Innovations in HIV-1 pre-exposure prophylaxis (PrEP) are needed to address the global HIV epidemic and meet the diverse needs of individuals at risk of acquiring HIV-1. Islatravir (ISL) is the first nucleoside reverse transcriptase translocation inhibitor (NRTTI) in development for the treatment and prevention of HIV-1. In this PK/PD work, we present the data that defined the exposure threshold for ISL for PrEP and the corresponding oral once monthly (QM) dose for the phase 3 clinical development program.
The lower efficacious exposure threshold for ISL PrEP efficacy was based on (1) the estimated protective ISL-triphosphate (ISL-TP) EC[sub]90[/sub] from a study of male rhesus macaque undergoing SHIV intra-rectal challenge using once weekly oral ISL, (2) the minimum efficacious ISL-TP concentration in a Phase 1b proof-of-concept trial (NCT02217904) in treatment-naïve adults with HIV-1, and (3) relevant data from the literature regarding the protective concentrations of FTC/TDF. Population PK simulations were conducted using data from the Phase 1 and 2 studies of ISL to determine the phase 3 oral QM dose.
Totality of the data from the rhesus macaque study, the Phase 1b trial, and benchmarking PK exposures from TDF-DP resulting from both pre-clinical and clinical studies suggest that full efficacy for HIV-1 prevention is achieved with approximate inhibitory quotient (IQ) of ~1-5 (Table). Based on these observations, the efficacious exposure threshold for ISL PrEP was set at 0.05 pmol/106 cells in PBMCs, which is ~5-fold above the in vitro IC50 (0.00974 pmol/106 cells) of ISL-TP against wild type HIV-1. In an ongoing Phase 2 trial (NCT04003103), the observed mean ISL-TP exposure 4 weeks after a 60-mg dose was ~26 fold above the PK threshold. Additionally, population PK simulations suggest that oral ISL 60-mg QM will achieve ISL-TP concentrations well above the PK threshold for all participants following the first monthly dose. All participants at this dose are predicted to be above the PK threshold with the lower 2.5th prediction interval having an ~IQ of 17.
To provide efficacious exposures for protection against HIV-1, a 60-mg oral QM dose of ISL was selected for the Phase 3 clinical program. This dose is expected to maintain ISL-TP concentrations above the conservative PK threshold of 0.05 pmol/106 cells for all participants with sustained exposures in the event of a delayed or missed monthly dose.
