Discovery and preclinical development of vismodegib

Abstract

Introduction: Vismodegib is the first Hedgehog (Hh) pathway inhibitor approved in the US for the treatment of adults with metastatic or locally advanced basal cell carcinoma (BCC). It was approved by the US FDA on 30 January 2012, and by the European Commission on 12 July 2013, for the treatment of adult patients with symptomatic metastatic BCC, or locally advanced BCC inappropriate for surgery or radiotherapy. Vismodegib selectively inhibits the Hh signaling pathway, binding to and inhibiting a critical signal-transducing component of the pathway, Smoothened (SMO). Vismodegib was discovered by Genentech, Inc., under a collaboration agreement with Curis, Inc.

Areas covered: This article reviews the development of vismodegib from its discovery, preclinical pharmacology and validation to the clinical pharmacokinetics and validation in Phase I and II clinical investigations. We also provide a survey of other Hh pathway inhibitors in clinical development.

Expert opinion: The authors’ experience in target-based drug discovery suggests that vismodegib’s path to the clinic deserves some reflection to identify key steps that have contributed to its success. Targeting the Hh pathway with vismodegib blocks the abberant signaling caused by mutational inactivation of the negative regulator PTCH1 or mutational activation of SMO. Vismodegib gives physicians a treatment option for patients with locally advanced or metastatic BCC for whom surgery or radiation is not recommended.

Keywords::

• basal cell carcinoma
• Erivedge™
• GDC-0449
• GLI1
• Gorlin’s syndrome
• Hedgehog pathway inhibitor
• Hedgehog signaling pathway
• Patched 1
• Smoothened
• targeted cancer therapy
• vismodegib

Acknowledgments

The authors thank the patients and their families who participated in the clinical studies of vismodegib, and the research and development teams for their effort guiding the discovery and clinical development of this molecule. Vismodegib was discovered by Genentech and was jointly validated through a series of preclinical studies performed under a collaborative agreement between Genentech, Inc. (So. San Francisco, CA) and Curis, Inc. (Lexington, MA).

Notes

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