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Gosselin: Telbivudine – from the discovery of its antiviral activity to a marketed drug (Tyzeka®, Sebivo®) for the treatment of chronic hepatitis B

A unique series of simple synthetic l-enantiomer nucleosides had been shown by our former laboratories to inhibit hepatitis B virus (HBV) replication.1 Among them, β-L-2′-deoxythymidine (LdT)2 (Figure 1) or telbivudine (Sebivo®, Novartis Pharmaceuticals, Basel, Switzerland) had the most potent, selective and specific activity against HBV replication, and was selected as an attractive clinical development candidate for the treatment of chronic HBV infection, a worldwide and significant cause of liver-related morbidity and mortality.3

FIGURE 1

Telbivudine (LdT).

Suppl-1-12-fig1.jpg

A novel synthetic route was developed to produce LdT on a 20-gram scale. The intracellular activation and the metabolism of LdT were studied in detail, and its pharmacology and pharmacokinetic profiles were assessed in the woodchuck, cynomolgus monkey and other animal models. These data supported the introduction of LdT (telbivudine) in clinical trials.

Telbivudine was developed by Idenix Pharmaceuticals, Inc., in collaboration with Novartis Pharma AG under a development and commercialization agreement signed in May 2003. In a pivotal international phase III clinical trial, known as the ‘GLOBE study’, which included more than 1350 patients from approximately 135 international clinical centres, telbivudine achieved greater reductions in serum HBV DNA, with a larger proportion of polymerase chain reaction negativity and less resistance than lamivudine (Epivir®, ViiV Healthcare, Brentford, UK) at week 52, which were maintained beyond 2 years.4

On 25 October 2006 and 24 April 2007, telbivudine received approval from the US Food and Drug Administration and the European Medicines Agency to be launched and sold in the USA under the brand name Tyzeka® (Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA) and in the European Union under the brand name of Sebivo®, as a once-a-day oral treatment for patients with chronic hepatitis B. Effective from 1 October 2007, Novartis Pharma AG assumed full responsibility for the development, manufacture and commercialization activities of telbivudine. Currently, telbivudine is approved, as Sebivo®, in more than 90 countries, including Canada, Switzerland, Russia and China.

References

1. 

Bryant ML, Bridges EG, Placidi L, et al. Antiviral l-nucleosides specific for hepatitis B virus infection. Antimicrob Agents Chemother 2001; 45:229–35. http://dx.doi.org/10.1128/AAC.45.1.229-235.2001

2. 

Smejkal J, Sorm F. Nucleic acids components and their analogues. LIII. Preparation of 1-2′-deoxy-β-l-ribofuranosylthymine “l-thymidine”. Collect Czech Chem Commun 1964; 29:2809–13. http://dx.doi.org/10.1135/cccc19642809

3. 

World Health Organization. Hepatitis B. Fact sheet No 204. URL: http://www.who.int/mediacentre/factsheets/fs204/en/

4. 

Liaw YF, Gane E, Leung, et al. 2-Year GLOBE trial results: telbivudine is superior to lamivudine in patients with chronic hepatitis B. Gastroenterology 2009; 136:486–95. http://dx.doi.org/10.1053/j.gastro.2008.10.026





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