Editor

Promising top-line data from a combination trial that tested glufosfamide with gemcitabine against the particularly devilish indication of pancreatic cancer lifted Threshold Pharmaceuticals Inc.'s shares in late December, but wise investors are watching and waiting. They likely won't need to wait long - Phase III results from a single-agent study in second-line disease are due this month.

A strong 21 percent of patients in the small Phase II trial gained a partial response (including one unconfirmed case), and 36 percent came out with stable disease. In all, 29 patients were treated, and researchers evaluated 28 who had previously been untreated with chemotherapy. Five achieved a confirmed partial response, characterized as shrinkage of the longest target lesions by 30 percent, absence of progression of all non-target lesions and no new ones. Ten patients' disease stabilized.

Preliminary analysis of safety data suggests the kidney toxicity might be "slightly higher" than previous treatments with glufosfamide or gemcitabine (sold as Gemzar by Eli Lilly and Co.), but enthusiasm over the results outweighed the finding.

It's tentative enthusiasm.

The response rate is higher than Gemzar has been shown to get in first-line patients (5 percent to 17 percent, with stable disease topping out between 27 percent and 42 percent), analyst Bret Holley with CIBC World Markets pointed out in a research note. But other drugs tried with Gemzar also have boosted response rates, while failing to confer a survival benefit. Six-month and 12-month survival data from the Phase II trial are due later this year.

The American Cancer Society expects the tallied cases of pancreatic cancer in 2006 will reach more than 33,700, and about 32,300 patients will die from the disease. Surgery is an option for only 15 percent to 20 percent of newly found cases, and it's usually followed by radiation and chemo - an approach taken across the board with inoperable tumors (unless the cancer spread; radiation doesn't help much then).

"It's a challenging domain," said Lloyd Segal, president and CEO of Caprion Pharmaceuticals Inc., the Montreal firm that made news last week with a plan to merge with Ecopia BioSciences Inc., also of Montreal. "A lot of things have failed, and a lot people are trying current drugs for other indications and brand new drugs."

Some have asked whether drugs can ever beat pancreatic cancer, a particularly wicked nemesis in the oncology field. The five-year survival rate falls in the low single percentage digits.

"I'm always amazed when press or pharma or venture capitalists ask that question," Segal told BioWorld Financial Watch. "Does [the difficulty] mean we should quit trying? Pancreatic cancer is a killer, but that's a reason to try harder."

Many are trying, and competition is lively in the relatively small indication. Along with Gemzar, there's Genentech Inc.'s Tarceva (erlotinib), expected to penetrate 35 percent of the market this year, according to a physician poll by Lazard Capital Markets. Tarceva, approved in the U.S. and the European Union for patients with locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemo regimen, is expected to grab 22 percent of the second-line NSCLC market and 10 percent of the third-line market.

Tarceva is the subject of a three-way deal between Genentech, OSI Pharmaceuticals Inc., and F. Hoffman-La Roche Ltd. Last month, OSI said the European Committee for Medicinal Products for Human Use recommended approval of the once-daily Tarceva in combination with Gemzar as first-line therapy for metastatic pancreatic cancer. The recommendation followed a request from Roche for a re-examination of the data supporting Tarceva's filing in that indication. Results from the pivotal Phase III study showed a 23 percent improvement in overall survival with Gemzar plus Tarceva vs. Gemzar plus placebo.

Among firms to make headlines recently with pancreatic-cancer bids is Biomira Inc., which started a Phase II trial last week with the thioredoxin inhibitor PX-12, gained through the buyout late last year of ProlX Pharmaceuticals Corp. The study will test two dose levels of PX-12 in advanced patients whose tumors have progressed despite treatment with Gemzar or Gemzar-containing regimens. Funded partially by the National Cancer Institute, the trial will enroll up to 80 patients.

PX-12, a first-in-class small molecule, hits a protein that regulates several transcription factors. Thioredoxin has been linked to the aggressive proliferation of solid tumors including those of the colon, lung and gastric system. The compound also is being studied in an ongoing Phase Ib trial in advanced gastrointestinal cancer. A Phase I trial showed PX-12 to be well tolerated, with seven of 38 patients achieving stable disease of up to 322 days.

In December, GenVec Inc. enjoyed a 37 percent stock jump on interim survival data from its Phase II/III trial of TNFerade in locally advanced pancreatic cancer. Results for the first 51 patients enrolled in the Phase II/III Pancreas Cancer Clinical Trial with TNFerade study, known as PACT, showed a 42.5 percent absolute increase in overall survival when TNFerade was added to chemo-radiation. At one year, survival reached 70.5 percent in the TNFerade plus standard-of-care arm vs. 28 percent for patients in the standard-of-care arm.

The Phase study is designed to enroll 330 patients to be randomized 2-to-1 to receive chemotherapy and radiation for a five-week period, either with or without TNFerade, an adenovector carrying the gene for tumor necrosis factor-alpha. Patients then get maintenance therapy of gemcitabine and possibly Tarceva. Primary endpoint: survival at 12 months. If the data stay good, GenVec probably has enough data to file for approval.

Soon-to-merge Caprion's early stage drug for pancreatic cancer, CAP-232, is a cyclic peptide that acts on the glycolytic pathway in tumor cells. The compound has completed Phase II trials for metastatic melanoma.

"We have not had [CAP-232] in humans in pancreatic cancer, but it's been through extensive preclinical work," said Segal, hopeful that a new mechanism of action will hold the key. "If you include Tarceva and a number of other drugs, many of them are working in the same pathway, and no one has really succeeded there," he said.