bemnifosbuvir (AT-527) / Atea Pharma - LARVOL DELTA

Multiscale Modeling of an 8-Week Combination Regimen of Bemnifosbuvir and Ruzasvir in Patients with Chronic Hepatitis C Virus Infection. (PubMed, Clin Pharmacol Ther) - P2 | "The estimated efficacy of therapy was similar across genotypes 1 to 4. Thus, our modeling supports the conclusions that BEM/RZR is pan-genotypic, has high antiviral effectiveness and leads to rapid viral clearance in both cirrhotic and non-cirrhotic patients."

Journal • Fibrosis • Hepatitis C • Immunology • Infectious Disease • Inflammation • Liver Cirrhosis

Novel Mechanisms of SARS-CoV-2 Drug Resistance and Rational Design of Anti-Resistant Antivirals. (PubMed, Molecules) - "Four recent studies have revealed two key resistance mechanisms: (1) Mutations in the main protease (Mpro)-including E166V, E166A, and S144-series variants-disrupt drug binding or active-site conformation, reducing nirmatrelvir efficacy. (2) The proofreading exoribonuclease (ExoN) removes incorporated nucleoside analogues (e.g., bemnifosbuvir, sofosbuvir), conferring resistance. Guided by structural and pharmacological insights, three effective countermeasures have been established: structure-based optimization of Mpro inhibitors, rational design of ExoN-evading nucleoside analogues, and synergistic combination therapies. These advances provide a solid framework for developing next-generation antivirals to combat emerging resistant SARS-CoV-2 variants."

Journal • Review • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

The guanosine nucleotide analog bemnifosbuvir inhibits hepatitis E virus infection in cell and organoid models. (PubMed, Virol Sin) - No abstract available

Journal • Infectious Disease • Inflammation

Proton-pump inhibitor Omeprazole did not affect the plasma pharmacokinetics of Bemnifosbuvir and Ruzasvir fixed-dose combination in healthy participants (EASL 2026) - "BEM/RZR FDC was safe and well-tolerated when administered alone or concomitantly with OMEP. While OMEP 20 mg, a common dose for GERD did not affect the plasma exposure to BEM/AT-273/RZR, a higher 40 mg dose of OMEP with BEM/RZR dosed 2h later to allow for maximal acid-suppressive effect did not meaningfully reduce plasma exposure to BEM/AT-273/RZR either. Results support concomitant use of OMEP 20 mg or 40 mg with BEM/RZR in HCV-infected individuals without restriction."

Clinical • PK/PD data • Gastroesophageal Reflux Disease • Hepatitis C • Infectious Disease

Bemnifosbuvir and ruzasvir administered as a fixed-dose-combination have low potential to inhibit P-gp, BCRP or OATP1B1/3 mediated transport (EASL 2026) - "A Ph 1 study in healthy participants was conducted to assess the clinical implications of these results using digoxin (DIG) and rosuvastatin (ROSU) as P-gp and BCRP/OATP1B1/1B3 index substrates, respectively... A single dose of BEM 550 mg/RZR 180 mg administered as 2xFDC tablets only slightly increased the plasma exposure of the P-gp and BCRP/OATP1B1/3 index drugs DIG and ROSU. With GMR<2, BEM/RZR therefore have low potential to exhibit clinically meaningful inhibition of these transporters. No dose adjustment will be needed for drugs that are sensitive substrates of P-gp or BCRP/OAT1B1/3 when co- administered with BEM/RZR; staggered dosing may lessen any DDI risk."

Breast Cancer • Solid Tumor

Bemnifosbuvir: An HCV NS5B Inhibitor With Multiple Modes of Action. (PubMed, Clin Pharmacol Ther) - "We observed a dose-dependent enhancement in the degradation of intracellular HCV RNA, with degradation rates 1.5-fold higher in patients receiving 300 mg/day and 2.7-fold higher in those receiving 600 mg/day than in patients receiving 150 mg/day. No significant differences in antiviral activity were detected between HCV genotypes 1b and 3 or between patients with and without compensated cirrhosis."

Journal • Fibrosis • Hepatitis C • Immunology • Infectious Disease • Inflammation

Bemnifosbuvir and remdesivir inhibit tick-borne encephalitis virus infection in complementary in vitro and ex vivo disease models. (PubMed, Antiviral Res) - "Notably, while we observed bemnifosbuvir to be well tolerated, we report important cytotoxicity of remdesivir when applied to human neural organoids. Our findings identify bemnifosbuvir and remdesivir as novel treatment strategies for TBE, providing an accessible and timely response to a clinical challenge of pressing concern."

Journal • Preclinical • CNS Disorders • Infectious Disease

In Vitro and Clinical Evaluation of Potential Interactions of Bemnifosbuvir with Drug-Metabolizing Enzymes. (PubMed, J Clin Pharmacol) - "Conversely, midazolam had no significant effect on the pharmacokinetics of bemnifosbuvir. Overall, bemnifosbuvir was a weak clinical inhibitor (geometric mean ratio <2) of CYP3A4."

Clinical • Journal • Preclinical • Hepatitis C • Infectious Disease • Inflammation • CYP3A4 • UGT1A1

ProTides for Antiviral Activity Beyond Liver Cells. (PubMed, Chemistry) - "This was first shown for remdesivir (REM), for which a cycloheptyl residue gave 50% inhibition against four different viruses at ≤110 nM concentration...These findings show how easily activity can be improved and broadened across different tissues through seemingly minor changes in ProTide structure. Our results may instruct the design of new antivirals with broad activity against RNA viruses to increase pandemic preparedness."

Journal • Dengue Fever

Substitutions M478K and A482G in the polymerase of yellow fever virus confer resistance to sofosbuvir and uprifosbuvir in vitro. (PubMed, Antiviral Res) - "A482G conferred slight cross-resistance to bemnifosbuvir, while no cross-resistance was observed for remdesivir, galidesivir, or NITD008...Sofosbuvir RAS described for other orthoflaviviruses did not substantially affect drug susceptibility in reverse-engineered YFV 17D. This study demonstrates that YFV can develop resistance to sofosbuvir and uprifosbuvir with only two NS5 substitutions that have slight impact on viral fitness."

Journal • Preclinical • Hepatitis C • Hepatocellular Cancer • Infectious Disease • Inflammation • Liver Cancer • Solid Tumor • RAS

Nucleotide analogue bemnifosbuvir inhibits hepatitis E virus replication in preclinical models. (PubMed, Gut) - "Given BEM's favourable safety profile in preclinical and clinical settings, our results suggest investigating its efficacy in patients with chronic HEV infection."

Journal • Preclinical • Hepatology • Infectious Disease • Inflammation

Mechanism of SARS-CoV-2 resistance to nucleotide analog-based antivirals. (PubMed, Nat Commun) - "Here, we reveal fundamental insights into how its unique proofreading exoribonuclease (ExoN) counteracts two representative NA antivirals, bemnifosbuvir and sofosbuvir, which are designed to inhibit the viral RNA polymerase (RdRp)...Furthermore, we identify an allosteric regulatory loop of ExoN that promotes the full activation of ExoN but is displaced by the binding of NAs exhibiting resilience to ExoN excision. These discoveries provide a molecular framework for understanding SARS-CoV-2 resistance to NA-based antivirals and highlight mechanisms that could be exploited to improve anti-coronavirus drug design."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Drug-drug Interaction Study of Bemnifosbuvir/Ruzasvir (BEM/RZR) and Ethinyl Estradiol/Levonorgestrel (EE/LNG) (clinicaltrials.gov) - P1 | N=24 | Not yet recruiting | Sponsor: Atea Pharmaceuticals, Inc.

New P1 trial

C-BEYOND: Efficacy and Safety of BEM/RZR vs. SOF/VEL in Subjects With Chronic HCV (clinicaltrials.gov) - P3 | N=880 | Active, not recruiting | Sponsor: Atea Pharmaceuticals, Inc. | Recruiting ➔ Active, not recruiting

Enrollment closed • Hepatitis C • Infectious Disease • Inflammation

MULTISCALE MODELING OF RESULTS: FROM A PHASE 2 STUDY OF AN 8-WEEK COMBINATION REGIMEN OF BEMNIFOSBUVIR AND RUZASVIR IN PATIENTS WITH CHRONIC HEPATITIS C VIRUS INFECTION (AASLD 2025) - P2 | "BEM/RZR for 8 weeks was highly effective in blocking both viral replication and viral assembly/secretion in HCV-infected patients independent of genotype and fibrosis score. The time to cure estimates support 8 wk treatment for non-cirrhotic patients and longer treatment duration (e.g., up to 12 wks) for those with compensated cirrhosis."

Clinical • P2 data • Fibrosis • Hepatitis C • Hepatology • Immunology • Infectious Disease • Inflammation • Liver Cirrhosis

BEMNIFOSBUVIR AND RUZASVIR PROVIDED AS A FIXED-DOSE-COMBINATION DEMONSTRATES HIGH RELATIVE BIOAVAILABILITY TO THEIR INDIVIDUAL FORMULATIONS AND CAN BE DOSED WITH NO REGARD TO FOOD (AASLD 2025) - P1 | "The BEM/RZR FDC was safe and well-tolerated when dosed without or with food or with famotidine. BEM/RZR FDC demonstrated a high rBA to the BEM and RZR individual reference formulations. A HFHC meal or simultaneously co-administered famotidine had no meaningful effect on plasma exposure of the FDC."

Clinical

AT-01B-010: Study of Bemnifosbuvir/Ruzasvir as a Fixed-dose Combination in Subjects With Normal or Severely Impaired Renal or Hepatic Function (clinicaltrials.gov) - P1 | N=28 | Recruiting | Sponsor: Atea Pharmaceuticals, Inc. | Trial completion date: Aug 2025 ➔ Nov 2025 | Trial primary completion date: Aug 2025 ➔ Nov 2025

Trial completion date • Trial primary completion date • Hepatology • Renal Disease

NO IMPACT OF RASS ON THE HIGH EFFICACY OF BEM AND RZR IN COMBINATION: RESISTANCE ANALYSIS FROM A PH 2 STUDY IN HCV-INFECTED PATIENTS (AASLD 2025) - P2 | "Background: Bemnifosbuvir (BEM) and ruzasvir (RZR) are potent pan-genotypic inhibitors of HCV NS5B and NS5A, respectively... The combination of BEM/RZR in this phase 2 study showed strong antiviral activity against all tested HCV genotypes (GT 1-4). VK and PK data indicated most VFs were due to poor adherence and resulted from NS5A resistance to RZR. BEM/RZR is currently in phase 3 development."

Clinical • Hepatitis C • Liver Cirrhosis

In Vitro and Clinical Evaluation of Potential Interactions of Bemnifosbuvir with Drug Transporters. (PubMed, J Clin Pharmacol) - "Phase 1 studies in healthy participants were subsequently conducted to assess the clinical significance of transporter-mediated DDI potentials of bemnifosbuvir as a precipitant using digoxin and rosuvastatin as P-gp and BCRP/OATP1B1 index substrates, respectively...No serious adverse events or drug discontinuations were observed. Dose adjustments are therefore unlikely for drugs that are substrates of P-gp or BCRP/OAT1B1 when coadministered with bemnifosbuvir, and staggered dosing may further reduce any DDI risk."

Journal • Preclinical • Breast Cancer • Hepatitis C • Infectious Disease • Oncology • Solid Tumor

Drug-drug Interaction Study of Omeprazole and Bemnifosbuvir/Ruzasvir (clinicaltrials.gov) - P1 | N=20 | Completed | Sponsor: Atea Pharmaceuticals, Inc. | Not yet recruiting ➔ Completed

Trial completion

Drug-drug Interaction Study of Bemnifosbuvir/Ruzasvir (BEM/RZR) and Digoxin and Rosuvastatin (clinicaltrials.gov) - P1 | N=38 | Completed | Sponsor: Atea Pharmaceuticals, Inc. | Recruiting ➔ Completed

Trial completion

C-Forward: Efficacy and Safety of BEM/RZR vs SOF/VEL in Subjects With Chronic HCV (clinicaltrials.gov) - P3 | N=880 | Recruiting | Sponsor: Atea Pharmaceuticals, Inc.

New P3 trial • Hepatitis C • Infectious Disease • Inflammation

Drug-drug Interaction Study of Omeprazole and Bemnifosbuvir/Ruzasvir (clinicaltrials.gov) - P1 | N=20 | Not yet recruiting | Sponsor: Atea Pharmaceuticals, Inc.

New P1 trial

AT-01B-010: Study of Bemnifosbuvir/Ruzasvir as a Fixed-dose Combination in Subjects With Normal or Severely Impaired Renal or Hepatic Function (clinicaltrials.gov) - P1 | N=28 | Recruiting | Sponsor: Atea Pharmaceuticals, Inc. | Not yet recruiting ➔ Recruiting | Trial completion date: May 2025 ➔ Aug 2025 | Trial primary completion date: May 2025 ➔ Aug 2025

Enrollment open • Trial completion date • Trial primary completion date • Hepatology • Renal Disease

Drug-drug Interaction Study of Bemnifosbuvir/Ruzasvir (BEM/RZR) and Digoxin and Rosuvastatin (clinicaltrials.gov) - P1 | N=36 | Recruiting | Sponsor: Atea Pharmaceuticals, Inc. | Not yet recruiting ➔ Recruiting

Enrollment open