Say "tadalafil," and most industry observers will think "Cialis," from Lilly ICOS LLC, the joint venture between ICOS Corp. and Eli Lilly and Co., a phosphodiesterase type 5 inhibitor for erectile dysfunction.
That drug competes against Pfizer Inc.'s groundbreaking PDE5 blocker Viagra (sildenafil) and yet another compound in the class, Levitra (vardenafil) from Bayer AG and GlaxoSmithKline plc.
But there's more. ICOS Lilly said last fall that the JV plans to try tadalafil in a Phase III study against benign prostatic hyperplasia, a condition of prostate-gland enlargement, the symptoms of which afflict almost all men more than 70 years of age, with about 6 million in the U.S. and Europe who could benefit from treatment. That trial was expected to start this year, but ICOS said in its fourth-quarter earnings report that the FDA wants another Phase IIb dose-ranging study first.
Now, the Phase III trial is delayed until 2007, which slows Lilly ICOS' label-expansion plans - not pleasant news, given an erectile-dysfunction market that analysts have suggested now is saturated.
Meanwhile, coming along is another product for BPH: Threshold Pharmaceuticals Inc.'s TH-070, which began Phase III trials in August. The compound is an indazole-3-carboxylic acid thought to disrupt energy metabolism by interfering with glycolysis, a production process for glandular prostate epithelial cells, which overgrow in BPH.
"We're a competitive company, but we don't really think of it in terms of a race to market," said Denise Powell, senior director of corporate communications for Threshold. "We just want to get our drugs to market as soon as possible so patients can use them."
TH-070, she said, "appears to address the underlying condition itself - it shrinks the prostate," and fairly quickly.
"We saw a pretty rapid reduction in the [results from the International Prostate Symptom Score questionnaire] after 30 days," she told BioWorld Financial Watch, citing a previous Phase II single-center study that was not placebo controlled. "It's apples to oranges, not anything we can compare" to any study of another drug that used placebo, she added, but results published in May proved encouraging just the same.
Threshold made news earlier this month by reporting positive data from the Phase I portion of a Phase I/II dose-escalation study of its glufosfamide in combination with gemcitabine for the treatment of advanced solid tumors and pancreatic cancer. The drug, an alkylating agent, was well tolerated and "warrants further investigation" at the maximum tolerated dose in combination with gemcitabine (Gemzar, from Lilly), the company said.
The company already had a Phase III study with glufosfamide under way. That study began in September 2004, to test the drug against metastatic pancreatic cancer patients refractory to first-line treatment, with a primary endpoint that will compare the median survival of patients treated with glufosfamide and best supportive care to those solely receiving best supportive care. Enrollment is expected to finish in the first half of this year, with data due in the second half.
Glufosfamide would face formidable competition, not only from Gemzar but from Tarceva (erlotinib) from OSI Pharmaceuticals Inc. and Genentech Inc., which was first approved for advanced non-small-cell lung cancer but won clearance in November for advanced pancreatic cancer in treatment-na ve patients in combination with gemcitabine. There's also generic 5-fluorouracil for the condition.
What's more, Camptosar (irinotecan) from Pfizer, and Taxotere (docetaxel), marketed by the Sanofi-Aventis Group, are under investigation as possible combination therapies for first-line pancreatic cancer. And Therion Biologics Inc. is expected to report data soon from its pivotal Phase III trial with Panvac-VF for pancreatic cancer.
Panvac-VF stimulates the immune system to target and destroy cancer cells expressing carcinoembryonic antigen and mucin-1, found on more than 90 percent of pancreatic tumor cells. The vaccine incorporates Therion's triad of co-stimulatory molecules (B7.1, ICAM-1 and LFA-3). In late December, preparing to file a biologics license application this year, Therion secured a $50 million line of credit.
Meanwhile, for BPH, treatments include herbal therapies, surgery and drugs. The two leaders in the last category are the alpha adrenergic receptor blocker Flomax (tamsulosin) from Boehringer Ingelheim GmbH, which sells more than $1 billion per year, and the 5-alpha reductase inhibitor Proscar (finasteride), from Merck & Co. Inc., which sells more than $600 million annually, although both carry side effects that lead some patients to prefer surgery.
Threshold, which went public about a year ago, raising around $37.3 million (5.3 million shares at $7 each) in an initial public offering that had targeted $86.25 million, is conducting the first of two pivotal trials with the BPH drug in Europe. A Phase II study in the U.S. began enrolling patients a few months before the Phase III trial overseas. A dose-comparison study, the Phase II 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. The main goal is to investigate the safety and efficacy of TH-070's dose-response relationship, and results are expected to be made public at the end of this year.
Data thus far with the drug suggested "an improvement in symptoms that appear superior to any single agent approved in BPH, and comparable even to combination therapies, which have a much more significant side effect profile," noted analyst Christopher Raymond, with Robert Baird & Co., in a research report. (He added that glufosfamide's Phase II study in pancreatic cancer "showed similar median survival to Gemzar, but with some promising long-term survivors.")
Threshold itself is doing well. As of Sept. 30, the firm had about $46 million in cash, cash equivalents and marketable securities, and in October offered 6.25 million shares of stock at $10.46 each to raise about $65.4 million.
Analysts at Morgan Stanley initiated coverage of Threshold in October with an "overweight" rating, and Banc of America followed in December with a "buy" rating, but Raymond downgraded the stock to "neutral" and lowered his price target to $16 from $17, citing the company's valuation, reduced news flow and possible dilution with another financing.
Powell said the $100 million or so that's on hand now should last until 2007, and declined to say whether Threshold would seek funds before then.
"It's possible," she said. "We haven't said definitively."