Preclinical evaluation of a Potent Novel Human Cytomegalovirus Lead Drug Candidate – PRECYVIR

The current pandemic made it clear how important antiviral drugs are; not only against coronaviruses, but against many other families of viruses as well, which can lead to life-threatening conditions, especially in children. As French experts in antiviral drug research and development, the fight against viruses is our priority.

This multidisciplinary project focuses on the development of a potent novel lead drug candidate, LAVR-289, which has excellent activity against DNA viruses and strong potential for use in treating human cytomegalovirus (hCMV). hCMV infects a large part of the world population and can be severe when it affects an unborn child or a person with a weak immune system activity (recent transplant recipient). hCMV is a major cause of morbidity and mortality in congenital infections, transplant recipients (solid organ and hematopoietic cell). Due to the limitations involved by current drugs (toxicity, prophylaxis, and emergence of resistances) there is still much room for innovation for potent new antiviral, with higher genetic barrier to resistance and enhanced availability. We recently patented a new family of acyclic nucleoside phosphonates bearing a (E)-4-phosphono-but-2-en-1-yl skeleton. Among them, LAVR-289 exhibits a highly potent broad antiviral activity against various DNA virus. As measured by in vitro, in vivo, ex vivo data (produced by this consortium), LAVR-289 has an EC50 in the nanomolar concentration range (10-9 mol) against hCMV, e.g. 100 times more active than standards.

PreCyVir, a consortium of 3 partners experts in antiviral chemistry, in HCMV biology and pathology and in pharmacokinetic, aims to push the LAVR-289 development from TRL-3 to TRL-4/5. The tasks required for preclinical evaluation are :

(1) Chemical process to produce several grams of LAVR-289, the synthesis of the phosphorylated metabolites and expected one also. We will address its physicochemical profile and estimate its enzymatic stability in different biological fluids;

(2) The in vitro LAVR-289 efficacy and potency, alone or in combination with the other antivirals, will be explored on wild-type and GCV, CDV, FOS, LTV or MBV-resistant strains, and its cytotoxicity on growing and confluent cells will be assessed on various cell-types (including mitochondrial toxicity). Ex vivo LAVR-289 efficacy and potency will be addressed in a congenital hCMV infection context, use a floating villi explant model from 1st trimester placenta. The LAVR-289 efficacy and potency in vivo will be done on a unique specific SCID-Hu mouse model by subcutaneously grafting the infected human placental villi. hCMV strains will be passaged in cell culture in presence of increasing concentrations of LAVR-289 to determine the time–to–resistance. The mechanism of action will be determined;

(3) Concentrations of LAVR-289 and its respective metabolite (diphosphate, triphosphate) will be determined in extracellular matrices (medium and plasma) using a UPLC-MS/MS method. The pharmacokinetic profile in mice ((Cmax, Cmin AUC,…) will be determined by a non-compartmental analysis; the penetration of LAVR-289 and its metabolites will be determined in cerebrospinal fluids and/or brain tissue, in parallel of the blood plasma compartment, as well as in an ex vivo placental transfer mode.

All these tasks will be realized through some innovative analytical/biological method developments as well as unique animal model. At the end of this project, we will have all required data to decide if LAVR-289 can enter into Investigational New Drug program, with further development necessary to obtain the permission of regulatory authorities to begin human clinical testing.