AL-516 was assessed in vivo in the dog after oral dosing for the ability to form the active AL-516 NTP in liver. Results: In the stable genotype (GT) 1b replicon assay, AL-516 exhibits potent antiviral activity with an EC50 of 6.5 nM. In transient chimeric GT-1b replicons with NS5B regions derived from GT 1-4, AL-516 demonstrates pan-genotypic activity with EC50 values < 10 nM. AL-516 retains activity versus replicon mutants resistant to nucleoside Y-27632 solubility dmso and non-nucleoside polymerase, NS3/4A protease and NS5A inhibitors. AL-516 exhibits an excellent selectivity profile with no inhibition of mitochondrial protein synthesis (IC50 >100 μM).
The AL-516 NTP is a potent inhibitor of the HCV NS5B polymerase with an IC50 of 240 nM and a Ki of 22 nM, and acts as a chain-terminator of RNA synthesis. The AL-516 NTP retains potency against the NS5B S282T variant with an IC50 of 180 nM. The AL-516 NTP is not a substrate for human mitochondrial RNA polymerase and demonstrates no inhibition (IC50 >100 μM) of human DNA or RNA polymerases. In primary human hepatocytes, the AL-516 NTP is rapidly formed and demonstrates a 11.4 hr half-life, indicating potential for QD dosing. Following
oral administration to dogs at 5 mg/kg parent nucleoside equivalent, the AL-516 NTP is formed at high levels in liver (AL-516 NTP levels at 4 hrs: LY2157299 in vivo 11.2 μM). Conclusions: AL-516 is a potent guanosine based nucleotide analog that demonstrates a desirable preclin-ical profile. The compound is currently advancing in preclinical studies as a potential treatment for CHC. Disclosures: Kenneth Shaw – Employment: Alios
Biopharma Andreas Jekle – Employment: Alios Biopharma; Stock Shareholder: Alios Bio-pharma Jerome Deval – Employment: Alios BioPharma Zhinan Jin – Employment: Alios BioPharma Inc. Amy Fung – Employment: Alios BioPharma Lawrence M. Blatt 上海皓元 – Management Position: Alios BioPharma Sushmita M. Chanda – Employment: Alios BioPharma Qingling Zhang – Employment: Alios BioPharma Guangyi Wang – Employment: Alios Biopharma, Inc. Julian A. Symons – Employment: Alios BioPharma David B. Smith – Employment: Alios BioPharma The following people have nothing to disclose: Hua Tan, Yuen Tam, Natalia Dyatkina, Leo Beigelman Purpose/Background: Both viral and host proteins are involved during the hepatitis C virus (HCV) life cycle. Direct Acting Anti-virals (DAAs) inhibit HCV infection by targeting viral proteins and are successfully used to treat HCV infections. However, therapy failure caused by the emergence of DAA-resistance associated variants (RAVs) remains a reasonable concern. Presumably, future anti-HCV therapies will consist of drug combinations that target distinct steps of the viral life cycle. The conserved host factors used by the virus for its propagation seem interesting alternative targets for antiviral intervention, complimentary to the action of DAAs.