Washington Editor

Phase III is under way for TH-070, an investigational drug for benign prostatic hyperplasia (BPH) in development by Threshold Pharmaceuticals Inc.

A European trial was launched as the first of two pivotal studies for the product; dosing, safety and efficacy will be measured in subjects with symptomatic BPH. The study has been designed in the footsteps of products already approved for that indication, which the company called the most common urological problem among older men.

"This marks our second product candidate in Phase III trials," said Threshold President George Tidmarsh, noting that glufosfamide already is in Phase III for pancreatic cancer. "So as a company, these late-stage products represent a couple shots on goal, if you will. And with regard to [TH-070], it tells our investors that we have the ability to execute on this program."

The company, of Redwood City, Calif., went public earlier this year, selling 5.3 million shares at $7 apiece, and Tidmarsh added that it has met all development milestones on time since that event. Data from the coming multicenter Phase III trial of TH-070 (lonidamine) are expected in about a year, after which Threshold plans to report its glufosfamide findings.

On Monday, Threshold's shares (NASDAQ:THLD) gained 15 cents to close at $10.01.

The newest study will follow a randomized, double-blinded protocol and enroll about 480 men between 50 and 80 years old. They will be followed for up to four and a half months to measure the trial's primary objective, an efficacy evaluation of 50-mg and 150-mg doses of TH-070 compared to placebo as measured by International Prostate Symptom Scores (I-PSS). The actual dosing period will last three months, after which placebo patients can cross into a drug arm and those already on TH-070 can stick with the regimen to add to the study's safety database.

"I-PSS is the clinically relevant endpoint that's been used for other [BPH] approvals," Tidmarsh told BioWorld Today. "It's clear that this is the endpoint for approval, and it's well-powered to show a difference based on results from our Phase II trial."

To that end, the study is designed to confirm Phase II findings from a month-long, single-center trial held last year in Italy. It met its primary endpoint in demonstrating a mean 11.2 percent reduction in prostate volume measured by transrectal ultrasound at day 28 compared to baseline (p<0.001), as well as all other day-28 endpoints. Also, six months after treatment ended, BPH symptoms remained significantly improved compared to baseline as measured by I-PSS, and additional improvements were seen in measurements of maximum urine flow, post-void urine volume and prostate specific antigen.

"These are all standard for this disease area," Tidmarsh said, adding that such secondary endpoints also will be evaluated in Phase III. TH-070, an oral tablet, is taken daily.

Concurrent with its first Phase III trial, a U.S.-based Phase II study has begun enrolling patients, as well. That ongoing dose-comparison study is testing about 200 patients in a randomized, double-blinded format for up to four and a half months. They could receive placebo or one of four doses of TH-070 daily for 28 days, and will be followed off therapy for an additional three months. Its primary objective is investigating TH-070's dose-response relationship with respect to efficacy and safety.

"The FDA wants some information on the correlation between response and dose, which we anticipated," Tidmarsh said. "It's a smaller study, and we intend to fairly rapidly complete it and then go into an additional Phase III trial."

He projected that later study to get under way in about a year.

The company said BPH affects about 18 million men in the U.S., 28 million in five major European countries and another 8 million in Japan. Should TH-070 eventually receive approval in those territories, Tidmarsh said Threshold would seek partnerships, especially overseas, though no time frame is set in stone.

TH-070, an indazole-3-carboxylic acid, is thought to disrupt energy metabolism by interfering with glycolysis, a production process for glandular prostate epithelial cells, which overgrow in BPH. The company said TH-070 can provide symptom improvement, decreased prostate size, increase in urine flow, decreased serum PSA and limited side effects in treating BPH, as opposed to current drug and surgical therapies that often have slow onset and side effects ranging from decreased libido, sexual dysfunction and reduced quality of life due to cardiovascular effects and/or surgical complications.

"We believe that TH-070's largest advantage over existing, approved therapies is its ability to provide symptomatic relief that a patient needs, while at the same time addressing the underlying enlargement of the prostate," Tidmarsh said. "None of the existing therapies have that duality."

In addition to advancing TH-070 into Phase III, Threshold's pivotal program for glufosfamide is moving ahead according to schedule. About 70 sites are open worldwide, with completion of enrollment targeted for the first half of next year and data due in the second half. That trial began nearly a year ago. (See BioWorld Today, Sept. 14, 2004.)

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