Erivedge (vismodegib) (advanced BCC)

Under Collaboration with Genentech

Curis’ most advanced program is our Hedgehog pathway inhibitor program under collaboration with Genentech, Inc., a member of the Roche Group.  Erivedge® (vismodegib), a first-in-class orally-administered small molecule Hedgehog pathway inhibitor, is the drug that came out of this collaboration.  Erivedge is being commercialized and developed by Roche and Genentech under a collaboration agreement between Curis and Genentech.  Erivedge is designed to selectively inhibit signaling in the Hedgehog pathway by targeting the Smoothened protein.  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.  However, mutations in the pathway that reactivate Hedgehog signaling are seen in certain cancers, including basal cell carcinoma (BCC).  Abnormal signaling in the Hedgehog pathway is implicated in over 90% of BCC cases.

Erivedge is currently approved for use in patients with advanced basal cell carcinoma in the U.S., the 28-member states of the European Union, Australia, Canada, Ecuador, Israel, Mexico, South Korea and Switzerland.  Erivedge and is also under regulatory review seeking commercialization in several additional other territories and is the subject of a Phase II clinical trial in patients with less severe forms of basal cell carcinoma.  There are a few additional Phase I and II clinical trials ongoing under a collaboration between Genentech and independent investigators and the National Cancer Institute.  Erivedge’s FDA approval and Roche’s regulatory submissions in regards to Erivedge are based on positive clinical data from ERIVANCE BCC/SHH4476g, a pivotal Phase II study of Erivedge in patients with advanced BCC.  

In June 2011, Genentech updated previously reported positive data from ERIVANCE BCC/SHH4476g.  ERIVANCEBCC/SHH4476g is an international, single-arm, multi-center, two-cohort, open-label Phase II study that enrolled 104 patients with advanced BCC, including metastatic (33) and locally advanced BCC (71).  Locally advanced BCC patients include patients whose lesions were inappropriate for surgery (inoperable, or for whom surgery would result in substantial deformity) and for which 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 showing 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 and 7.6 months for metastatic BCC and locally advanced BCC patients, respectively.  The median duration on treatment was 10 and 9.7 months for metastatic BCC and locally advanced BCC patients, respectively.  In June 2012, Genentech updated certain investigator-assessed data as of a May 26, 2011 data cut-off date.  Genentech had previously reported results based on a November 26, 2010 cut-off date.  In its June presentation, Genentech updated that the median duration on treatment for all patients had increased to 12.8 months.

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, which is the absence of a 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.

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