S-892216 for COVID-19

Abstract Background COVID-19 caused by SARS-CoV-2 remains a global public health concern. Although oral direct-acting antivirals for COVID-19 (such as molnupiravir, nirmatrelvir/ritonavir, ensitrelvir) were approved for clinical use, there are concerns about drug-drug interactions (DDI) and safety, so development of new therapeutics is needed. In this study, we describe enzyme inhibitory and antiviral activity of S-892216, a second-generation small molecular 3C-like protease (3CLpro) inhibitor. Methods The 3CLpro enzymatic assay was conducted by mass spectrometry system. In vitro antiviral activity was evaluated using VeroE6/TMPRSS2 cells and human airway epithelial cells (hAEC) following infection by several SARS-CoV-2 variants. In vivo efficacy was evaluated using Balb/c mice, intranasally infected with SARS-CoV-2, and S-892216 was orally administered. Results S-892216 showed high 3CLpro inhibitory activity (IC50 = 0.697 nmol/L) and exhibited in vitro antiviral activity against several SARS-CoV-2 strains, including Omicron variants (EC50 = 2.27-12.5 nmol/L in VeroE6/TMPRSS2 cells, EC90 = 2.31-2.41 nmol/L in hAECs). Furthermore, S-892216 suppressed lung virus titer in Balb/c mice infected with SARS-CoV-2 in a dose-dependent manner. Conclusion S-892216 has stronger 3CLpro inhibitory and antiviral activity than approved 3CLpro inhibitors and has been confirmed to be effective in vivo. Due to the strong antiviral activity of S-892216, it is suggested to be effective at low doses in clinical settings. DDI and safety will be evaluated in clinical trials. Disclosures Haruaki Nobori, PhD, Shionogi & Co., Ltd.: Employee|Shionogi & Co., Ltd.: Stocks/Bonds (Private Company) Sho Kawashima, Shionogi & Co., Ltd.: Employee Reiko Dodo, n/a, Shionogi & Co., Ltd.: Employee Yuki Maruyama, PhD, Shionogi & Co., Ltd.: Employee|Shionogi & Co., Ltd.: Stocks/Bonds (Private Company) Takayo Haruna, n/a, Shionogi & Co., Ltd.: Employee Keiichiro Hirai, PhD, Shionogi & Co., Ltd.: Employee Yuto Unoh, PhD, Shionogi & Co., Ltd.: Employee Kenji Nakahara, PhD, Shionogi & Co., Ltd.: Employee Shota Uehara, Ph.D., Shionogi & Co., Ltd.: Employee|Shionogi & Co., Ltd.: Stocks/Bonds (Private Company) ryosuke watari, n/a, Shionogi & Co., Ltd.: Employee tomoyuki kawachi, n/a, Shionogi & Co., Ltd.: Employee yuka Natsume, n/a, Shionogi & Co., Ltd.: Employee katsumoto hata, n/a, Shionogi & Co., Ltd.: Employee yukiko orita, n/a, Shionogi & Co., Ltd.: Employee kae fujisawa, n/a, Shionogi & Co., Ltd.: Employee tetsuya miyano, PhD, Shionogi & Co., Ltd.: Employee hideko kaneda, n/a, Shionogi..

Background/Objectives: S-892216 is a poorly water-soluble drug developed as a novel oral treatment for COVID-19, although its oral absorption is low. For Phase 1 (Ph1) studies and commercial use, both oral solution and solid dispersion technologies are evaluated to enhance drug solubility. Methods: The solubility enhancement technology was selected by considering physicochemical factors such as stability and oral absorption, along with patient and customer acceptability. Results: Pharmacokinetics study in rats revealed that both the polyethylene glycol 400 oral solution and polyvinylpyrrolidone-vinyl acetate (PVPVA) amorphous solid dispersion powder suspension showed almost 100% oral bioavailability. Therefore, they can be proposed as clinical formulations for Ph1 studies. PVPVA solid dispersion tablets were developed as a to-be-marketed formulation showed higher bioavailability in dogs than the anhydrous crystal formulation. Additionally, the stability of the developed solid dispersion tablet was acceptable. Conclusions: This study demonstrates that multiple solubility enhancement technologies can be adopted for S-892216 development, and amorphous solid dispersion technology was selected for commercialization.