Curis, Inc., a drug development company seeking to develop next generation targeted small molecule drug candidates for cancer treatment, announced topline results from a phase II clinical trial conducted by Roche and Genentech, Curis' collaborator and a wholly owned member of the Roche Group, of GDC-0449, a first-in-class Hedgehog pathway inhibitor. GDC-0449 was tested in combination with Avastin (bevacizumab) and FOLFOX or FOLFIRI chemotherapy in first-line metastatic colorectal cancer patients.

Roche has informed Curis that the trial did not meet its primary endpoint of extending the time from randomization to disease progression or death in study patients who received GDC-0449 in addition to the current standard of care of bevacizumab and chemotherapy when compared to those patients that received only the current standard of care treatment. GDC-0449 is being developed by Roche and Genentech under a collaboration agreement between Curis and Genentech. It is expected that data from the Phase II study will be submitted for presentation at a future medical meeting.

"Despite these disappointing results in metastatic colorectal cancer, we remain encouraged that Genentech and Roche's clinical development of GDC-0449 in other cancers continues to make good progress," said Dan Passeri, Curis' president and chief executive officer. "We continue to believe that GDC-0449 may offer potential benefit in other cancer indications because the Hedgehog pathway is thought to act via different mechanisms of action in other tumour types. For example, proof of concept has already been shown in advanced basal cell carcinoma, the subject of a pivotal phase II clinical trial of GDC-0449 being conducted by Roche and Genentech. Further, Roche has indicated that it expects to initiate a phase II clinical trial in operable basal cell carcinoma patients during the second half of 2010 and we believe that this may ultimately greatly expand the commercial opportunity of GDC-0449 in basal cell carcinoma. Basal cell carcinoma is almost always the result of a specific mutation in a component of the Hedgehog pathway, an entirely different mechanism than that of metastatic colon cancer."

Genentech and Roche are also conducting a randomized double-blind placebo-controlled phase II trial in advanced ovarian cancer in a maintenance setting, which is evaluating the ability of GDC-0449 to slow the time to recurrence of cancer in patients whose disease is in complete remission, by impeding the residual cancer cells' ability to grow. Roche has indicated that results from this study are expected during the second half of 2010.

Passeri added, "We also were encouraged by interim safety data from this colorectal cancer study that were presented at this year's ASCO meeting. The data demonstrated a safety profile that was reasonably consistent with that of the first-line metastatic colorectal cancer standard of care treatment of bevacizumab and FOLFOX or FOLFIRI chemotherapy. We believe that this safety profile may provide opportunities for either Genentech or the NCI to test GDC-0449 in combination with chemotherapy and other anticancer agents in other tumour types."

Genentech initiated the phase II colorectal cancer study in May 2008 and completed enrolment in the second quarter of 2009. GDC-0449 was evaluated in this study in 199 patients with metastatic colorectal cancer in combination with the current standard of care in a randomized, placebo-controlled, double-blind Phase II trial. Of the 199 patients enrolled and randomized in this study, 195 received either a FOLFOX chemotherapy or FOLFIRI chemotherapy regimen in combination with bevacizumab every 14 days and were randomized to receive either a 150 mg daily dose of GDC-0449 or a placebo. A total of 123 patients received the FOLFOX chemotherapy regimen plus bevacizumab, with 62 of these patients receiving placebo and 61 receiving GDC-0449. The other 72 patients received the FOLFIRI chemotherapy regimen plus bevacizumab, with 35 of these patients receiving placebo and 37 receiving GDC-0449. Four patients did not receive study drug after randomization. The primary objective of the trial was to measure the period of progression-free survival from randomization to disease progression or death. Secondary outcome measures include the measurement of Hedgehog protein expression in archival tissue and tracking of adverse events.

In addition to this phase II colorectal study evaluating GDC-0449, Genentech and Roche have completed enrolment in a pivotal Phase II trial in advanced basal cell carcinoma (BCC). Results from an earlier Phase I clinical trial demonstrated a 55% response rate in 33 advanced BCC patients. GDC-0449 was well tolerated in this Phase I study, with the most frequent adverse events including muscle spasms, altered taste, weight loss and hyponatremia. Roche has indicated that it expects data from the pivotal Phase II study in 2011 and, pending successful results, that it could also submit regulatory approval submissions in 2011.

Under the ongoing collaboration agreement between Genentech, a wholly owned member of the Roche Group, and Curis, GDC-0449 was discovered by Genentech and was jointly validated through a series of preclinical studies. Through this collaboration, Genentech and Roche are responsible for the clinical development, and Genentech (US), Roche (Ex-U.S. excluding Japan) and Chugai Pharmaceuticals (Japan) are responsible for commercialization, of GDC-0449. Curis is eligible to receive cash payments upon the successful achievement of specified clinical development and regulatory approval milestones, as well as royalties upon commercialization of GDC-0449 by Genentech and its sublicensees, which include Roche and Chugai.

In addition to this colorectal cancer study, GDC-0449 is currently being developed in two additional phase II clinical trials by Genentech and Roche, including a pivotal trial in advanced basal cell carcinoma and a Phase II trial in advanced ovarian cancer. Roche has also indicated that it expects to initiate a Phase II clinical trial in operable basal cell carcinoma patients during the second half of 2010. Through a collaborative research and development agreement (CRADA) with the National Cancer Institute (NCI), the molecule is also being tested in several additional NCI-sponsored trials.