Editor

As the impact reverberates from Threshold Pharmaceuticals Inc.'s word earlier this month that the FDA had put Phase II work with TH-070 (lonidamine) for benign prostatic hypoplasia on partial clinical hold because of liver enzyme abnormalities, analysts still are sifting data.

Wall Street hammered Threshold's shares by more than 75 percent on the news, closing at $3.44 that day, and last week had only recovered to around the $4 mark. After the company's stock went to the dogs, so did Christopher Raymond - and his research found "troubling" data from a 1996 canine study with oral lonidamine, which showed unpredictable pharmacokinetics and histolic lesions in the liver after 30 days.

"After further scrutinizing the full universe of lonidamine's clinical and preclinical literature," and after talking with management as well as investigators last week at the American Urology Association meeting in Atlanta, Raymond believed the "market's severe reaction to the discovery of liver toxicity was indeed appropriate," he wrote in a report.

An indazole-3-carboxylic acid, lonidamine apparently disrupts energy metabolism by interfering with glycolysis, a production process for glandular prostate epithelial cells, which overgrow in BPH. The orally administered drug was approved in many European countries in the mid-1980s for cancer, and the drug is given at much higher doses for that indication.

Overseas, lonidamine has been dosed for cancer at 450 mg to 950 mg per day for many months, and sometimes for years. The European Phase III in BPH trial randomized patients to three dosing arms (placebo, 50 mg or 150 mg daily). In the U.S., the Phase II trial randomized patients to five dosing arms (placebo, 5 mg, 25 mg, 50 mg or 150 mg daily).

In Threshold's human research, abnormalities included three serious adverse events after three months of dosing in the Phase III European/Canadian trial (which Threshold halted, as well) and three cases of elevated enzymes in other, ongoing trials.

Liver abnormalities were observed at 50 mg and 150 mg in the European study, and at similar or possibly lower doses in the U.S. Phase II trial at 28 days - and showed up within five days at "extremely high doses" in a recent pharmacokinetic study, said analyst Bret Holley at CIBC World Markets.

Among the three patients with enzyme abnormalities in the Phase III trial, one arrived at the hospital with acute alcohol intoxication, elevated liver enzymes and bilirubin, and jaundice, but the other two had no conditions that might have led to trouble. Since the U.S. study involved 28-day dosing and the overseas study was three months, the extended dosing might be to blame, causing a buildup in toxicity related to the varying pharmacokinetic profiles of patients, Raymond postulated.

In the dog study, results of which were published in Cancer Chemotherapy Pharmacology, lonidamine was given intravenously. The toxicity didn't appear when dogs got the compound orally, but a report did note "cellular changes" at the end of the one-month dosing period, Raymond found.

Threshold, which pointed out in a conference call with investors that Phase II trials in the U.S. had finished and no others were planned when the FDA declared the partial clinical hold, is assembling data from more than 700 patients in the U.S. and Europe who have been given the drug for up to 28 days.

"We will get those in house as quickly as we can and get them analyzed," said Alan Colowick, chief medical officer, adding the analysis is likely to be available in the third quarter.

Meanwhile, Lilly ICOS LLC, the joint venture between ICOS Corp. and Eli Lilly and Co., will be doing another Phase IIb dose-ranging study of tadalafil, the active ingredient in the erectile-dysfunction drug Cialis, for BPH. (See BioWorld Financial Watch, Jan. 30, 2006.)

Already on the market are the alpha adrenergic receptor blocker Flomax (tamsulosin) from Boehringer Ingelheim GmbH, which chalks up more than $1 billion in sales per year, and the 5-alpha reductase inhibitor Proscar (finasteride), from Merck & Co. Inc., which sells more than $600 million annually - although both bring side effects that lead some patients to prefer surgery.

What are Threshold's chances with TH-070? Investigators at the AUA meeting told Raymond that intermittent dosing might be the way forward, "introducing greater clinical complexity," Raymond wrote. Holley's word was "complicated." Since BPH, or swelling of the prostate gland, is not lethal and other drugs are available, the FDA is "likely to err on the side of caution" when evaluating risks and safety, he predicted.

Some "lifestyle" drugs with known toxicities have been allowed on the market, Raymond acknowledged. Among them are Lamisil (terbinafine hydrochloride) from Novartis AG, for toenail fungus, and Accutane (isotretinoin) from F. Hoffmann-La Roche Ltd. for acne.

And though a delay is certain, the challenge of intermittent dosing is not - or wasn't when Threshold officials disclosed the FDA's action.

"We think we have a reasonable sense" of the issues that concern the agency, Colowick said. "We believe and I think FDA agrees that [the plan for the future] would look something like a shorter duration, certainly shorter than has been used in the current European study."