Alios BioPharma, Inc. has discovered novel, proprietary, and highly potent nucleoside analogs that are currently in late stage preclinical development for the treatment of chronic hepatitis C.

Due to their broad activity across HCV genotypes and because they exhibit a higher barrier to the selection of drug-resistant virus variants vs. other HCV treatments, nucleoside analogs are emerging as an important component in combination therapy for the treatment of chronic hepatitis C. With excellent potency and selectivity, along with a strong intellectual property estate, the Alios nucleoside portfolio offers a competitive advantage over other existing approaches.

Nucleosides role in the treatment of chronic hepatitis C

Nucleosides exert their activity against the hepatitis C virus by mimicking cellular nucleotides (the building blocks of RNA) and inhibiting RNA synthesis. Through this disruption of RNA production, incomplete and therefore incompetent copies of the hepatitis C viral genome are produced. Nucleoside analogs that have entered development for the treatment of chronic hepatitis C have demonstrated a high barrier to the development of resistance. While nucleoside analogs show great promise for the treatment of chronic hepatitis C, there are a limited number of compounds in development and none have progressed beyond phase II studies.

In order to be active, nucleoside analogs must first be metabolized to the 5’-triphosphate form by cellular kinases in the target cell. The efficiency of these metabolic steps, especially the initial conversion from the nucleoside to the nucleoside monophosphate form, is an important determinant in the efficacy of the compound. Due to this limitation, the first generation of nucleoside analogs entering the clinic for the treatment of chronic hepatitis C required multi-gram dosing levels to be efficacious, and several had to be given twice daily. Given the need for such high and frequent dosing, it is not surprising that most of the first generation nucleoside analogs that entered the clinic were discontinued due to unacceptable safety profiles.

Alios proprietary nucleoside analogs

The Alios clinical development compounds are nucleoside monophosphate prodrugs and thus bypass the need for the formation of the monophosphate form of the nucleoside. As prodrugs, these compounds are expected to be absorbed and penetrate cells more efficiently than their nucleoside counterparts, and the projected doses for these second generation nucleoside analogs are significantly lower than that required for the first generation nucleosides. The Alios compounds have demonstrated excellent oral bioavailability and have the shown the potential to be dosed once daily. These compounds have demonstrated excellent potency against the hepatitis C virus in vitro, and show promising preclinical in vitro and in vivo safety profiles. It is anticipated that the Alios nucleoside portfolio will deliver multiple compounds that will be highly suitable for use in combination treatment of chronic hepatitis C.

About Chronic Hepatitis C

Chronic hepatitis C is a liver disease that results from infection with the hepatitis C virus (HCV) and that currently affects ~170 million people worldwide. HCV infection has two stages, an initial acute stage which may be an asymptomatic, short-term illness, and for 85% of infected individuals, a chronic stage which can progress slowly, without any signs or symptoms for several decades. Chronic infection can lead to liver fibrosis, cirrhosis, end-stage liver disease and hepatocellular carcinoma over a period of 15 to 30 years. Many chronic hepatitis C patients require a liver transplant at late stages of the disease, making HCV infection the most frequent indication for liver transplantation in the United States, Japan and in the European Union.

Interferon based therapy has become the standard of care for the treatment of chronic hepatitis C. While there have been modest advances in improving the tolerability and convenience of interferon-based therapy through Pegylation, the overall efficacy is somewhat limited with <50% of patients infected with HCV genotype 1 achieving a Sustained Virologic Response (SVR). In addition to low response rates, current therapy is associated with numerous side effects. Overall, adverse events result in 10–20% withdrawal from therapy, while an additional 20–30% of patients require dose modifications.

These drawbacks in the current treatment regimen have lead to an active search for new classes of drugs for the treatment of chronic hepatitis C. In recent years there have been significant breakthroughs identifying essential functions within the HCV replication cycle that can be directly targeted for antiviral therapy. The first viral proteins to be clinically validated as therapeutic targets for Direct-acting Antiviral Agents (DAAs) were the NS3/4A protease and the NS5B polymerase. NS3/4A protease and NS5B polymerase are non-structural proteins with well defined enzymatic functions that can be inhibited with small molecules. Similar to what has been achieved against HIV, the advanced development of protease and polymerase inhibitors brings hope for new treatment options for chronic hepatitis C.

When treating viral infections, combination therapy using several drugs with different mechanisms of action has been shown to lead to higher rates of efficacy and better clinical outcomes. It is widely held that nucleoside analog inhibitors of the NS5B polymerase will become critical components of combination therapy for chronic hepatitis C due to their broad activity across the HCV genotypes and because they exhibit a higher barrier to the selection of drug-resistant virus variants vs. other HCV treatments in development. No nucleoside analog has advanced beyond Phase II trials and there is a need to develop additional nucleosides to meet this unmet medical need.