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Erivedge Development Timeline

Date	Event
1940's - 1950's	Sheep-herders observed that normal adult sheep were giving birth to one-eyed lambs. U.S. Department of Agriculture (USDA) investigation revealed that sheep ate corn lilies that caused developing lambs to form a single eye^1,2
1960's - 1970's	USDA scientists identified the compound in corn lilies that causes abnormalities in developing sheep and named the compound “cyclopamine.” Independently, researchers identified mutations in a gene that cause a fruit fly to develop abnormally. The fruit flies look curled up and spiky, which led the scientists to name the gene and pathway “Hedgehog”^1-3
1995	Nobel Prize in Physiology or Medicine awarded for identification of genes, including Hedgehog, that control embryonic development to researchers at European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany and California Institute of Technology (Caltech).¹
1996	Genentech began a project, initiated by Frederic de Sauvage, in the Hedgehog pathway's role in neurology and development and discovered that the pathway plays a role in cancer¹
1996	Genentech scientists published a paper in Nature elucidating Hedgehog pathway signaling in cancer⁴
1998	Genentech scientists published a paper in Nature identifying Hedgehog pathway mutations and abnormal signaling in basal cell carcinoma (BCC)⁵
1998	Genentech conducted a search of compounds that inhibit the Hedgehog pathway¹
2000	Scientists from Johns Hopkins University published a paper in Nature demonstrating that cyclopamine can inhibit the Hedgehog pathway; Genentech searched for a compound that can similarly inhibit the pathway^1,6
2003	Genentech signed a collaboration agreement with Curis for preclinical development of compounds that inhibit the Hedgehog pathway¹
2004	Genentech identified GDC-0449 (Erivedge; vismodegib) and conducted preclinical research in collaboration with Curis¹
September 2006	Genentech submitted an Investigational New Drug (IND) application for GDC-0449 with the U.S. Food and Drug Administration (FDA)¹
December 2006	Genentech scientists published a paper about targeting the Hedgehog pathway in cancer in Nature Reviews Drug Discovery⁷
January 2007	Genentech initiated SHH3925g Phase I study of GDC-0449 in adults with locally advanced or metastatic solid tumors that are refractory to standard therapy or for whom no standard therapy exists. Initial results of the study helped identify GDC-0449 activity in adults with advanced BCC; Genentech amended the study to include additional adults with advanced BCC¹
December 2007	Genentech initiated SHH4429g Phase II study in metastatic colorectal cancer¹
April 2008	SHH3925g Phase I study results were presented at American Association for Cancer Research (AACR) Annual Meeting¹.
May 2008	Genentech initiated SHH4489g Phase II study in advanced ovarian cancer in second or third remission¹
June 2008	SHH3925g Phase I study results were presented at American Society of Clinical Oncology (ASCO) Annual Meeting¹
September 2008	Genentech scientists published a paper in Nature further elucidating Hedgehog pathway signaling, its communication with the environment around the tumor and its role in cancer⁸
January 2009	Genentech initiated pivotal Phase II ERIVANCE BCC (SHH4476g) study in people with advanced BCC¹
August 2009	United States Adopted Name (USAN) Council accepted the name “vismodegib” (pronounced vis-mo-DEJ-ib) as non-proprietary name for GDC-0449 in the United States, defining Hedgehog inhibitors as a new class of molecules¹
September 2009	Genentech scientists published two clinical papers in New England Journal of Medicine: Data from the Phase I study in the advanced BCC subset and separately a case study of vismodegib in a patient with medulloblastoma^9,10
October 2009	Genentech scientists published a paper about vismodegib and mutations in the Hedgehog pathway based on the medulloblastoma patient case report in the journal Science¹¹
October 2010	Genentech initiated Phase II study in operable BCC¹
October 2010	SHH4429g Phase II study results were presented at the European Society for Medical Oncology (ESMO) Congress¹
October 2010	SHH4489g Phase II study results were presented at the ESMO Congress¹
February 2011	World Health Organization (WHO) approved “vismodegib” as generic name, defined Hedgehog Pathway Inhibitors as new class of molecules worldwide¹
June 2011	Pivotal ERIVANCE BCC data presented at European Association of Dermato-Oncology (EADO)¹
September 2011	Genentech submitted new drug application (NDA) for vismodegib to the FDA¹
September 2011	Pivotal ERIVANCE BCC data presented at European Multidisciplinary Cancer Congress (EMCC)¹
October 2011	Pivotal ERIVANCE BCC data presented at European Academy of Dermatology and Venereology (EADV)¹
November 2011	FDA accepted and grants priority review for vismodegib NDA¹
January 2012	FDA approved Erivedge™ (vismodegib) capsule for the treatment of adults with metastatic basal cell carcinoma, or with locally advanced basal cell carcinoma that has recurred following surgery or who are not candidates for surgery, and who are not candidates for radiation.¹²

Important Safety Information and Serious Side Effects

Erivedge can cause your baby to die before it is born (be stillborn) or cause your baby to have severe birth defects
For females who can become pregnant, talk with your healthcare provider about the risks of Erivedge to your unborn child. Your healthcare provider should do a pregnancy test within 7 days before you start taking Erivedge to find out if you are pregnant. Avoid pregnancy by using highly effective birth control before starting Erivedge, and continue during treatment and for 7 months after your last dose. Tell your healthcare provider right away if you have unprotected sex or think that your birth control has failed. For males, always use a condom with a spermicide during sex with female partners while you are taking Erivedge and for 2 months after your last dose, even if you have had a vasectomy
Tell your healthcare provider right away if you or your female partner could be pregnant or thinks she is pregnant while you are taking Erivedge

Exposure to Erivedge during pregnancy:

Pregnant women are encouraged to participate in a program that collects information about exposure and the effects on the mother and her unborn child by calling the Genentech Adverse Event Line at (888) 835-2555.

What should I tell my healthcare provider before taking Erivedge?

If you are pregnant or plan to become pregnant
If you are breast-feeding or plan to breast-feed

What should I avoid while taking Erivedge?

Do not donate blood or blood products while you are taking Erivedge and for 7 months after your last dose.

What are the possible side effects of Erivedge?

The most common side effects of Erivedge are

Muscle spasms
Hair loss
Change in how things taste or loss of taste
Weight loss
Tiredness
Nausea
Diarrhea
Decreased appetite
Constipation
Vomiting
Joint aches

These are not all of the possible side effects of Erivedge. For more information, ask your healthcare provider or pharmacist. Because everyone is different, it is not possible to predict what side effects any one person will have or how severe they may be. If you have questions or concerns about side effects, you should talk to your doctor.

Please see the full Prescribing Information and the Medication Guide that come with this [booklet, letter, etc] for serious side effects and additional important safety information.

References

¹ Data on file.

² Incardona J, Gaffield W, Kapur R, Roelink H. The teratogenic Veratrum alkaloid cyclopamine inhibits Sonic hedgehog signal transduction. Development 1998; 125, 3553-3562.

³ Ingham PW, McMahon, AP. Hedgehog signaling in animal development: paradigms and principles. Gene Dev 2011;15:3059-30870.

⁴ Stone DM, Hynes M, Armanini M, et al. The tumor-suppressor gene patched encodes a candidate receptor for Sonic hedgehog. Nature 1996 Nov 14; 384 (6605):129-34.

⁵ Jingwu Xie, Maximilien Murone, Shuih-Ming Luoh, et al. Activating Smoothened mutations in sporadic basal-cell carcinoma. Nature 1998 Jan 1;391(6662):90-2.

⁶ Taipale J, Chen J, Cooper M, et al. Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine. Nature 2000 Aug 31; 406: 1005-1009.

⁷ Rubin LL, de Sauvage FJ. Targeting the hedgehog pathway in cancer. Nat Rev Drug Discovery 2006; 5:1026-1033.

⁸ Yauch R, Gould S, Scales S, et al. A paracrine requirement for hedgehog signaling in cancer. Nature 2008; 455: 406-410.

⁹ Von Hoff D, LoRusso P, Rudin C, et al. Inhibition of the Hedgehog Pathway in Advanced Basal-Cell Carcinoma. New England Journal of Medicine 2009;361:1164-72.

¹⁰ Rudin C, Hann C, Laterra J, et al. Treatment of Medulloblastoma with Hedgehog Pathway Inhibitor GDC-0449. New England Journal of Medicine 2009;361:1173-8.

¹¹ Yauch R, Dijkgraaf G, Alicke B, et al. Smoothened Mutation Confers Resistance to a Hedgehog Pathway Inhibitor in Medulloblastoma. Science 2009; 326: 572-574.

¹² Genentech. Erivedge (vismodegib) capsule. Full Prescribing Information. 2012