Editor

You could almost hear the sales pitch.

"Hey, buddy, can I interest you in a late-stage cancer drug? Failed in Phase III, yeah, but we had a promising subset. Wait, don't walk away. The drug turns on the immune system - targets the gastrin growth hormone, starves the cancer, get it? Hey, come back. Check out this price."

Receptor BioLogix Inc., though, hardly needed street vendor-like persuasion from Aphton Corp., which sought to sell the fizzled cancer therapy Insegia. Thomas Glaze, CEO of Receptor, said his firm became interested after a venture capital investor - who decided not to help bail out the bankruptcy-bound Aphton with cash - pointed to Insegia not as a fake Rolex but as a serious potential opportunity for a company with more resources. Glaze's firm went for it, agreeing last week to pay Aphton just $750,000 cash for the compound in a bankruptcy sell-off.

Insegia's blow-up when used in combination with Eli Lilly and Co.'s Gemzar (gemcitabine) against pancreatic cancer came in February of last year. Gemzar is an immune suppressor, which "somewhat explains why it not might have been effective, when used with a drug that requires an immune response," as Insegia does, Glaze said.

"It was odd and probably ill conceived," he told BioWorld Financial Watch, adding that Aphton had been "pushed by the FDA, the way we hear it." But the FDA no doubt was acting on its best knowledge several years ago when the agency provided Aphton with guidance on design of the Phase III trial. Things might be different now.

Even if they're not, Glaze pointed out, Insegia - which works by generating antibodies to gastrin and its receptor, which could neutralize the hormone's ability to help cancers grow - did show benefit despite the Gemzar factor against pancreatic cancer in the subset of patients: antibody responders. They represented 70 percent of those in the Insegia treatment group and were said to have achieved a "clinically meaningful difference" in survival.

Better still, Insegia has been tested against stomach cancer when paired with 5FU, a more logical choice, and it worked nicely, according to recently published results, Glaze said, and a monotherapy study by Aphton in Europe also has yielded data in pancreatic cancer that Glaze liked better (despite the missed endpoint) than those from the Gemzar combo trial.

Regulators overseas, he noted, recently adopted a conditional-approval procedure, whereby a safe drug with apparent efficacy can be cleared for marketing, followed by Phase IV trials.

Pancreatic cancer is not only one of the more virulent, but also one of the more challenging for drug developers. Among the failures to make news recently is Therion Biologics Corp.'s Panvac-VF, which late last month failed to meet its primary endpoint of improving overall survival compared with palliative chemotherapy for patients in a second-line setting. That news followed closely the word from Genentech Inc. that the colorectal cancer blockbuster Avastin (bevacizumab) also missed its primary endpoint of overall survival when used, like Insegia, with Gemzar.

Panvac-VF also is an immune stimulator, which prompts the system to destroy cancer cells expressing carcinoembryonic antigen and mucin-1, found on more than 90 percent of pancreatic tumor cells. The vaccine puts together Therion's triad of co-stimulatory molecules (B7.1, ICAM-1 and LFA-3), and is being tested in several studies sponsored by the National Cancer Institute to treat advanced breast, ovarian, colorectal and non-small-cell lung cancers.

Genentech, for its part, plans to keep trying Avastin against 25 types of cancer, and the compound is undergoing 130 trials.

Other would-be products to become casualties against pancreatic cancer include Orathecin, from SuperGen Inc., which - used in combination with Gemzar as a first-line therapy for advanced disease - yielded an estimated median survival of six months in a Phase II study, thus falling short of the threshold for advancing to a Phase III study. The data came in April of this year, well after the company's decision in January 2005 to withdraw its new drug application for Orathecin because the FDA suggested the filing would not support approval, and after the withdrawal of a marketing authorization application in the European Union, as well.

Companies making news lately that have drugs in the pancreatic-cancer space also include Threshold Pharmaceuticals Inc., which dropped its compound for benign prostatic hyperplasia, TH-070, as a result of bombs in Phase II and Phase III. Two months earlier, the firm had disclosed a partial clinical hold on the TH-070 (lonidamine) program due to toxicities associated with elevated liver enzymes.

Investors had put most of their hopes on the BPH drug, but Threshold also has glufosfamide in a pivotal Phase III study as a second-line treatment in metastatic pancreatic cancer, an indication for which it has fast-track status, and a Phase II trial is ongoing to evaluate glufosfamide in combination with (what else?) gemcitabine as a first-line therapy. Top-line results from that study also are expected by year end.

A list of all the potential pancreatic-cancer players would be too long to provide here, but another in the field is ArQule Inc., with ARQ 501, its lead Activated Checkpoint Therapy (ACT) compound. Gained in the $25 million buyout of Cyclis Pharmaceuticals Inc., the technology is at the center of a potential $290 million-plus deal with Roche Holding Ltd. (See BioWorld Financial Watch, April 19, 2004, and Oct. 3, 2005.)

ACT is based on the discovery almost 20 years ago of the DNA damage checkpoint, a critical zone in the cell-division signaling pathway - a landmark finding that led to a Nobel Prize for yeast biologist Leland Hartwell in 2001. An important paper on ACT was published one year ago in Cancer Research, which highlighted data showing the direct activation of human checkpoint kinase 2 caused the death of cancer cells and inhibited their growth and proliferation. Two others appeared in Nature.

Last month, ArQule enrolled and dosed the first patient in a Phase II trial of ARQ 501 in combination with gemcitabine, and plans to sign up 60 to 70 patients with treatment-na ve, unresectable pancreatic adenocarcinoma. The primary endpoint is the objective response rate.

Receptor BioLogix's Glaze said his firm will be evaluating the gastric opportunities with Insegia, but pancreatic and stomach cancers seem the most likely to go after. The compound, after all, has long been known to be active. Figuring out how - and in whom - to test Insegia will be an important task.

"We hope to pick up the pieces and make it work," Glaze said.