CROI 2025 Abstract eBook

Abstract eBook

Poster Abstracts

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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Fixed Dosing Versus Body-Weight-Based Dosing of HIV-1 Prophylactic Monoclonal Antibodies in Adults Yunda Huang 1 , Lily Zhang 1 , Huub Gelderblom 1 , Kelly Seaton 2 , Nicole Yates 2 , Carmen Paez 1 , Julie Ledgerwood 3 , Stephen Walsh 4 , Magdalena E. Sobieszczyk 5 , Sri Edupuganti 6 , Colleen Kelley 7 , Michael Pensiero 8 , Peter Gilbert 1 , Richard A. Koup 3 , Georgia D. Tomaras 9 1 Fred Hutchinson Cancer Center, Seattle, WA, USA, 2 Duke Human Vaccine Institute, Durham, NC, USA, 3 Vaccine Research Center, Bethesda, MD, USA, 4 Harvard Medical School, Boston, MA, USA, 5 Columbia University Irving Medical Center, New York, NY, USA, 6 Emory University, Atlanta, GA, USA, 7 Emory Vaccine Center, Atlanta, GA, USA, 8 National Institute of Allergy and Infectious Diseases, Baltimore, MD, USA, 9 Duke University School of Medicine, Durham, NC, USA Background: Body-weight-based dosing has been typically used in phase 1 trials of therapeutic and prophylactic monoclonal antibodies (mAbs). In recent years, pharmacokinetics (PK) modeling and simulations aided label changes of multiple marketed mAbs for alternative fixed dosing regimens that reduce inter-individual PK variability while maintaining the same average mAb concentrations. We aimed to evaluate fixed dosing versus weight-based dosing for 3 IgG1-based HIV-1 mAbs, VRC07-523LS, PGT121.414.LS and PGDM1400LS, that are planned for HIV-1 prevention efficacy testing, based on data from earlier clinical trials of these mAbs in people without HIV-1. Methods: For each mAb, we used a 2-compartment population PK model to describe the overall trend and inter-individual variabilities in serum concentrations over time post mAb administration from 251 individuals for VRC07-523LS, 113 for PGT121.414.LS and 95 for PGDM1400LS. We evaluated the effect of body weight on each PK parameter. Using the final best-fitting PK model, we performed simulations of mAb serum concentrations to compare inter-individual variabilities in concentrations at 1 day, 12 weeks and 24 weeks post IV infusion and in area under the time-concentration curve (AUC) between the two dosing regimens. To mirror real-world populations, the simulations were based on sex-specific weights observed in 1302 females-at-birth and 1779 males-at-birth in a recent HIV-1 mAb efficacy study. Results: For all 3 mAbs, we observed a significant but generally modest effect of body weight on PK parameters -- clearance rate, volume of central compartment, and volume of peripheral compartment -- with an estimate of ~5% increase of each PK parameter per 10% increase in body weight. Correspondingly, overall magnitude and variability in the time-specific concentrations and in AUC were comparable between the two dosing regimens for both females- and males-at-birth. Consistent with the PK models, the relationship between body weight and concentrations differs between the 2 dosing regimens with a generally positive correlation for weight-based dosing but a negative correlation for fixed dosing (Figure). For individuals with body weight below the 15th or above the 85th percentiles, fixed dosing results in < 3% difference in median AUC compared to the overall population. Conclusions: Given the advantage of fixed dosing in reducing vial wastage and increasing operational efficiency, fixed dosing is recommended for these 3 HIV-1 mAbs in future clinical testing.

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Preclinical Pharmacokinetic Assessment of a Long-Acting Solid Injectable for Hepatitis C Virus Usman Arshad 1 , Henry Pertinez 1 , Joanne Sharp 1 , Joanne Herriott 1 , Edyta Kijak 1 , Helen Cox 1 , Jonathan Massam 1 , Andrew B. Dwyer 1 , Alison C. Savage 1 , James J. Hobson 1 , Catherine Unsworth 1 , David Thomas 2 , Paul Curley 1 , Steve Rannard 1 , Andrew Owen 1 , for the Centre of Excellence for Long-acting Therapeutics (CELT) 1 University of Liverpool, Liverpool, UK, 2 The Johns Hopkins University School of Medicine, Baltimore, MD, USA Background: Approximately 58 million people are chronically infected with HCV globally, with approximately 1.5 million new infections per year and a disproportionate burden in low- and middle-income countries. Approved oral treatments, administered over 8 – 12 weeks, are highly effective demonstrating >98% sustained virological response (SVR) in RCTs. However, in some populations intention to treat analyses have indicated SVR rates <50%. Long-acting drug delivery in HCV holds promise to reduce loss of patients to follow-up, mitigate resistance and adherence challenges, and facilitate test and cure strategies. Surveys of patient and provider groups have consistently demonstrated high potential acceptability of such an approach. Methods: Glecaprevir and pibrentasvir were formulated using a spray drying technology and processed to form a 11 mm x 2 mm solid using vacuum compression moulding. Resultant solid injectable formulations were administered to Male Sprague Dawley rats (n = 4, 250-300g) within each flank of the scapular region using a 12-gauge needle. Each solid consisted of 30 wt% glecaprevir, 30 wt% pibrentasvir, and 40% excipient. Total dose was 27mg for each drug. Whole blood was collected from the tail vein over 13 weeks and following processing, drug concentrations were quantified in plasma using a validated LC MS/MS assay. Results: Following administration, Cmax concentrations of 2490 ± 500 ng / mL glecaprevir and 248 ± 46 ng / mL pibrentasvir were achieved. Tmax occurred at ~2 hours post dose for glecaprevir and ~10 hours post dose for pibrentasvir. AUC 0-8weeks was 169 ± 69 μg·h/ml for glecaprevir and 47.3 ± 6.6 μg·h/ml for pibrentasvir. Both drugs remained detectable within plasma for the full 13 weeks. No behavioural issues were encountered, animals gained weight throughout and no overt injection site issues were visible upon inspection. Conclusions: Preclinical data for a novel glecaprevir / pibrentasvir solid injectable demonstrated sustained concentrations of both drugs in rats for greater than 8 weeks. High concentrations were achieved rapidly after administration possibly mitigating the need for oral lead-in which would be sub-optimal for treatment of chronic infection. Further work is required to understand variability in pharmacokinetic exposure of solid injectables relative to their liquid counterparts, and acceptability of the solid injectable approach to patients.

Poster Abstracts

CROI 2025 176