Washington Editor

Bad news for Threshold Pharmaceuticals Inc.: a Phase III trial of glufosfamide missed statistical significance on its primary endpoint, meaning the company isn't likely to file for FDA approval anytime soon.

As a result, investors fled and its shares (NASDAQ:THLD) fell 58 percent on Tuesday, or $2.06, to close at $1.52. Volume was more than 12 times heavier than normal on a generally down-market day.

"It's always hard to say exactly why studies have the outcomes that they do," said Denise Powell, Threshold's senior director of corporate communications, "especially until we dive in deeper on the data, which we're in the process of doing."

In the 303-patient study, the drug failed to produce a statistically significant improvement in overall survival compared to best supportive care in patients with metastatic pancreatic cancer who had relapsed after chemotherapy with gemcitabine, a second-line indication for which there are no approved therapies. Specifically, 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.

Admittedly, the study involved a heavily pre-treated population, patients who "were very, very ill," Threshold CEO Barry Selick said on a conference call. As a result, Powell told BioWorld Today, the majority of patients received two or fewer cycles of therapy, minimizing exposure to glufosfamide. Therefore, those results don't necessarily portend negative findings in the future for other patients in less dire circumstances, they said.

Data on secondary endpoints will be released down the road, following further analysis. The trial began in 2004, when the Redwood City, Calif.-based company was more financially constrained and seeking a quick path for approval, which successful second-line findings likely would have provided. In addition, earlier clinical testing produced a single complete response that lasted for more than five years in the second-line setting, as well as positive survival evidence in a front-line study, providing further rationale for moving into Phase III.

Threshold in-licensed glufosfamide from Baxter Healthcare Corp., of Deerfield, Ill., and would owe a low single-digit royalty if it gets to the market.

The Phase III trial's primary efficacy comparison of overall survival was based on 261 deaths. The hazard ratio of glufosfamide to best supportive care was 0.85 (95 percent confidence interval of 0.66 to 1.08). The latest data translate to an 18 percent higher overall survival rate for those treated with glufosfamide, a good deal lower than the 50 percent improvement Selick conceded to be the study's desired outcome.

Powell said "the odds are low" that Threshold would seek FDA approval on such findings, though she said there would be a meeting with the agency to review the data, and Selick said the company would engage outside consultants on the matter.

Still, because those final numbers trended toward some measure of benefit - the drug "definitely appears to be active," he said, without raising any safety concerns - Threshold isn't giving up on the compound and is continuing studies in earlier-stage pancreatic cancer as well as ovarian and small-cell lung cancers.

Phase II enrollment is complete in patients with locally advanced and/or metastatic pancreatic adenocarcinoma previously untreated with chemotherapy. They are receiving a standard gemcitabine dose plus glufosfamide to investigate the combination's efficacy by measuring response rate, duration of response, progression-free survival, overall survival, six- and 12-month survival and change in serum tumor marker levels. Top-line results demonstrated a 21 percent partial response rate, and final results from 29 patients, including 12-month survival data, are expected by the end of the third quarter or earlier, possibly at June's meeting of the American Society of Clinical Oncology.

"Pancreatic tumors are fairly hypoxic," said Powell, noting that glufosfamide works by up-regulating glucose uptake, mirroring more hypoxic tumors that "tend to have more glucose up-regulation." The drug combines the active part of ifosfamide, a member of the alkylator class of chemotherapy drugs, with a glucose molecule. Such a structure gets the active drug into cancer cells without needing to be broken down by the body, avoiding certain toxicities.

Additionally, the company recently began two Phase II trials to evaluate glufosfamide's activity and safety in women with platinum-resistant ovarian cancer and in patients with recurrent, sensitive small-cell lung cancer. The company also expects to start a clinical trial in soft tissue sarcoma in the first half of this year. Top-line results from those studies, which Powell said are based on ifosfamide's widespread use in these indications, are expected next year.

She indicated Threshold's openness to a marketing partnership down the road, per the right terms.

Elsewhere in its portfolio, the company is continuing to develop 2-deoxyglucose, for which Phase I findings should come out this year. It also has a preclinical candidate called HAP-302, a hypoxically activated prodrug that should lead to an investigational new drug application this year. Last year, a drug for benign prostatic hyperplasia, TH-070 (lonidamine), was abandoned following Phase II and III misses. (See BioWorld Today, July 18, 2006.)

Selick expects Threshold to be able to finance all those operations going forward, with the expectation that its cash reserves would last at least through the middle of next year. As of Sept. 30, the company had $63.5 million in cash and marketable securities, and its next quarterly report is due next week.