Combination of bemnifosbuvir and ruzasvir for HCV

Seeking to improve upon the standard of care

We are developing bemnifosbuvir in combination with ruzasvir for the treatment of HCV. The combination of bemnifosbuvir and ruzasvir has the potential to improve upon the current standard of care by offering a short duration, pangenotypic, protease inhibitor-free treatment for patients with HCV, with or without cirrhosis. As single agents, both bemnifosbuvir and ruzasvir have demonstrated potent pan-genotypic antiviral activity against HCV.

Bemnifosbuvir has been shown to be approximately 10-fold more active than sofosbuvir (SOF) in vitro against a panel of laboratory strains and clinical isolates of HCV genotypes 1–5. In vitro studies demonstrated bemnifosbuvir remained fully active against SOF resistance-associated strains (S282T), with up to 58-fold more potency than SOF. In clinical studies to date, the pharmacokinetic profile of bemnifosbuvir supports once-daily dosing for the treatment of HCV and bemnifosbuvir has been well tolerated at doses up to 550 mg for durations up to 8-12 weeks in healthy and HCV infected subjects.  Rapid and potent pan-genotypic antiviral activity was observed with bemnifosbuvir in HCV infected subjects, regardless of cirrhosis status.

Ruzasvir, an oral NS5A inhibitor, has demonstrated highly potent and pangenotypic antiviral activity in preclinical (picomolar range) and clinical studies.  Ruzasvir has been administered to over 1,200 HCV-infected patients at daily doses of up to 180 mg for up to 24 weeks and has demonstrated a favorable safety profile. Ruzasvir’s PK profile supports once-daily dosing.

Based on our preclinical and clinical data to-date, the combination of bemnifosbuvir and ruzasvir has the potential to offer the following potential benefits:

  • Convenient and short duration (eight weeks) protease inhibitor-free treatment in HCV‑infected patients with or without cirrhosis.
  • Equivalent antiviral potency across all genotypes, regardless of cirrhosis status, including the difficult to treat genotype-3 population.
  • Obviate the need for extensive pretreatment assessments, including genotyping, procedures to assess cirrhosis, and liver function assessment.
  • Well tolerated regimen, with low potential for drug-drug interactions.

HCV Phase 2 Program

We are conducting a Phase 2 trial of bemnifosbuvir in combination with ruzasvir in treatment-naïve, HCV-infected patients either without cirrhosis or with compensated cirrhosis.  This study is designed to evaluate the safety and efficacy of the pan-genotypic combination consisting of 550 mg QD of bemnifosbuvir and 180 mg QD of ruzasvir after eight weeks of treatment.  Approximately 280 HCV-infected, direct-acting antiviral naive patients across all genotypes, including a lead-in cohort of approximately 60 patients are expected to enroll in this Phase 2 study. The primary endpoints of the study are safety and sustained virologic response (SVR) at Week 12 post-treatment. Other virologic endpoints include virologic failure, SVR at Week 24 post-treatment and resistance.

Rationale supporting the combination of bemnifosbuvir and ruzasvir for HCV

In support of the development of the combination of bemnifosbuvir and ruzasvir in patients, we conducted in vitro synergy experiments in HCV GT1b replicon assays (Huh-luc/neo-ET), where HCV replicon cells were treated with multiple concentrations of AT-511, the free base of bemnifosbuvir, and ruzasvir either alone or in combination.  As shown in the figure below, these experiments demonstrated that the combination resulted in substantially greater inhibition of HCV replication than either agent alone, suggesting a synergistic antiviral effect between the two inhibitors.