Earlier today, the US Food and Drug Administration (FDA)accepted and filed Roche’s New Drug Application (NDA) for vismodegib (GDC-0449)for the treatment of adults with advanced basal cell carcinoma (BCC) for whom surgery is considered inappropriate. The application has been granted Priority Review status and the FDA confirmed the action date is March 8, 2012.

Vismodegib is an investigational, oral, targeted medicine belonging to the 2-arylpyridine class which was discovered by Genentech Inc. and is and jointly validated in collaboration with Curis Inc. through a series of preclinical studies. The drug is designed to selectively inhibit signaling in the Hedgehog (Hh) pathway, which is implicated in tumorigenesis, thus providing a strong rationale for its use in the treatment of a variety of cancers, including more than 90% of all 90% of basal cell carcinoma cases (BCC). Vismodegib suppresses Hh signaling by binding to and interfering with smoothened, a membrane protein that provides positive signals to the Hh signaling pathway. Because of its low toxicity and specificity for the Hh pathway, vismodegib has potential advantages compared with conventional chemotherapy, and may also be used in combination treatments. Clinical trials with other Hh inhibitors are also ongoing and their therapeutic potential will need to be compared with vismodegib.

Most common type of Skin Cancer
Basal cell carcinoma cases is the most common type of skin cancer in Europe [1], Australia [1,2] and the USA [3]. The disease is generally considered curable if the cancer is restricted to a small area of the skin. When the disease advances, BCC can cause disfiguring and debilitating effects and in some patients can ultimately be life-threatening. In a very small group of people, if the disease is left untreated or recurs after surgery, it becomes locally advanced, and the cancer may invade further into surrounding tissues such as sensory organs (ears, nose and eyes), bones or other tissues. In a small proportion of patients (estimated at less than one percent of those affected), BCC can metastasize, spreading to other parts of the body. Currently, there are no effective treatment options for advanced BCC.

The Hedgehog signaling pathway plays an important role in regulating proper growth and development in the early stages of life and becomes less active in adults. In addition to BCC, mutations in the pathway that reactivate Hedgehog signaling are seen in several types of cancer.

?We’re looking forward to working with the FDA on the review of the data,” said Hal Barron, M.D., Chief Medical Officer and Head, Global Product Development. ?We hope to provide people with the first FDA-approved medicine for this potentially disfiguring, and in some cases fatal, disease as soon as possible.?

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Clinical study
The vismodegib application is based on results from the pivotal ERIVANCE BCC/SHH4476g Study, an international, single-arm, multicentre, two-cohort, open-label Phase II study that enrolled 104 patients with advanced BCC, including locally advanced BCC (laBCC) (71) and metastatic BCC(mBCC) (33). laBCC patients had lesions that were inappropriate for surgery (inoperable, or for whom surgery would result in substantial deformity) and for which radiotherapy was unsuccessful or contraindicated. mBCC was defined as BCC that had spread to other parts of the body, including the lymph nodes, lungs, bones and/or internal organs. Study participants received 150mg vismodegib orally, once daily until disease progression or intolerable toxicity.

The trial showed vismodegib substantially shrank tumours or healed visible lesions (objective response rate, or ORR) in 43% of patients with locally advanced BCC (laBCC) and 30% of patients with metastatic BCC (mBCC), as assessed by independent review, the primary endpoint of the study. The ORR as assessed by study investigators, a secondary endpoint, was 60% for laBCC and 46% for mBCC. The median progression-free survival (PFS) by independent review for both metastatic and locally advanced BCC patients was 9.5 months.

The most common drug-related adverse events were muscle spasms, hair loss, altered taste sensation, weight loss, fatigue, nausea, decreased appetite and diarrhoea. Serious adverse events (SAEs) were observed in 26 patients (25%). Four patients (4%) had SAEs that were considered to be related to vismodegib, including one case each of: blocked bile flow from the liver (cholestasis), dehydration with loss of consciousness (syncope), pneumonia accompanied by an inability of the heart to pump enough blood (cardiac failure) and a sudden arterial blockage in the lung (pulmonary embolism). Fatal events were reported in seven patients (7%); none were considered by investigators to be related to vismodegib. In all cases, patients had other pre-existing diseases or symptoms that were related to their presumed cause of death.

Clinical trials
Roche is also evaluating vismodegib in a Phase II trial in people with operable forms of BCC. To help people with advanced BCC (who are appropriate candidates) access to vismodegib while Roche discusses next steps with the European Medicines Agency, the company is conducting a Phase II safety study in the EU and other countries. For more information about available studies, please click here.

[1] N.R.Telfer, G.B.Colver and C.A.Morton. Guidelines for the management of basal cell carcinoma. The British Journal of Dermatology. 2008;158(7):35-48
[2] Gilbody JS, et al. What causes basal cell carcinoma to be the commonest cancer? Aust J Public Health.1994; 18(2):218-21
[3] Von Hoff et al. Inhibition of the hedgehog pathway in advanced basal-cell carcinoma. New Engl J Med. 2009;361:1164-1172.

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