Ready to go. The newly approved Erivedge stems from work initiated by Genentech scientist Frederic de Sauvage in 1996, according to company files. Credit: Genentech

The US Food and Drug Administration's recent approval of Curis/Genentech's Erivedge (vismodegib), is a “watershed event” for the small biotech, according to San Francisco–based RBC Capital Markets biotech analyst Jason Kantor. The approval is all the more notable because it was based on a single-arm, phase 2 study (Nat. Biotechnol. 29, 957, 2011). The drug shrank lesions in 43% of the 100 patients enrolled, for a median duration of 7.6 months. For the S. San Francisco, California–based Genentech, now wholly owned by Roche, the first-in-class compound for otherwise untreatable basal cell carcinoma is unlikely to become one of its bigger products.

News of the approval in late January clashed with a trial failure. Infinity, based in Cambridge, Massachusetts, announced it was stopping its phase 2 trials in pancreatic cancer with Hedgehog pathway inhibitor saridegib for lack of efficacy. The two drugs in question, however, represent two substantively different mechanisms. “There are at least two possible mechanisms of Hedgehog pathway involvement in tumorigenicity and cancer growth,” says Daniel R. Passeri, president and CEO of Cambridge, Massachusetts–based Curis.

The Hedgehog pathway plays a key role in embryonic development. Its dysregulation—either due to mutations and/or as a result of ligand-dependent means—can contribute to tumor growth and survival. In the first cancer-forming mechanism, tumors are driven by a Hedgehog mutation and subsequently depend on upregulated Hedgehog to survive. “In this case, the tumors are addicted to the signaling pathway,” says Passeri. Erivedge binds to, and inhibits, the transmembrane protein Smoothened, which is a key player in Hedgehog signal transduction. Erivedge's success elegantly illustrates the power of tackling the cancer cells' addiction to Hedgehog. Unfortunately, only a few other cancers, including rhabdomyosarcoma and meduloblastoma, are known to follow a similar path.

The second mechanism by which Hedgehog is involved in tumor growth is its upregulation through ligand-dependent signaling from the tumor itself or the surrounding microenvironment. Disrupting that signaling is the approach taken by Infinity with saridegib. Infinity's results contrast starkly with those obtained by Curis/Genentech. Patients taking gemcitabine with saridegib did noticeably worse than those on the standard treatment gemcitabine and placebo. “That's a surprising result that we now need to analyze carefully,” says Julian Adams, Infinity's president of R&D, adding that pancreatic cancer is a notoriously tough indication.

Others are not entirely surprised at Infinity's results. Although the ligand-dependent upregulation of the Hedgehog pathway is well documented, “We have not seen one indication yet where compounds affecting ligand-dependent signaling have worked,” says Mani Mohindru, an analyst at San Francisco–based ThinkEquity. She also points out that, to date, all Hedgehog pathway inhibitors work by inhibiting Smoothened.

Infinity hasn't thrown in the towel yet on saridegib. Two additional phase 2 trials are going forward in chondrosarcoma and myelofibrosis, neither of which is thought to be mutation-driven.

A slew of companies, among them Novartis of Basel, Pfizer of New York, Bristol-Meyers Squibb in collaboration with Exelixis, and Millennium with Takeda are pursuing Hedgehog signaling pathway inhibitors. All are currently in early development (Table 1).

Table 1 Companies developing sonic Hedgehog signaling inhibitors

Erivedge, meanwhile, will soon be tested in other malignancies. “Genentech and the National Cancer Institute are doing a broad swath survey to see where the signal may be observed and follow that with a rationally designed clinical trial,” says Curis' Passeri. Over 20 trials are ongoing in multiple indications, using different drug combinations and dosing.

“The hope,” Passeri says, “is to gain insight on where [Erivedge] has therapeutic application outside of the mutation-driven cancers.”