Staff Writer

Curis Inc. could soon collect an $8 million milestone payment from partner Genentech Inc., assuming the FDA accepts the newly filed new drug application (NDA) for vismodegib (RG3616/GDC-0449) in advanced, inoperable basal cell carcinoma (BCC).

Acceptance of an NDA isn't a given – particularly when that NDA is based on a single-arm Phase II trial. Genentech learned that lesson the hard way: last fall, its breast cancer drug T-DM1 got slapped with a refuse-to-file letter when the FDA decided a single-arm Phase II study wasn't sufficient support for an accelerated approval bid. Two Phase III trials are now under way. (See BioWorld Today, Aug. 30, 2010.)

Analysts don't seem to think vismodegib will face the same fate as T-DM1, despite the fact that it, too, is backed by a single-arm Phase II trial. That study, in 104 patients, showed an overall response rate of 43 percent for locally advanced BCC and 30 percent for metastatic BCC. (See BioWorld Today, June 21, 2011.)

Median progression-free survival was 9.5 months, and Genentech spokeswoman Emmy Wang said it's "challenging to estimate a historical response rate" for the sake of comparison because, although BCC accounts for an estimated 80 percent of skin cancer cases, it is generally curable with surgery so advanced, inoperable BCC is rare.

Wang added that the vismodegib Phase II study was single-arm because there is no adequate comparator to use as a control in a randomized study. The study was designed "as a registrational study in consultation with the FDA," she said.

Analyst Joseph Pantginis of Roth Capital Partners wrote in a research note that he expects the Phase II study to be sufficient for vismodegib's approval. He estimated peak sales of $475 million, assuming a $50,000 price tag and 30 percent penetration of the 30,000-patient advanced BCC market.

That could mean $38 million in peak royalties for Curis, based on Pantginis' assumption of an 8 percent royalty rate. Curis partnered with Genentech on small molecule and antibody inhibitors of the Hedgehog pathway for oncology back in 2003. The $240 million potential deal included $8.5 million up front, and Curis told BioWorld Today in June that it had also received $15 million in research support and an additional $18 million in milestones thus far. (See BioWorld Today, June 12, 2003.)

Pantginis noted that sales could be further boosted if vismodegib is expanded into earlier-stage BCC.

Genentech is conducting a Phase II trial for operable BCC, and various investigator-sponsored trials are under way in other indications. But earlier-stage patients might be put off by the drug's side effects: In the Phase II trial, 25 percent of patients experienced serious adverse events, and there were seven deaths, although none of the deaths were attributed to the drug.

The most common drug-related adverse events were muscle spasms, hair loss, altered taste sensation, weight loss, fatigue, nausea, decreased appetite and diarrhea. At the cut-off date for data collection, 57.6 percent of metastatic BCC patients and 45.1 percent of locally advanced BCC patients remained on treatment.

South San Francisco-based Genentech and parent Roche AG also are in discussions with European regulators regarding a path to approval, which would trigger further milestones and royalties for Curis.

Vismodegib is the most advanced Hedgehog inhibitor in the clinic, and its progress bodes well for the field, which has faced some setbacks.

Previously, Wyeth terminated a Hedgehog deal with Curis in cardiovascular indications, and Procter & Gamble Pharmaceuticals terminated a deal with the biotech in hair growth.

A Phase II trial of vismodegib for colorectal cancer failed, as did a Phase II trial in ovarian cancer. (See BioWorld Today, March 11, 2008, June 17, 2010, and Aug. 10, 2010.)

Research published in The New England Journal of Medicine also detailed that while vismodegib produced a stunning response in a patient with advanced metastatic medulloblastoma, the patient quickly acquired a mutation that prevented the drug from binding and died five months after starting treatment. (See BioWorld Today, Sept. 3, 2009.)

Vismodegib is designed to selectively inhibit signaling in the Hedgehog pathway by targeting a protein called Smoothened. Wang explained that in BCC, components of the pathway inside the cell are mutated, which causes abnormal signaling. In ovarian and colorectal cancers, however, the abnormal signaling is thought to be driven by overproduction of the Hedgehog protein itself.

She added that abnormal signaling in the Hedgehog pathway is implicated in more than 90 percent of BCC cases.

Infinity Pharmaceuticals Inc. is also targeting the Hedgehog pathway with a Smoothened inhibitor.

A Phase Ib/II trial in metastatic pancreatic cancer is under way, and a Phase II trial in myelofibrosis is in the works. Exelixis Inc. and Bristol-Myers Squibb Co. also have a Phase I Hedgehog inhibitor aimed at advanced solid tumors.

Shares of Lexington, Mass.-based Curis (NASDAQ:CRIS) gained 18 cents, to close at $3.09 Monday.