Lilly ICOS LLC plans to move tadalafil into a Phase III program for benign prostatic hyperplasia after it reached statistical significance in a Phase II proof-of-concept study.

Tadalafil is the active ingredient in Lilly ICOS' erectile dysfunction drug, Cialis, which was approved in the U.S. in November 2003 and had worldwide sales of $552.3 million in 2004 ($207 million in the U.S.). Bothell, Wash.-based ICOS Corp. partnered with Indianapolis-based Eli Lilly and Co. in October 1998 to form the Lilly ICOS joint venture, which markets Cialis and has worldwide rights to tadalafil for all other indications, including benign prostatic hyperplasia and pulmonary arterial hypertension.

"Benign prostatic hyperplasia, or BPH, represents a very large opportunity for Lilly ICOS," said David Goodkin, ICOS' senior vice president of development and chief medical officer. "The majority of men over the age of 50 suffer from lower urinary tract symptoms as a consequence of BPH. Also, there's a very large overlap of the group of men with BPH who also suffer from erectile dysfunction, and vice versa."

BPH is a non-cancerous enlargement of the prostate gland that can irritate the bladder and exert pressure on the urethra. Its symptoms include difficulty initiating urination, straining to pass urine, frequent urination, repeated awakening at night to urinate, incomplete emptying of the bladder and the inability to urinate. More than half of men older than 50 have symptoms, and more than half of those with the condition also have erectile dysfunction (ED).

While Lilly ICOS has not given a timeline for when it will start Phase III development and submit regulatory filings, Goodkin said tadalafil has the potential to capture a large share of the BPH market since current medications can cause sexual dysfunction side effects, alienating the men who also have ED.

"It's very exciting that there's a potential here for a single agent, tadalafil, to relieve symptoms of both conditions with a single medication," Goodkin told BioWorld Today.

In the Phase II study, the product demonstrated clinically meaningful and statistically significant improvement in the primary endpoint, the International Prostate Symptom Score (IPSS), a seven-item questionnaire that assesses the severity of disease symptoms and the response to therapy. Tadalafil also demonstrated statistically significant improvement relative to placebo on most of the secondary endpoints included in the study.

Patients who took 5 mg of tadalafil once per day over six weeks experienced a mean 2.8-point improvement from baseline in the IPSS, compared to placebo patients who had a mean 1.2-point improvement. By stepping up the dose to 20 mg and continuing therapy once per day over another six weeks, patients showed a mean 3.8-point improvement from baseline in the IPSS, compared to a mean 1.7-point improvement for placebo patients. Lilly ICOS did not release any more information about the endpoints.

"We're saving the details for an appropriate medical meeting," Goodkin said.

In less than 5 percent of the 250 patients that participated in the study, side effects included dyspepsia, back pain and headache, and generally were consistent with other studies involving tadalafil. About 3.6 percent of tadalafil patients discontinued the study due to adverse events, compared with 1.4 percent of placebo patients.

If tadalafil were approved for BPH, Lilly ICOS would be able to use its Cialis sales force, since the same physicians treat both conditions.

"That's part of the appeal," Goodkin said. "The majority of prescriptions for BPH are written by urologists. We already call quite heavily on the urology market, so there's great synergy for our sales force."

About 6 million men in the U.S. and Europe are treated for symptoms associated with BPH. In 2004, sales of medications for the condition in both regions combined were about $2.5 billion.

An inhibitor of the phosphodiesterase type 5, tadalafil is designed to cause relaxation of the smooth muscle within the prostate, the same way it relaxes smooth muscle in blood vessels in penile tissue.

"It's always exciting to have a new mechanism of action to treat any disease condition," Goodkin said. "This is the first PDE5 inhibitor in a registrational clinical trial to help BPH."

In August, Threshold Pharmaceuticals Inc., of Redwood City, Calif., began pivotal trials of its BPH candidate, TH-070, 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. (See BioWorld Today, Aug. 9, 2005.)

ICOS also is developing tadalafil for pulmonary arterial hypertension, and it expects to soon move some of its preclinical molecules into clinical trials for cancer and inflammatory disorders.

ICOS' stock (NASDAQ:ICOS) rose $1.08 Wednesday to close at $26.46.