Curis’ most advanced program is our Hedgehog pathway inhibitor program under collaboration with Genentech, Inc., a member of the Roche Group.  The lead drug candidate being developed under this program is Erivedge® (vismodegib), a first-in-class orally-administered small molecule Hedgehog pathway inhibitor.  Erivedge is being 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.

In January 2012, Erivedge was approved by the FDA as the first and only FDA-approved medicine for people with advanced forms of basal cell carcinoma.  Curis earned a $10 million milestone payment from Genentech as a result of the FDA's approval of Erivedge in this indication and the Company is also entitled to receive royalties on Genentech’s net sales of the product. 

During the fourth quarter of 2011, Roche submitted a Marketing Authorization Application, or MAA, for Erivedge to the European Medicines Agency, or EMA, for which we earned a $6 million milestone payment.  Roche has indicated that it anticipates potential EMA approval for Erivedge during the second half of 2012 or the first half of 2013.  Roche has also filed new drug applications in 2012 for marketing registration with Australian, Canadian, Israeli, Mexican and Swiss health agencies seeking approval for Erivedge in advanced BCC.  Curis will receive additional milestone payments if Erivedge receives marketing authorization in Europe and Australia, as well as royalties on any future sales in these territories.

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.  ERIVANCE BCC/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 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 cutoff 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.

About Basal Cell Carcinoma (BCC) and the Hedgehog Pathway

Basal cell carcinoma is the most common type of skin cancer in Europe, Australia and the United States. The disease is generally considered curable if the cancer is restricted to a small area of the skin. In advanced BCC, if the disease is left untreated or recurs in the same location after surgery or radiotherapy, it may advance further into surrounding areas such as sensory organs (ears, nose and eyes), bone or other tissues. Depending on the location of the lesion, some cases of advanced BCC can be disfiguring, and treatment with surgery or radiation can lead to the loss of sensory organs and their functions such as eyesight or hearing.

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 is implicated in more than 90 percent of BCC cases.