Strategies to improve efficacy and safety of a novel class of anti‐viral hyper‐activation limiting therapeutic agents (AV‐HALT): the VS411 model in HIV/AIDS

Background and purpose: Anti‐viral hyper‐activation limiting therapeutic agents (AV‐HALT) are a novel experimental drug class designed to both decrease viral replication and down‐regulate excessive immune system activation for the treatment of chronic infections, including HIV/AIDS. VS411, a first‐in‐class AV‐HALT, is a single dosage form combining didanosine (ddI, 400 mg), an antiviral, and hydroxyurea (HU, 600 mg), a cytostatic agent, designed to provide a slow release of ddI to reduce its maximal plasma concentration (C_max) to potentially reduce toxicity while maintaining total daily exposure (AUC) and the antiviral activity.

Experimental Approach: This was a pilot Phase I, open‐label, randomized, single dose, 4‐way crossover trial to investigate the fasted and non‐fasted residual variance of AUC, C_max and the oral bioavailability of ddI and HU, co‐formulated as VS411, and administered as two different fixed dose combination (FDC) formulations compared to commercially available ddI (Videx^® EC) and HU (Hydrea^®) when given simultaneously.

Key Results: Formulation VS411‐2 had a favorable safety profile, displayed a clear trend for lower ddI C_max (p= 0.0603) compared to Videx^®EC, and the 90% confidence intervals around the least square means ratio of C_max did not include 100%. ddI AUC_∞ was not significantly decreased compared to Videx^®EC. HU pharmacokinetic parameters were essentially identical to Hydrea^® although there was a decrease in HU exposure under fed versus fasted conditions.

Conclusions and Implications: A Phase IIa trial utilizing VS411‐2 formulation has been fielded to identify the optimal doses of HU plus ddI as an AV‐HALT for the treatment of HIV disease.