Topical tenofovir alafenamide/elvitegravir insert for on-demand protection against mucosal HIV-1 infection: proof-of-concept from bench to clinic
Poster #: 191
Session/Time: B
Author:
Abenan Louise Ouattara, PhD
Mentor:
Gustavo F. Doncel, MD, PhD
Research Type: Product development and preclinical and clinical research
Abstract
INTRODUCTION:
With 1.3 million new infections in 2024 , HIV/AIDS continues to have a major impact on global health. Several antiretroviral drugs (ARVs), mainly in oral and injectable forms, have received approval for HIV pre-exposure prophylaxis (PrEP). On-demand PrEP remains an important gap, especially for women. CONRAD has developed a user-centered, topical, on-demand, peri-coital, vaginal and/or rectal insert containing two ARVs exhibiting different mechanisms of action, tenofovir (TFV) alafenamide (TAF) and elvitegravir (EVG), for prevention of HIV under PrEP or post-exposure prophylaxis (PEP) conditions. Here, we present certain aspects of the preclinical and clinical evaluation of these inserts for vaginal administration.
METHODS:
Initially, TAF and EVG activity against HIV-1BaL was evaluated in vitro in a luciferase-reporter cell line, TZM-bl, and ex vivo in cervicovaginal (CV) tissues exposed to serial dilutions of TAF and EVG alone or in combination at different time points to mimic PrEP and PEP dosing. Next, after formulation development and in vitro testing, a pharmacokinetic (PK) study was performed in macaques, with different fixed-dose combinations of TAF and EVG in topical inserts administered vaginally, to select a dose compatible with prophylactic activity. Inserts were then advanced to a Phase I clinical study in women, evaluating safety and PK, and pharmacodynamics (PD). PD was modeled ex vivo by assessing anti-HIV-1 and anti-HSV-2 activity in vaginal fluid and CV tissues.
RESULTS:
In vitro cellular and ex vivo CV tissue models showed potent dose-dependent anti-HIV-1 activity of TAF and EVG under both PrEP and PEP conditions. Due to their complementary physicochemical properties, tissue penetration and mechanisms of action, when combined, TAF and EVG showed overlapping and synergistic antiviral activity providing an extended window of protection. Showing the highest vaginal tissue levels of EVG and TFV-diphosphate (TFV-DP), the active metabolite of TFV and TAF, a dose of 20mg/16mg TAF/EVG was selected for clinical advancement. A Phase I clinical trial, conducted at EVMS , showed that the TAF/EVG insert, when applied vaginally, was safe and well-tolerated, with high local drug levels in fluid and tissue lasting at least 72 hours after a single application. Vaginal fluids collected from participants significantly inhibited HIV-1 and HSV-2 replication in target TZM-bl and HEC-1A cells, respectively. Consistent with high CV tissue drug concentrations, ex vivo challenge of CV biopsies with HIV-1 was inhibited.
CONCLUSION:
TAF/EVG-containing vaginal inserts, from concept to first-in-human clinical trial, were rationally designed and demonstrated excellent safety, PK and PD profiles, supporting a potential high efficacy preventing mucosal HIV infection under PrEP and PEP dosing regimens. Altogether these data support further clinical deve
With 1.3 million new infections in 2024 , HIV/AIDS continues to have a major impact on global health. Several antiretroviral drugs (ARVs), mainly in oral and injectable forms, have received approval for HIV pre-exposure prophylaxis (PrEP). On-demand PrEP remains an important gap, especially for women. CONRAD has developed a user-centered, topical, on-demand, peri-coital, vaginal and/or rectal insert containing two ARVs exhibiting different mechanisms of action, tenofovir (TFV) alafenamide (TAF) and elvitegravir (EVG), for prevention of HIV under PrEP or post-exposure prophylaxis (PEP) conditions. Here, we present certain aspects of the preclinical and clinical evaluation of these inserts for vaginal administration.
METHODS:
Initially, TAF and EVG activity against HIV-1BaL was evaluated in vitro in a luciferase-reporter cell line, TZM-bl, and ex vivo in cervicovaginal (CV) tissues exposed to serial dilutions of TAF and EVG alone or in combination at different time points to mimic PrEP and PEP dosing. Next, after formulation development and in vitro testing, a pharmacokinetic (PK) study was performed in macaques, with different fixed-dose combinations of TAF and EVG in topical inserts administered vaginally, to select a dose compatible with prophylactic activity. Inserts were then advanced to a Phase I clinical study in women, evaluating safety and PK, and pharmacodynamics (PD). PD was modeled ex vivo by assessing anti-HIV-1 and anti-HSV-2 activity in vaginal fluid and CV tissues.
RESULTS:
In vitro cellular and ex vivo CV tissue models showed potent dose-dependent anti-HIV-1 activity of TAF and EVG under both PrEP and PEP conditions. Due to their complementary physicochemical properties, tissue penetration and mechanisms of action, when combined, TAF and EVG showed overlapping and synergistic antiviral activity providing an extended window of protection. Showing the highest vaginal tissue levels of EVG and TFV-diphosphate (TFV-DP), the active metabolite of TFV and TAF, a dose of 20mg/16mg TAF/EVG was selected for clinical advancement. A Phase I clinical trial, conducted at EVMS , showed that the TAF/EVG insert, when applied vaginally, was safe and well-tolerated, with high local drug levels in fluid and tissue lasting at least 72 hours after a single application. Vaginal fluids collected from participants significantly inhibited HIV-1 and HSV-2 replication in target TZM-bl and HEC-1A cells, respectively. Consistent with high CV tissue drug concentrations, ex vivo challenge of CV biopsies with HIV-1 was inhibited.
CONCLUSION:
TAF/EVG-containing vaginal inserts, from concept to first-in-human clinical trial, were rationally designed and demonstrated excellent safety, PK and PD profiles, supporting a potential high efficacy preventing mucosal HIV infection under PrEP and PEP dosing regimens. Altogether these data support further clinical deve