Background
Long-Acting antiretroviral therapy (LA-ART) is considered an integral tool to improve adherence and decrease stigma, but its global implementation has met barriers, including cost and resources for administration. The TLC-ART program, a public-private partnership, engineered a novel 3-drug combination nanoparticle (DcNP) for subcutaneous injection containing lopinavir (LPV), ritonavir (RTV), and tenofovir (TVF) “TLC-ART 101” bound with DSPC and mPEG-DSPE lipid excipients. We report safety and pharmacokinetics (PK) from the completed first-in-human (FIH) study, NCT06850728.
Methods
This open-label FIH study with pharmacologically guided adaptive design allowed for dose escalation or de-escalation between cohorts. TLC-ART 101 DcNP contains 10.4mg of LPV, 2.7mg RTV, and 6.1mg of TFV per ml. Participants were healthy and without HIV. The LOW Dose cohort received 1.5ml; MID-Dose received 2x 1.5ml each; HIGH Dose received 2x 2ml each as subcutaneous peri-umbilical injection(s) on Day 0 as a single dose. Participants were evaluated over 24hrs and on days 1, 2, 3, 7, 10, 14, 21, 28, 35, 49, 57, and 63. Blood was collected for plasma PK analysis and safety.
Results
We enrolled 8 men and 4 women, (mean age 37; 50% non-white). Injection site reactions (ISR) included 7 Grade 1 ISRs and 3 Grade 2 ISRs (erythema). A HIGH Dose participant experienced anaphylaxis 6hrs after dosing, recovering after intervention including epinephrine. The dose was then decreased by 25% and the final 3 participants (MID) experienced no systemic AEs. Additional AEs: Gr 2 Lip swelling (LOW), Gr 2 erythematous rash (HIGH), Gr 1 generalized pruritis (n=2, LOW, HIGH); no gastrointestinal side effects occurred. No participants had increases in IgE or tryptase after dosing.
Each drug average Cmax was within the safety parameters of oral dosing. Average T1/2 was 33 days for LPV, 1 day for RTV, and 4 days for TFV. Drug components were detectable on average at 63 days (LPV), 4 days (RTV), and 20 days (TFV).
Conclusions
A single subcutaneous dose of LPV/RTV/TFV-in-DcNP resulted in the first known long-acting HIV protease inhibitor; boosting by RTV was not apparent. TFV half-life was extended but not to the degree expected from primate models. Systemic hypersensitivity was not Type I (non-IgE) and is under mechanistic exploration. This FIH trial will support development of complete subcutaneously administered LA-ART regimens, including TLC-ART 301 [dolutegravir/lamivudine/TFV (LA-TLD)], currently in pre-clinical studies.
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