HCV continues to be a recognized healthcare crisis in the US with between 2-4 million people living with HCV, and new challenges continue to hinder progress toward eliminating it globally. New chronic HCV cases in the US of approximately 100,000 are reported each year exceeding annual cures.
The profile of the patient has changed since the introduction of direct-acting antivirals. Today, most US infected patients are younger in age, and infections are highest among the age group between 30-39 years old, they are recently infected and less than 10% are cirrhotic. A high proportion of the current patients take multiple concomitant medications including HIV medications, antipsychotics, statins, and proton pump inhibitors. In addition, populations at the highest risk for HCV are frequently poorly adherent to their medication due to substance abuse disorders including opioid use or other drugs, and mental health disorders.
For this population, a direct acting antiviral with low risk of drug-drug interactions combined with short treatment duration, and no food effect could address the current needs unmet by the existing treatment options.
The combination of bemnifosbuvir and ruzasvir has demonstrated a potential best-in-class profile that combines the most compelling attributes of current HCV drug treatments. Atea’s combination regimen is protease inhibitor-free with a short, 8-week treatment duration, has a low risk of drug-drug interactions and there is no food effect.
We are currently conducting a global Phase 2 clinical trial of bemnifosbuvir, an oral nucleotide NS5B polymerase inhibitor, in combination with ruzasvir, an oral NS5A inhibitor, in treatment-naïve, in HCV-infected patients either without cirrhosis or with compensated cirrhosis. This study is designed to evaluate the safety and efficacy of eight weeks of treatment with the combination consisting of once-daily bemnifosbuvir 550 mg and ruzasvir 180 mg. The trial enrolled 275 HCV-infected, treatment-naïve patients across all genotypes (GT), including the lead-in cohort of 60 patients without cirrhosis. SVR12 results from all patients in the Phase 2 trial are expected during the fourth quarter of 2024.
The primary endpoints of the study are safety and sustained virologic response (SVR) at Week 12 post-treatment (SVR12). Other virologic endpoints include virologic failure, SVR at Week 24 post-treatment (SVR24) and resistance.
In June 2024, Atea presented new data at the European Association for the Study of the Liver (EASL) Congress 2024 from the lead-in cohort (n=60) of the ongoing Phase 2 study of the combination of bemnifosbuvir and ruzasvir for the treatment of HCV. With an 8-week treatment duration, data from the lead-in cohort of non-cirrhotic patients showed a 97% SVR12 rate, which is the primary efficacy endpoint of the study. Among the 60 patients in the lead-in cohort, two subjects (GT1b and GT2b) experienced post-treatment relapse or failure. Each of these patients had low plasma drug levels and similar viral mutations at both the baseline and 12-weeks post-treatment timepoint, which indicate that the relapse or failure was due to treatment non-adherence rather than viral failure due to resistance. These results also showed a 100% SVR12 rate in participants infected with genotype 3 (n=13), a historically difficult-to-treat genotype of HCV. The combination regimen was well tolerated, with no drug-related serious adverse events or treatment discontinuations.
In the lead-in cohort, very rapid viral kinetics were observed with viral load for each patient near or below the lower limit of quantification (LLOQ) at four weeks of treatment, which is supportive of an eight-week treatment regimen for the combination of bemnifosbuvir and ruzasvir. All 60 patients in the lead-in cohort achieved viral load below the LLOQ by the end of the eight-week treatment.
In addition to the clinical trial results at EASL, Atea also presented preclinical data further demonstrating a high barrier to resistance and favorable pharmacokinetics for bemnifosbuvir and a low risk of drug-drug interactions for ruzasvir. Atea has previously reported a low risk of drug-drug interactions for bemnifosbuvir.
In in vitro studies, bemnifosbuvir has been shown to be approximately 10-fold more active than sofosbuvir (SOF) against a panel of laboratory strains and clinical isolates of HCV GT 1–5. In vitro studies have also demonstrated bemnifosbuvir remained fully active against SOF resistance-associated strains (S282T), with up to 58-fold more potency than SOF. The pharmacokinetic (PK) profile of bemnifosbuvir supports once-daily dosing for the treatment of HCV. Bemnifosbuvir has been administered to over 2,200 healthy and HCV-infected subjects and has been well-tolerated at doses up to 550 mg for durations up 12 weeks.
Ruzasvir has demonstrated highly potent and pan-genotypic antiviral activity in preclinical (picomolar range) and clinical studies. Ruzasvir has been administered to over 1,500 HCV-infected patients at daily doses of up to 180 mg for 12 weeks and has demonstrated a favorable safety profile. Ruzasvir’s PK profile supports once-daily dosing.
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.
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