Editor

Glufosfamide's Phase III fizzle in second-line pancreatic cancer pared away almost 60 percent of Threshold Pharmaceuticals Inc.'s value last week and put a dent in hopes raised by Phase II data in late December, but the compound can't be counted out yet.

In the small, earlier Phase II trial, fully 21 percent of patients gained a partial response (including one unconfirmed case), and 36 percent emerged with stable disease. Researchers evaluated 28 who had not previously been given 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. (See BioWorld Financial Watch, Jan. 8, 2007.)

Although preliminary analysis of safety data suggested kidney toxicity might be a bit above the renal trouble seen with previous treatments with glufosfamide or gemcitabine (sold as Gemzar by Eli Lilly and Co.), investors greeted the findings with cautious cheer.

In the 303-patient Phase III study, though, glufosfamide failed to produce a statistically significant improvement in overall survival compared to best supportive care in patients with metastatic disease who had relapsed after chemo with Gemzar. Glufosfamide-treated patients' median survival was 105 days compared to 84 days for patients who received best supportive care (p=0.19). The 148 patients who received the drug were dosed intravenously in 21-day cycles with 4,500 mg/m2 of glufosfamide.

Although the drug "definitely appears to be active," Threshold CEO Barry Selick said during a conference call, he declined to discuss secondary-endpoint results, preserving the full data set for presentation at an upcoming scientific meeting.

"It's probably worth pointing out that the data was only locked this past Thursday afternoon," he said during the Tuesday call, and Threshold officials had been sifting through the results "to this very minute."

Nothing is approved for second-line pancreatic cancer, a particularly challenging foe in the field of oncology, and analyst Joel Sendek with Lazard Capital Markets raised the question of whether it "might make sense to roll the dice and file [for approval] anyway."

Selick said no decision had been made. "We're still analyzing the data, to be quite honest, and we're engaging some outside experts to weigh in on that question," he said. "I think right now the likelihood of that would be low, but I do think that it's important to reserve the option depending on what our further analysis reveals about the data."

Another drug used against the disease is Genentech Inc.'s Tarceva (erlotinib), expected to penetrate 35 percent of the market this year, according to a physician poll by Lazard. Tarceva was cleared 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.

Others with pancreatic-cancer bids that made news lately include Calgary, Alberta-based Oncolytics Biotech Inc., which in February raised C$12 million (US$10.3 million) in a public offering to boost ongoing and planned Phase I and Phase II trials with Reolysin, a formulation of the human reovirus that has been shown to target the activated Ras pathway found in many tumor cells. Oncolytics has widened its early clinical program to monotherapy and combination trials in multiple cancer indications, including a recently approved study testing Reolysin plus Gemzar against advanced pancreatic (as well as lung and ovarian) cancers.

Also last month, Montreal-based Caprion Pharmaceuticals Inc. upped proceeds of a financing related to its takeover of Ecopia Biosciences Inc., also of Montreal, with subscription commitments from investors putting the gross proceeds at the upper end of the deal's projected range of C$30 million (US$25.6 million) to C$45 million. The C$45 million is coming as payment for 180 million units of the new company, to be known as Thallion Pharmaceuticals Inc., issued at a price of C25 cents per unit. Caprion brings to the table CAP-232, a cyclic peptide that acts on the glycolytic pathway in tumor cells, which has finished Phase II trials for metastatic melanoma and is expected to enter the clinic this year for pancreatic cancer.

But the main buzz last week involved glufosfamide. Virginia Langmuir, medical monitor for Threshold in the failed studies, also presided over Genentech's unsuccessful Phase III breast-cancer trial with the colorectal cancer drug Avastin (bevacizumab). She pointed to similarities between the two studies. Both were done in patients with refractory disease who had been previously treated, both were open-label studies, and both had three months as time to measuring the primary endpoint (though progression-free survival was the endpoint with Avastin, compared to overall survival with glufosfamide).

In the case of Avastin, despite the negative outcome in refractory patients, the Phase III study for first-line tumors in breast cancer using Avastin plus Taxol (paclitaxel, Bristol-Myers Squibb Co.) yielded positive results, Langmuir noted. Glufosfamide's blowup "does not necessarily predict negative results in less heavily pre-treated patient populations," she said.

Bret Holley, analyst with CIBC World Markets, said there was "certainly a little bit more theoretical basis" for Avastin's efficacy as a first-line therapy, and this might not be said as confidently for glufosfamide.

Michael Brawer, interim chief medical officer for Threshold, said patients "with less burden of disease may have better overall performance, [and be able to] tolerate longer dosing" with glufosfamide. Selick said patients in the latest study "were very, very ill, and the actual total number of cycles that each patient got was relatively low."

Holley wanted to know if the company had a backup plan for the next six months to nine months, given the glufosfamide delay.

"Threshold is continuously looking for interesting in-license and acquisition opportunities," Selick said. "That would be our first preference, at this point," although not only glufosfamide but also other, earlier stage compounds in the firm's pipeline could draw partners.

Meanwhile, Sendek took 2008's worldwide sales estimates for glufosfamide against pancreatic cancer out of his model, estimating Threshold has enough cash to last through the first half of that year, when the firm expects to offer data from Phase II trials testing the compound in platinum-resistant ovarian cancer and recurrent small-cell lung cancer. Another trial in soft-tissue sarcoma is expected to begin in the second half of 2007.

Holley, for his part, wrote in a research report that he had been "somewhat guarded" about the pancreatic cancer trial, given the indication, but seemed heartened by the results, especially the 18 percent improvement in survival observed with glufosfamide as compared to best supportive care. Without a new product in-licensing, partnership or "other strategic solution," the current year will be "challenging" for Threshold, Holley wrote.