Editor

Targeted, lower side-effect therapies get oncology docs excited, but "good" old-fashioned chemotherapy still takes the main vote for cancer - grisly consequences and all. Pharma companies are pushing for solutions to their own medicines.

One is Amgen Inc.'s keratinocyte growth factor Kepivance (palifermin), launched in the U.S. during the first quarter of 2005 for severe oral mucositis in blood-cancer patients undergoing high-dose chemotherapy with or without radiation, followed by a bone marrow transplant.

At the end of the same year, CuraGen Corp.'s velafermin (also known as fibroblast growth factor-20, or CG53135), given less frequently than Kepivance, missed its primary endpoint in a Phase II trial, but showed a 50 percent reduction in grade 3 or 4 oral mucositis incidence in the 0.03 mg/kg velafermin dose arm compared to placebo. CuraGen is carrying the program forward, and started the second, 400-patient Phase II in May of this year, with data expected shortly.

MGI Pharma Inc. expects word this month on the new drug application for Saforis, an oral formulation of glutamine for mucositis, which afflicts about 20 percent of chemo patients. Serenex Inc. kicked off a Phase II study this summer with its lead mucositis product, SNX-1012, in patients with solid tumors, and results are due early next year. And in March, RxKinetix Inc. concluded its end-of-Phase II meeting with the FDA for the mucositis drug RK-0202, and is proceeding with its plans for Phase III development. The Phase II trial tested the compound in head and neck cancer patients.

Last month, Access Pharmaceuticals Inc., of Dallas, submitted a premarket notification 510(k) application to the FDA to market MuGard, an oral rinse that blocked mucositis in 47 percent of patients tested. Despite efforts, Access noted in a press release, there is no "well-accepted" therapy for the condition - which represents a potential $1 billion market.

Mucositis causes ulcers that often make chewing and swallowing a painful ordeal. But much better known, and at least as dreaded, chemo problems are nausea and vomiting. Here, MGI Pharma Inc.'s Aloxi (palonosetron) has been doing well, but a generic competitor on the horizon caused MGI in July to reduce its full-year sales estimates to between $250 million and $270 million. Aloxi is "the drug to beat right now, clearly," said Russell McAllister, analyst with Merriman Curhan Ford & Co.

MGI had been expecting a generic ondansetron (Zofran, from GlaxoSmithKline plc), the first-generation 5-HT3 antagonist, to hit the market at the end of 2006 but, "based upon new market intelligence" and industry trends, the product might become available sooner, MGI told investors as part of the second-quarter earnings report. American Pharmaceutical Partners Inc. in March won approval for its generic Zofran.

Still, MGI "remains confident in [Aloxi's] best-in-class clinical profile," and believes the drug still has growth potential in chemo-induced as well as postoperative vomiting. Joel Sendek, analyst with Lazard Capital Markets, agreed. In a research note, he projected that the firm will "regain nearly all the early 2007 share loss" later that year.

Ondansetron also is the active ingredient in mighty Hana Biosciences Inc.'s oral spray Zensana to prevent chemo-, radiation- and postoperative-associated nausea and vomiting. At the end of the August, the FDA accepted for review Hana's new drug application, and the PDUFA date is April 30. Hana partnered with NovaDel Pharma Inc. for Zensana in North America, and the NDA acceptance triggered a milestone payment for NovaDel.

Zensana is "certainly attractive, relative to the existing products, because most of them are injectables," McAllister said, but the duration of response might not be optimal. "And frankly, in other categories, the advantage of a noninvasive mechanism would be more than it is here. If you're getting chemo, you're already very uncomfortable."

He acknowledged, though, that the discomfort of chemo could make patients that much more grateful for a spray, rather than another needle, and Zensana might lend itself nicely to use in combination with other therapies.

Another company to have news lately in the space - good and bad - is A.P. Pharma Inc., which last week granted to RHEI Pharmaceuticals Inc. an exclusive license to develop and sell APF530, in Phase III trials for preventing acute and delayed chemo-induced nausea and vomiting. The license covers China, Taiwan, Hong Kong and Macau, and A.P. got an undisclosed up-front fee, with possible milestone payments and double-digit royalties in the deal.

That's the good news. The bad news came a few days earlier, when A.P. said enrollment in the trials was going slower than expected, and results won't be available until the second half of next year, rather than the first half - but there may be cause to expect positive data, when they come.

A.P.'s study randomizes 1,350 chemotherapy patients, half getting "moderately emetogenic" chemo and half getting "highly emetogenic," and each half is divided into three arms of about 225 patients each. Participants are given a high dose of APF530, a low dose of the drug, or Aloxi.

The primary endpoint is efficacy in the prevention of both acute and delayed-onset chemo-induced vomiting in patients who get either form of chemo. A.P. wants to show non-inferiority to Aloxi in the treatment of acute vomiting in both moderately and highly emetogenic chemo groups, non-inferiority in delayed-onset vomiting in the moderate group, and superiority in delayed-onset in the highly emetogenic patients.

After the initial treatment period, patients who choose to take more cycles of treatment get either a high or low dose of APF530 - but not Aloxi. A.P., in its press release about the sluggish enrollment, said progress at certain sites was "particularly strong," and a number of patients elected for "multiple cycles of treatment," which means they are getting either a high or low dose of APF530, and apparently it's working.

The delay was "definitely somewhat disappointing, but not terribly unexpected either," McAllister told BioWorld Financial Watch, noting that enrollment in such trials tends to follow a curve - slow, then fast.

"Rather than enrolling a large number of patients at once, doctors tend to test the product somewhat on a small number of patients [first]," he said.

He estimated the market for chemo-induced nausea and vomiting at about $900 million. The post-op nausea market is "somewhat less defined, but I think larger overall," McAllister said. The market for anti-emetics in general is about $2 billion.

"It's a category that's seen surprisingly little development, given its size," he said. "It's a big market, and there's going to be more competitors in the future, certainly."

McAllister predicted A.P.'s product would take 30 percent of the market by 2010, and "that leaves plenty of room for other players," he said.

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