MDL-001: an Oral, Direct-Acting Broad-Spectrum Antiviral for Influenza-Like Illness (ILI) and Chronic Hepatitis In Vivo

Abstract

Background/Objectives: Endemic viral respiratory illnesses caused by influenza, RSV, and coronaviruses impose a global disease burden of hundreds of millions of infections and hundreds of thousands of deaths annually. Chronic hepatitis B and C infections persist in 254 million and 58 million people worldwide, respectively. No approved therapy addresses these viruses simultaneously. MDL-001 is an oral, direct-acting, broad-spectrum antiviral targeting the Thumb-1 allosteric site of viral polymerases. Methods: Here we evaluated the antiviral activity of MDL-001 in vitro in influenza A/B, RSV, SARS-CoV-2, endemic human coronaviruses, and hepatitis B/C/D. We next evaluated MDL-001 antiviral activity in vivo in H1N1, SARS-CoV-2, HCV, and HBV. MDL-001's in vivo efficacy was compared head-to-head versus standards of care including oseltamivir, remdesivir, sofosbuvir, and tenofovir alafenamide, or through literature comparison with nirmatrelvir and molnupiravir. Lastly, we evaluated the pharmacokinetics, metabolism, tolerability, and safety profile of MDL-001. Results: Here, we report MDL-001 inhibits influenza A/B, RSV, SARS-CoV-2, endemic human coronaviruses, and hepatitis B/C/D viruses with nanomolar EC90 potency in vitro. MDL-001 demonstrated equivalent in vivo efficacy to oseltamivir against mouse-lethal influenza A virus infection, reducing lung viral load by 2.6 log10 and preventing weight loss and mortality. MDL-001 demonstrated equivalent symptom reduction to subcutaneous remdesivir after SARS-CoV-2 infection. MDL-001 reduced SARS-CoV-2 lung viral titers by 2.9 log10, superior to literature reported 1.4 log10 and 1.0 log10 reductions for nirmatrelvir and molnupiravir, respectively. MDL-001 reduced HCV viremia by 3.3 log10, equivalent to sofosbuvir. Oral MDL-001 reduced plasma HBV surface antigen by 2.5 log10, superior to tenofovir alafenamide from Day 8 through Day 21. MDL-001 demonstrated an in vitro EC50 of 79.4 nM against infection with RSV strain A2, a 416-fold improvement over literature-reported ribavirin. Oral pharmacokinetics studies demonstrate MDL-001 is rapidly absorbed and partitioned into Lung (Kp=39-52) and Liver (Kp=71-104) tissues. MDL-001 produced no treatment-related tolerability adverse events across 376 animals and showed no hERG, Ames genotoxicity, or micronucleus safety issues. Conclusions: These findings support MDL-001 as a broad-spectrum, direct-acting non-nucleoside antiviral clinical candidate.