Assistant Managing Editor

Shares of Curis Inc. took a hit on news of a Phase II miss with Hedgehog pathway inhibitor GDC-0449 in colorectal cancer, though it's unlikely to dampen optimism for the drug's ongoing pivotal testing in basal-cell carcinoma (BCC).

In fact, analyst Joseph Pantginis, of Roth Capital Partners, said he still remains "positive on the overall prospects for GDC-0049," which also is being tested in ovarian cancer in a trial run by partner Roche AG, as well as eight additional studies at the National Cancer Institute in multiple tumor types.

That didn't keep Cambridge, Mass.-based Curis' stock (NASDAQ:CRIS) from getting walloped Wednesday - shares closed at $1.69, down $1.57, or 48.2 percent.

Data were disappointing, particularly given that previous studies had shown a link between the growth of colorectal cancer to abnormal expression of the Hedgehog signaling pathway.

There might also be some lingering doubts on the overall drug class, left over from Curis' terminated Hedgehog deals with Wyeth in cardiovascular indications and with Procter & Gamble Pharmaceuticals in hair growth. (See BioWorld Today, March 11, 2008.)

Genentech Inc. (now part of Roche) had been working with Curis in cancer since 2003, and in 2007, announced its plan to move forward with Phase II trials in several indications, news that gave the Hedgehog pathway approach some much-needed validation. (See BioWorld Today, Dec. 13, 2007.)

And since the start of the collaboration, Genentech has "invested heavily in this pathway and mechanism," said Curis President and CEO Dan Passeri.

The big biotech firm has initiated a pivotal Phase II study in BCC, which Passeri characterized as a "very-low-risk-very-high-probability-of-success trial."

Data from an earlier Phase I trial wowed, with GDC-0449 showing a 55 percent response rate in 33 patients with advanced BCC.

If data from the Phase II come back positive, Roche anticipates submitting approval applications in 2011. The Basel, Switzerland-based firm also plans to start a second Phase II trial in operable BCC patients later this year aimed at boosting the drug's potential in the small BCC market. (See BioWorld Today, Sept. 3, 2009.)

Activation of the Hedgehog pathway in cancers such as basal-cell carcinoma and medulloblastoma is mutation-driven. But most other solid tumors involve a different mechanism; they are ligand-driven. Whether that means that the failed first-line colorectal cancer study bodes ill for some of the other solid tumor types is anyone's guess, though analyst Reni Benjamin, of Rodman & Renshaw, suggested in a research note that the "trial design, not the drug, may be the issue."

The trial, which started in May 2008, enrolled 199 patients with metastatic colorectal cancer. All patients received either a FOLFOX or FOLFIRI chemotherapy regimen in combination with Avastin (bevacizumab) and then were randomized to receive either GDC-0449 or placebo. The primary objective had been progression-free survival.

Benjamin said that a higher rate of chemotherapy/Avastin dose reductions in the GDC-0449 arm could be at least partly to blame for the lack of an efficacy signal.

The companies are refraining from speculation until the data can be analyzed further, and hoping that a separate trial in ovarian cancer yields better results.

"We don't know fully why we didn't get the signal we wanted," Passeri told BioWorld Today. "We just have to be patient and wait for the ovarian data to read out."

The Phase II advanced ovarian cancer study is testing GDC-0449 as a single agent in a maintenance setting. That trial will test the drug's ability to slow the time to recurrence of cancer in subjects who have responded to therapy and are in complete remission. Results are expected in the second half of this year.

Genentech's strategy has been to conduct a "broad survey" of GDC-0449 in cancer indications, Passeri said.

"There's been a lot of research into the Hedgehog pathway," he added, with a "growing body of evidence [that Hedgehog activation] is up-regulated in a myriad of cancer types."

Curis and Genentech have the most advanced Hedgehog programs, but they are not alone.

Coming up behind is another Cambridge, Mass.-based firm, Infinity Pharmaceuticals Inc., which is in Phase Ib/II testing with IPI-926 in combination with gemcitabine in pancreatic cancer.

Beyond its Hedgehog program, Curis has been working to build out its cancer portfolio to include several multitarget inhibitors.

The firm recently completed enrollment in a Phase I trial testing CUDC-101, an HDAC, EGFR and HER2 inhibitor, and plans to start a Phase I/II trial in non-small-cell lung cancer in the second half of this year. It also presented promising preclinical data in April for CU-906, a dual HDAC and PI3K/mTOR inhibitor with activity against a range of tumors.

Earlier this year, Curis earned an $8 million milestone payment from Debiopharm SA after the Lausanne, Switzerland-based firm gained approval for a Phase I trial of Debio 0932 (formerly CUDC-305) a heat-shock protein 90 inhibitor.

The company's partnerships have helped keep development costs down. Curis reported operating expenses of $6.9 million for the first quarter, along with net income of $4.8 million, or 7 cents per share. As of March 31, the firm had cash totaling $47.8 million.