First-in-Human Study of Long-Acting Injectable HIV Nanoparticle Combination Therapy
Rachel A Bender Ignacio, MD, MPH explores safety, pharmacokinetics, and future directions for HIV treatment.
Rachel A Bender Ignacio, MD, MPH
Image credits: UW UMedicine
A first-in-human study has evaluated the safety and pharmacokinetics of a new long-acting injectable antiretroviral therapy (LA-ART), developed as part of the Targeted Long-Acting Combination Antiretroviral Therapy (TLC-ART) Program, a collaboration between US research institutions, including the University of Washington and the National Institute of Allergy and Infectious Diseases. Rachel A Bender Ignacio, MD, MPH, a physician-scientist specializing in infectious diseases and HIV/AIDS, is the principal investigator of this study and discussed the key findings and implications.
“This is the first study in humans of any product in the TLC-ART pipeline,” Rachel Bender Ignacio explained. “The drug formulation contains lopinavir, ritonavir, and tenofovir within a lipid nanoparticle, and it is designed to be a long-acting injectable formulation for HIV treatment.”
Results
The nanoparticle combination was well-tolerated by most participants, with injection site reactions (ISRs) reported in seven participants (Grade 1) and three (Grade 2 erythema). One participant in the HIGH Dose cohort experienced anaphylaxis six hours post-dosing, treated with epinephrine. The dose was reduced by 25%, and no further systemic adverse events occurred in the MID Dose cohort. Other adverse events included Grade 2 lip swelling (LOW Dose), Grade 2 erythematous rash (HIGH Dose), and Grade 1 pruritus (two participants). No gastrointestinal side effects or significant changes in IgE or tryptase levels were observed, indicating no Type I hypersensitivity reactions.
Pharmacokinetic analysis showed varying half-lives for each drug: lopinavir (33 days), ritonavir (1 day), and tenofovir (4 days). Drug components were detectable for different durations: LPV (63 days), RTV (4 days), and TFV (20 days).
The open-label trial enrolled 12 healthy participants (mean age 37) to evaluate the pharmacokinetics and safety of TLC-ART 101, a nanoparticle containing lopinavir (LPV), ritonavir (RTV), and tenofovir (TFV). Participants received a single subcutaneous dose in one of three cohorts: LOW (1.5 mL), MID (2x 1.5 mL), and HIGH (2x 2 mL). Blood samples were collected over 63 days to measure drug levels and monitor adverse events, with dose adjustments based on participant responses.
Bender Ignacio emphasized several important findings from the study. “First, we were able to achieve the first known long-acting injectable protease inhibitor. Lopinavir is not what many of us use in clinical practice anymore, but it was selected for its long safety track record, its generic availability, and its ability to be used in children over the last decade,” she said. “What we found in this study is that, although the drug contains ritonavir, we did not see a boosting effect from the ritonavir. This means that we think this is the first long-acting protease inhibitor that does not require boosting, which is an exciting finding.”
She also pointed out that “the half-life of tenofovir was extended in plasma, though not to the extent we saw in preclinical models, and not as long as lopinavir, which remained at high levels even two months after the study ended. The drug is injected subcutaneously into the abdomen, and it enters the lymphatic space directly from the subcutaneous space. Based on preclinical data and our trial data, we know that the concentrations of the three antiretroviral drugs are much higher intracellularly than in the plasma. While we normally measure drug levels in plasma (as the FDA approves drugs based on plasma levels), the actual compartment of action is inside the white cells, where the drug is most effective.”
Study Design and Next Steps
The study was designed as a dose escalation and de-escalation study with an adaptive protocol, aiming to identify a safe and effective dose. “We started with a low dose of 1.5 mL, and based on the safety and pharmacokinetic results, we increased the dose to the maximum prescribed dose of four milliliters,” Rachel Bender Ignacio explained. “After one participant in the HIGH Dose cohort experienced anaphylaxis, we consulted with our safety and monitoring board and decided to reduce the dose for the remaining participants.”
Looking ahead, the next steps for the study involve refining the compound and moving forward with the development of the TLC-ART platform. “TLC ART 101 was intended as a proof-of-concept,” Bender Ignacio said. “We’re not planning further studies with this specific compound. Instead, we’re using what we’ve learned to expedite the development of TLD, which is about to enter its first phase 1 study. The study is being sponsored by UNITAID and the Medicines Patent Pool, along with the TLC ART program, to move the TLD compound rapidly through early-phase trials.”
