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Discovery and development of telaprevir: an NS3-4A protease inhibitor for treating genotype 1 chronic hepatitis C virus

Nature Biotechnology volume 29, pages 993–1003 (2011)Cite this article

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Abstract

Infection with hepatitis C virus (HCV) is a major medical problem with over 170 million people infected worldwide. Substantial morbidity and mortality are associated with hepatic manifestations (cirrhosis and hepatocellular carcinoma), which develop with increasing frequency in people infected with HCV for more than 20 years. Less well known is the burden of HCV disease associated with extrahepatic manifestations (diabetes, B-cell proliferative disorders, depression, cognitive disorders, arthritis and Sjögren's syndrome). For patients infected with genotype 1 HCV, treatment with polyethylene glycol decorated interferon (peginterferon) α and ribavirin (PR) is associated with a low (40–50%) success rate, substantial treatment-limiting side effects and a long (48-week) duration of treatment. In the past 15 years, major scientific advances have enabled the development of new classes of HCV therapy, the direct-acting antiviral agents, also known as specifically targeted antiviral therapy for hepatitis C (STAT-C). In combination with PR, the HCV NS3-4A protease inhibitor telaprevir has recently been approved for treatment of genotype 1 chronic HCV in the United States, Canada, European Union and Japan. Compared with PR, telaprevir combination therapy offers significantly improved viral cure rates and the possibility of shortened treatment duration for diverse patient populations. Developers of innovative drugs have to blaze a new path with few validated sign posts to guide the way. Indeed, telaprevir's development was once put on hold because of its performance in a standard IC50 assay. Data from new hypotheses and novel experiments were required to justify further investment and reduce risk that the drug might fail in the clinic. In addition, the poor drug-like properties of telaprevir were a formidable hurdle, which the manufacturing and formulation teams had to overcome to make the drug. Finally, novel clinical trial designs were developed to improve efficacy and shorten treatment in parallel instead of sequentially. Lessons learned from the development of telaprevir suggest that makers of innovative medicines cannot rely solely on traditional drug discovery metrics, but must develop innovative, scientifically guided pathways for success.

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Figure 1: Important research and commercial milestones in telaprevir development.
Figure 2: From natural substrate to peptidomimetic: highlights in telaprevir medicinal chemistry strategy.
Figure 3: Challenges in telaprevir formulation.
Figure 4: The role of telaprevir and PR in the treatment regimen.

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Acknowledgements

We would like to thank all patients, study coordinators, nurses and investigators of the telaprevir clinical trials program. We thank the contract manufacturing organizations who contributed to the development and manufacturing of drug substance and drug product. We thank former and current Vertex and Tibotec employees who contributed to telaprevir development. We would like to thank T. Kieffer, J. Kirk and B.G. Rao for assistance with figure preparation; K. Stephan and S. Wu for medical writing and editorial coordination support; and V. Philippon for helpful discussions.

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  1. Vertex Pharmaceuticals, Cambridge, Massachusetts, USA

    Ann D Kwong, Robert S Kauffman, Patricia Hurter & Peter Mueller

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  1. Ann D Kwong
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  2. Robert S Kauffman
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Correspondence to Ann D Kwong.

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All authors are employees and stock owners of Vertex Pharmaceuticals, Inc.

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Kwong, A., Kauffman, R., Hurter, P. et al. Discovery and development of telaprevir: an NS3-4A protease inhibitor for treating genotype 1 chronic hepatitis C virus. Nat Biotechnol 29, 993–1003 (2011). https://doi.org/10.1038/nbt.2020

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