Erivedge® (vismodegib) for Advanced BCC

Erivedge® (vismodegib) is a first-in-class orally-administered small molecule which is designed to selectively inhibit the Hedgehog signaling pathway by targeting a protein called Smoothened.  Genetic mutations that lead to unregulated activation of Hedgehog signaling are found in basal cell carcinoma (BCC) and medulloblastomas.  Aberrant signaling in the Hedgehog pathway is implicated in over 90% of BCC cases.

Erivedge® is being developed and commercialized by Roche and Genentech under a 2003 collaboration agreement between Curis and Genentech whereby Genentech obtained an exclusive, global, royalty-bearing license with the right to sublicense, to make, use, sell and import small molecule and antibody Hedgehog pathway inhibitors for human therapeutic applications, including cancer therapy.

Erivedge® is approved for use in patients with advanced basal cell carcinoma in the U.S., the 28-member states of the European Union, and several other countries worldwide.  It is also under regulatory review for commercialization in a number of additional territories.  Roche and Genentech are also continuing the development of Erivedge® in less severe forms of BCC as well as development in other non-oncology indications such as idiopathic fibrosis (IPF) and myelofibrosis.

Erivedge®'s marketing approval in various countries and Roche's regulatory submissions in regards to Erivedge® are based on positive clinical data from ERIVANCE BCC/SHH4476g, a pivotal Phase 2 study of Erivedge® in patients with advanced BCC.  The ERIVANCE study enrolled 104 patients with advanced BCC, including metastatic (n=33) and locally advanced BCC (n=71).  Locally advanced BCC patients included patients whose lesions were inappropriate for surgery (inoperable, or for whom surgery would result in substantial deformity) and for whom radiotherapy was unsuccessful or contraindicated.  Metastatic BCC was defined as BCC that had spread to other parts of the body, including the lymph nodes, lung, bones and/or internal organs.  The study was conducted at 31 sites in the United States, Australia and Europe.  Study participants received 150 mg of Erivedge® orally once daily until disease progression or intolerable toxicity.  Tumor responses for metastatic BCC were measured by RECIST criteria. For locally advanced BCC, a novel composite endpoint was designed which included reduction of size of lesions of at least 30% in longest dimension and/or complete resolution of locally advanced BCC ulceration.

The study met its primary endpoint and demonstrated that Erivedge® substantially shrank tumors or healed visible lesions with observed response rates of 43% of patients in the locally advanced BCC cohort, and 30% of patients in the metastatic BCC cohort as assessed by an independent review facility.  The median duration of progression-free survival by independent review for both metastatic and locally advanced BCC patients was 9.5 months.  The median duration of response by independent review was 7.6 months for both metastatic and locally advanced BCC patients.  The median duration of response as assessed by study investigators was 12.9 months and 7.6 months for metastatic BCC and locally advanced BCC patients, respectively.  The median duration on treatment was 10 months and 9.7 months for metastatic BCC and locally advanced BCC patients, respectively.

The most common adverse events observed in the study (observed in greater than 10% of patients) were muscle spasms, alopecia (hair loss), dysgeusia (altered taste sensation), weight loss, fatigue, nausea, diarrhea, decreased appetite, constipation, arthralgias (joint pain), vomiting, and ageusia (loss of taste).  In addition, a total of 3 of 10 pre-menopausal women developed amenorrhea (absence of a menstrual period) while receiving Erivedge®.  Treatment emergent grade 3 laboratory abnormalities included hyponatremia (low sodium) in 6 patients, hypokalemia (low potassium) in 2 patients and azotemia (elevation of blood urea nitrogen) in 3 patients.  Previous animal studies have indicated that Erivedge® is embryotoxic and teratogenic.  The FDA-approved labeling thus carries a boxed warning stating that Erivedge® can cause fetal harm when administered to pregnant women and recommends the use of contraception during and after treatment.

In March 2014, Genentech updated certain investigator-assessed data that the median duration on treatment for all patients had increased to 12.9 months.  Genentech also reported that the median duration of response as assessed by study investigators had increased to 14.8 months and 26.2 months for metastatic BCC and locally advanced BCC patients, respectively.

About BCC and the Hedgehog Pathway

Basal cell carcinoma is the most common type of skin cancer in Europe, Australia and the United States.  The American Cancer Society estimates that each year approximately 2 million people in the US are diagnosed with non-melanoma skin cancer.  Most of these are basal cell carcinomas or BCC.  The majority of BCC lesions are localized to a small area of the skin and are routinely addressed with surgery.  In advanced BCC, which are estimated to account for approximately 1.5% of the diagnosed patients1, the lesion has either recurred in the same location after surgery or radiotherapy, or it may have advanced further into surrounding areas such as sensory organs (ears, nose and eyes), bone or other tissues.

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.  Abnormal Hedgehog signaling due to genetic alterations in the Hedgehog signaling pathway is implicated in more than 90% of all BCC cases, independent of their severity.

1J Clin Oncol 29.  2011; (supple; abstr e16517)


Erivedge® (vismodegib) for Idiopathic Pulmonary Fibrosis

In January, 2016 Roche initiated a study of Erivedge® in combination with pirfenidone in patients with idiopathic pulmonary fibrosis (IPF).  The Phase 1b study is a single arm, multicenter, open label trial designed to assess the safety and tolerability of 150 mg dose of Erivedge® once daily in combination with pirfenidone (up to 2403 mg daily) in patients with IPF currently being treated with pirfenidone. Additional details of the study can be found at www.clinicaltrials.gov (identifier: NCT02648048).

About Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a chronic, debilitating lung disease with unknown cause that occurs in adults and has very poor prognosis.  The disease is characterized by thickening or scarring of lung tissue (fibrosis) over time, resulting in decreased oxygen supply to the brain and other organs.  Currently, there is no cure for IPF and life expectancy for most people is approximately 3 to 5 years after diagnosis.  Respiratory failure is the most common cause of death due to IPF.  The prevalence of IPF is approximately 1 per 5,000 in men and 1 per 7,700 in women. In the United States, the National Heart, Lung and Blood Institute estimates an incidence of approximately 10 to 40 per 10,000 adults.


Erivedge® (vismodegib) for Myelofibrosis

Roche is investigating Erivedge®for the treatment of myelofibrosis in combination with ruxolitinib in patients with intermediate- or high-risk myelofibrosis.  The Phase 1 multicenter study is designed as a randomized, double blind placebo controlled study to evaluate the efficacy and safety of vismodegib in combination with ruxolitinib versus placebo plus ruxolitinib in patients with intermediate- or high-risk myelofibrosis.  Additional details of the study can be found at www.clinicaltrials.gov (identifier: NCT02593760).

About Myelofibrosis

Myelofibrosis is a serious bone marrow disorder that disrupts the body's normal production of blood cells.  The result is extensive scarring in bone marrow, leading to anemia, weakness, fatigue, and often, an enlarged spleen and liver.  The prognosis for myelofibrosis is varied - some people in the good prognostic group can live for many years without major symptoms where as those with poor prognosis progress very rapidly.  In a small subset of patients, myelofibrosis can transform to acute myeloid leukemia, a serious bone marrow cancer with rapid progression and bad prognosis.  According to a study published in 2014 that was based on data from two large health plans, the incidence of primary myelofibrosis in the United States between 2008 and 2010 was 1 per 100.000 per year1.

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1Leuk Lymphoma. 2014; 55(3):595-600