. Importantly, the Nanoddi addresses user preferences for discretion and longer dose duration.

Here we will test the hypothesis that constant and sustained ISL delivery from Nanoddi will achieve preventative drug levels for a 2-year duration and effectively prevent SHIV infection in non-human primates (NHP). This proposal outlines a comprehensive preclinical framework fundamental for developing Nanoddi as an HIV PrEP platform, leveraging the team's experience in pre-clinical and clinical HIV PrEP, long-acting drug delivery, drug formulation, and antiretroviral pharmacology.

We aim to:
1) Develop and optimize Nanoddi and ISL formulation for sustained and constant release;
2) Assess pharmacokinetics (PK), tolerability, and safety of Nanoddi-ISL for 2 years in NHP and evaluate the effectiveness of transcutaneous drug refilling; and
3) Comprehensively evaluate PrEP efficacy of Nanoddi-ISL in NHPs using 4 routes of simian HIV transmission, namely rectal, penile, vaginal, and intravenous.

Our multidisciplinary team has a solid history of collaborative HIV PrEP studies with long-acting drug delivery implants and will receive Merck's scientific and technical support and drug supply for this study. We will use a milestone-driven research approach to advance the Nanoddi-ISL technology towards the ultimate goal of clinical translation.

Methodist Hospital

TO ASSIST PUBLIC AND PRIVATE NONPROFIT INSTITUTIONS AND INDIVIDUALS TO ESTABLISH, EXPAND AND IMPROVE BIOMEDICAL RESEARCH AND RESEARCH TRAINING IN INFECTIOUS DISEASES AND RELATED AREAS, TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS. TO ASSIST PUBLIC, PRIVATE AND COMMERCIAL INSTITUTIONS TO CONDUCT DEVELOPMENTAL RESEARCH, TO PRODUCE AND TEST RESEARCH MATERIALS, TO PROVIDE RESEARCH SERVICES AS REQUIRED BY THE AGENCY FOR PROGRAMS IN INFECTIOUS DISEASES, AND CONTROLLING DISEASE CAUSED BY INFECTIOUS OR PARASITIC AGENTS, ALLERGIC AND IMMUNOLOGIC DISEASES AND RELATED AREAS. PROJECTS RANGE FROM STUDIES OF MICROBIAL PHYSIOLOGY AND ANTIGENIC STRUCTURE TO COLLABORATIVE TRIALS OF EXPERIMENTAL DRUGS AND VACCINES, MECHANISMS OF RESISTANCE TO ANTIBIOTICS AS WELL AS RESEARCH DEALING WITH EPIDEMIOLOGICAL OBSERVATIONS IN HOSPITALIZED PATIENTS OR COMMUNITY POPULATIONS AND PROGRESS IN ALLERGIC AND IMMUNOLOGIC DISEASES. BECAUSE OF THIS DUAL FOCUS, THE PROGRAM ENCOMPASSES BOTH BASIC RESEARCH AND CLINICAL RESEARCH. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM EXPANDS AND IMPROVES PRIVATE SECTOR PARTICIPATION IN BIOMEDICAL RESEARCH. THE SBIR PROGRAM INTENDS TO INCREASE AND FACILITATE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. THE SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM STIMULATES AND FOSTERS SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH AND DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. RESEARCH CAREER DEVELOPMENT AWARDS SUPPORT THE DEVELOPMENT OF SCIENTISTS DURING THE FORMATIVE STAGES OF THEIR CAREERS. INDIVIDUAL NATIONAL RESEARCH SERVICE AWARDS (NRSAS) ARE MADE DIRECTLY TO APPROVE APPLICANTS FOR RESEARCH TRAINING IN SPECIFIED BIOMEDICAL SHORTAGE AREAS. IN ADDITION, INSTITUTIONAL NATIONAL RESEARCH SERVICE AWARDS ARE MADE TO ENABLE INSTITUTIONS TO SELECT AND MAKE AWARDS TO INDIVIDUALS TO RECEIVE TRAINING UNDER THE AEGIS OF THEIR INSTITUTIONAL PROGRAM.

93.855 - Allergy and Infectious Diseases Research

National Institute of Allergy and Infectious Diseases (NIAID) [HHS - NIH]

Houston, Texas 77030 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 452% from $808,087 to $4,459,174.