NS5A Inhibitor Daclatasvir Has Dual Mode of Action Against Hepatitis C Virus

The promising investigational hepatitis C virus (HCV) NS5A inhibitor daclatasvir targets 2 steps of the viral replication process, enabling very rapid HCV RNA reduction, according to a mathematical model described in the February 19, 2013, advance edition of Proceedings of the National Academy of Sciences.

The advent of direct-acting antiviral agents has brought about a new paradigm of treatment for chronic hepatitis C, but the real breakthrough is the forthcoming approval of all-oral regimens that eliminate interferon and its difficult side effects.

Some of the most promising interferon-free combinations under study contain NS5A inhibitors such as Bristol-Myers Squibb's daclatasvir (formerly BMS-790052) and Gilead Sciences' GS-5885. While the NS5A enzyme apparently play an important role in viral replication in conjunction with the NS5B polymerase inhibitor, its precise mode of action is not fully understood.

Jeremie Guedj from Los Alamos National Laboratory modeled HCV viral kinetics during treatment in an attempt to determine how NS5A inhibitors work. They noted that daclatasvir shows more rapid and potent antiviral activity than other types of direct-acting agents, reducing HCV RNA levels by about 2 orders of magnitude within 6 hours after administration.

Their model suggested that daclatasvir efficiently blocks 2 distinct stages of the viral lifecycle: HCV RNA synthesis, and assembly and release of new viral particles or virions. While daclatasvir and an experimental polymerase inhibitor (NM107) both reduced intracellular HCV RNA levels in a laboratory study, daclatasvir also led to an "immediate and rapid decline" of extracellular virus levels.

Below is an edited excerpt from a press release issued by Loyola University Health System describing the study and its findings.

New Study on Hepatitis C Drug Treatment In Vivo and In Vitro

February 15, 2013 -- Hepatitis C virus (HCV) infection affects about 4 million in the United States and is the primary cause of liver cirrhosis and liver cancer. Current therapy against HCV is suboptimal. Daclatasvir, a direct acting antiviral (DAA) agent in development for the treatment of HCV, targets one of the HCV proteins (i.e., NS5A) and causes the fastest viral decline (within 12 hours of treatment) ever seen with anti-HCV drugs. An interdisciplinary effort by mathematical modelers, clinicians and molecular virologists has revealed that daclatasvir has two main modes of action against HCV and also yields a new, more accurate estimate of the HCV half-life.

Results of the NS5A study are published in the prestigious Proceedings of the National Academy of Sciences (PNAS) on February 18th, 2013.

"Ultimately, our study will help design better DAA drug cocktails to treat HCV," said Loyola University Health System (LUHS) and Stritch School of Medicine (SSOM) mathematical modeler Harel Dahari, PhD, who co-led the study. Dahari is one of five members of the Division of Hepatology at Loyola headed by Scott Cotler, MD who authored the study along with Thomas Layden, MD, HCV virologist Susan L. Uprichard, PhD and Dr. Uprichard’s PhD graduate student Natasha Sansone. The study was co-led with Jeremie Guedj (Institut National de la Santé et de la Recherche Médicale) and conducted with Drs. Alan Perelson (Senior Fellow at Los Alamos National Laboratory), Libin Rong (Oakland University) and Richard Nettles (Bristol-Myers Squibb).

The new study documents HCV kinetic modeling during treatment both in patients and in cell culture that provides insight into the modes of action of daclatasvir. In addition, the study suggests a more accurate estimate of HCV clearance from circulation previously estimated in 1998 by Drs. Dahari, Layden, Perelson and colleagues in Science.

"Our modeling of viral kinetics in treated patients predicts that daclatasvir not only blocks the synthesis of the viral RNA within infected cells but also blocks the secretion of infectious virus from the cells," explained Dahari. This prediction was confirmed in Dr. Uprichard’s laboratory using cultured liver cells that support the entire life cycle of HCV infection. Drs. Dahari and Uprichard are directors of a new program for experimental and translational modeling recently established at Loyola to promote the type of interdisciplinary research exemplified in this publication.

2/20/13

Reference

J Guedj, H Dahari, L Rong, et al. Modeling shows that the NS5A inhibitor daclatasvir has two modes of action and yields a shorter estimate of the hepatitis C virus half-life. Proceedings of the National Academy of Sciences. February 19, 2013 (Epub ahead of print).

Other Source

Loyola University Health System. New Study on Hepatitis C Drug Treatment In Vivo and In Vitro. Press release. February 15, 2013.