Atea Pharma Publishes More Data on Bemnifosbuvir’s Metabolic Activation

Atea Pharmaceuticals, Inc. (Nasdaq: AVIR), a clinical-stage biopharmaceutical company, has recently announced the publication of significant research regarding the metabolic activation pathway of their antiviral drug candidate, bemnifosbuvir. The findings were published in the reputable journal, PLOS Biology, under the title, “The activation cascade of the broad-spectrum antiviral bemnifosbuvir characterized at atomic resolution.” Bemnifosbuvir is an oral nucleotide RNA-dependent RNA polymerase (RdRp) inhibitor that is currently in Phase 3 clinical trials for COVID-19 treatment and in Phase 2 trials for hepatitis C virus (HCV) infection when combined with ruzasvir, an oral NS5A inhibitor.

The study provides an in-depth look at the processes required to convert bemnifosbuvir (AT-527) into its active form, AT-9010, a 5'-triphosphate. AT-9010 has shown selective inhibition of crucial RNA viral enzymes, leading to strong antiviral effects. The activation pathway of AT-9010 halts HCV RNA synthesis through RNA chain termination and disrupts SARS-CoV-2 RNA synthesis by targeting two different sites of the replicase complex.

Jean-Pierre Sommadossi, PhD, CEO and Founder of Atea Pharmaceuticals, emphasized the importance of these findings. He stated that understanding the sequence of reactions converting bemnifosbuvir into its active form, AT-9010, which selectively inhibits essential viral enzymes, adds to the mounting evidence supporting bemnifosbuvir’s potential as an antiviral treatment for COVID-19, HCV, and potentially other RNA viruses.

Data from in vitro testing and clinical trials have indicated that bemnifosbuvir is among the few antiviral purine nucleotide analogues that do not exhibit significant cellular toxicity. Bruno Canard, PhD, the study’s lead investigator from Architecture et Fonction des Macromolécules Biologiques, CNRS and Aix-Marseille University, noted that the research has provided a clearer understanding of bemnifosbuvir’s antiviral activity. The study identifies the enzymes involved in the drug’s activation pathway and clarifies their structural and functional interactions with activation intermediates. This work further contributes to the understanding of bemnifosbuvir's selective mechanism of action as a direct-acting antiviral.

Bemnifosbuvir, an oral nucleotide polymerase inhibitor, specifically targets the SARS-CoV-2 RNA polymerase (nsp12), a gene critical for the virus's replication and transcription. Its dual mechanism includes chain termination (RdRp) and nucleotityltransferase (NiRAN) inhibition, potentially creating a robust barrier to resistance. In vitro data has confirmed bemnifosbuvir’s effectiveness against various variants of concern and interest, including recent subvariants like BA.5, XBB, EG.5.1, and JN.1.

The U.S. Food and Drug Administration (FDA) has granted Fast Track designation to bemnifosbuvir for the treatment of COVID-19. Additionally, the drug has shown to be approximately 10 times more effective than sofosbuvir (SOF) against multiple HCV strains in in vitro studies. Bemnifosbuvir has remained active against SOF-resistant strains (S282T), with up to 58-fold greater potency. Its pharmacokinetic profile supports once-daily dosing for HCV treatment. Across both HCV and COVID-19 programs, bemnifosbuvir has been administered to over 2,200 subjects and has been well-tolerated at doses up to 550 mg for up to 12 weeks.

Ruzasvir, an oral HCV NS5A inhibitor, has also shown highly potent and pan-genotypic antiviral activity in preclinical and clinical studies. Administered to over 1,500 HCV-infected patients at daily doses up to 180 mg for 12 weeks, ruzasvir has demonstrated a favorable safety profile and a pharmacokinetic profile supporting once-daily dosing.

Atea Pharmaceuticals remains dedicated to discovering, developing, and commercializing oral antiviral therapies to meet the unmet medical needs of patients with serious viral infections. Their proprietary nucleos(t)ide prodrug platform focuses on developing treatments for single-stranded ribonucleic acid (ssRNA) viruses, which cause many serious viral diseases. Currently, Atea is concentrating on developing oral antiviral agents for SARS-CoV-2 and HCV.