International Society for Antiviral Research

Lessons Learned from the Discovery of an HCV protease Inhibitor Applied to the Discovery of an Influenza PB2 inhibitor

Ann Kwong, PhD

Dewpoint Therapeutics, Boston, Massachusetts, United States of America

Developers of innovative drugs have to blaze a new path with few validated signposts to guide the way. Telaprevir, a hepatitis C virus NS3-4A protease inhibitor that was approved in combination with PEGylated interferon and ribavirin in 2011 was no exception. Indeed, telaprevir’s development was put on hold because of its performance in a standard IC50 assay. Data from new hypotheses and novel experiments generated in “midnight experiments” were required to justify further investment and reduce risk that the drug might fail in the clinic (1-3). Lessons learned from telaprevir were applied to the development of a pimodivir, a novel PB2 influenza virus inhibitor in collaboration (4).  These results suggest that makers of innovative medicines cannot rely solely on traditional drug discovery metrics, but must develop innovative, scientifically guided pathways for success. 

1.     Kwong, AD, Perni, RB and Graham, CS. (2019) Development and Marketing of INCIVEK (Telaprevir; VX-950): A First-Generation HCV Protease Inhibitor, in Combination with PEGylated Interferon and Ribavirin (ed. M Sofia). In: Topics in Medicinal Chemistry. Springer, Berlin, Heidelberg.

2.     Kwong, et al (2011) Discovery and development of telaprevir: an NS3-4A protease inhibitor for treating genotype 1 chronic hepatitis C virus. Nat Biotechnol. 29(11):993. 

3.     Perni et al (2006) Preclinical profile of VX-950, a potent, selective, and orally bioavailable inhibitor of hepatitis C virus NS3-4A serine protease. AAC 50(3):899.

4.     Byrn et al (2015)Preclinical activity of VX-787, a first-in-class, orally bioavailable inhibitor of the influenza virus polymerase PB2 subunit. AAC. 59(3):1569.