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Endo Pharmaceuticals Inc.'s happy news last week from an interim analysis of its Phase III trial with oral Rapinyl - licensed in North America from the Swiss firm Orexo AB - for breakthrough cancer pain put the spotlight on an $800 million market where the competition grows ever fiercer.

The players to beat: Cephalon Inc.'s Actiq, a fentanyl lozenge on a stick; and market leader Fentora, the next-generation, effervescent fentanyl tablet. Actiq made up about 34 percent of Cephalon's total sales last year, and in the fall, Barr Laboratories Inc. launched a generic version that has eroded sales this year.

Cephalon - which has a license and supply deal with Barr, and sells its own generic Actiq through Watson Pharmaceuticals Inc. - has faced other problems lately. In November, the company reached an agreement with the U.S. Attorney's Office and the Department of Justice to pay $425 million as a settlement of the probe into promotional practices regarding Actiq, the epilepsy drug Gabitril (tiagabine) and Provigil (modafinil) for excessive sleepiness associated with narcolepsy, obstructive sleep apnea/hypopnea syndrome and shift-work sleep disorder.

More recently, the firm reported better news. Earlier this month, the FDA accepted and granted priority review to the new drug application for Treanda (bendamustine) in first-line therapy of patients with chronic lymphocytic leukemia, a therapeutic zone easily as busy as breakthrough cancer pain.

Another up and comer in the latter space is BioDelivery Sciences International Inc., with its late-stage BEMA Fentanyl buccal patch, which yielded positive Phase III results in the spring, with statistically significant improvements in pain scores at 15 minutes, 30 minutes, as well as - in a subjective measure of patient satisfaction - at one hour. Though it's an opioid like Fentora, the BEMA Fentanyl patch showed a better side effect profile, noted Russell McAllister, analyst with Merriman Curhan Ford, who started coverage of BDSI last week with a "buy" rating.

BDSI's FEN-201 study in 80 opioid-tolerant patients deployed a two-week open-label titration period to identify the lowest effective doses, followed by a double-blind, placebo-controlled crossover period of the same length to test BEMA Fentanyl starting five minutes after the dosage and continuing through 60. The summary of pain intensity difference (SPID) served as the primary endpoint.

Patients on the drug gained a statistically significant improvement in SPID at 30 minutes (p<0.004), as well as in various secondary endpoints, including SPID at 15 minutes (p=0.047) and, subjectively, patient satisfaction at 60 minutes (p<0.001). Most were able to build their doses until they reached relief, with only 3 percent - five patients - not reaching that point.

By measures, the well-tolerated BEMA Fentanyl showed a side effect profile matching other opioids, mainly nausea and vomiting plus some instances of somnolence, dizziness and headache. A key finding: no reports of changes to the oral mucosa, which is problematic among Fentora patients, 10 percent of whom got irritation in trials. Three percent ended up with ulcers, and 2 percent of patients dropped out.

BDSI has another Phase III trial ongoing to test long-term safety. The open-label evaluation period will last 90 days or longer, with at least 100 patients at doses from 200 mcg to 2,400 mcg, with some patients from the first study enrolled at the same dose as before, and the company aims to sign up more than 200 more patients, upping their doses by the same methodology as used in the first trial. The FDA requires 100 patients, and these already have been enrolled, but the trial cannot close until all of them either drop out or drug is approved. The NDA for BEMA Fentanyl was filed on Oct. 31, with marketing clearance possible at the end of next August, and launch to follow in the fourth quarter of 2008.

IMS Health's most recent numbers show more than $15 billion in sales of prescription analgesics, a market that could hit $24 billion in 2014. Pain is the cause of about half of all doctor visits and generates over 270 million prescriptions every year. Patients with moderate-to-severe chronic pain typically get either OxyContin (oxycodone), from Purdue Pharma LP, or Endo's Opana (oxymorphone).

Breakthrough pain, though, calls for a fast-acting opioid. Oral drugs as liquid or pills take about half an hour to work. The intravenous route has an obvious disadvantage, and suppositories are inconvenient.

Enter Actiq and Fentora, which together sold $659 million last year. The number for the first half of 2007 (including Barr's generic Actiq) was $314 million. BEMA Fentanyl would wade into that fight, along with Endo's Rapinyl, which could launch in the first half of 2009.

BDSI gained a worldwide license to the BEMA platform (developed by QLT Inc.) through its summer 2004 buyout of the specialty firm Arius Pharmaceuticals Inc., and in August 2006, BDSI bought non-U.S. rights to the technology - small, dissolvable polymer discs that adhere to the lining of the cheek - along with an option to acquire U.S. rights, from QLT for $1 million up front plus $2 million in milestone payments.

If BEMA reaches the market, BDSI stands to keep all gains. The firm exercised its option in September, when the firm paid QLT $3 million up front and $4 million in milestones, thus eliminating any future royalty payments or other liabilities on sales of BEMA Fentanyl or other BEMA products.

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