Virostatics Srl

This paper will review recent discoveries in the field of viral pathogenesis and the development of a new antiretroviral class known as AntiViral-HyperActivation Limiting Therapeutics^# (AV-HALTs) that has been specifically designed in response to these findings.AV-HALTs are characterized by the combination of two distinct activities - the direct inhibition of viral replication (antiviral activity) and the reduction of excessive chronic immune system hyperactivation (hyperactivation limiting effect).These two effects can be achieved by combining two drugs (a first-generation AV-HALT) or by a single mol. (second-generation AV-HALTs).The medical need for AV-HALTs is best illustrated in the treatment of the Human ImmunoDeficiency Virus Type 1 (HIV-1).Paradoxically, it is the chronic, excessive hyperactivation of the immune system, resulting in cellular hyperproliferation and systemic inflammation - throughout the course of HIV disease - that is now recognized as the major driver of not only the continual loss of CD4⁺ T cells and progression to the Acquired Immunodeficiency Syndrome (AIDS), but also of the emergence of both AIDS-defining and non-AIDS-defining events that neg. impact upon both morbidity and mortality despite otherwise successful (ie, fully virus suppressive) HIV therapy.This review will focus upon the establishment of the human proof of concept for AV-HALTs using a two-drug, first-generation AV-HALT (VS411) and the development of single-mol., second-generation AV-HALTs for the treatment of HIV-1 disease and other chronic viral infections.

BACKGROUND AND PURPOSEAntiviral hyper‐activation‐limiting therapeutic agents (AV‐HALTs) 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 human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome. VS411, a first‐in‐class AV‐HALT, is a single‐dosage form combining didanosine (ddI, 400 mg), an antiviral (AV), and hydroxyurea (HU, 600 mg), a cytostatic agent, designed to provide a slow release of ddI to reduce its maximal plasma concentration (Cmax) to potentially reduce toxicity while maintaining total daily exposure (AUC) and the AV activity.EXPERIMENTAL APPROACHThis was a pilot phase I, open‐label, randomized, single‐dose, four‐way crossover trial to investigate the fasted and non‐fasted residual variance of AUC,Cmaxand the oral bioavailability of ddI and HU, co‐formulated as VS411, and administered as two different fixed‐dose combination formulations compared to commercially available ddI (Videx EC) and HU (Hydrea) when given simultaneously.KEY RESULTSFormulation VS411‐2 had a favourable safety profile, displayed a clear trend for lower ddICmax(P= 0.0603) compared to Videx EC, and the 90% confidence intervals around the least square means ratio ofCmaxdid 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 IMPLICATIONSA 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.