West Coast Editor

Although its treatment for Crohn's disease missed the primary endpoint in a Phase II trial, Millennium Pharmaceuticals Inc. said the drug hit a secondary endpoint and the company is awaiting results from another Phase II study, this one for ulcerative colitis, with the monoclonal antibody MLN02.

"The diseases are similar, but there are important differences," said John Maraganore, senior vice president of strategic product development for Cambridge, Mass.-based Millennium. He said the trials are different, too, "in terms of patients at entry and how we measure the primary endpoint."

Millennium's shares (NASDAQ:MLNM) dipped 13 percent on the news Monday, or $1.52, closing at $10.19.

The primary endpoint in the 180-day Crohn's trial in 185 patients was a decrease of more than 70 points on the Crohn's Disease Activity Index, met in neither the .5 mg/kg nor the 2.0 mg/kg treatment group. But the secondary endpoint, disease remission, was met by the 2.0 mg/kg group, and MLN02 - which works by binding to a T-cell integrin, alpha4beta7 - was well tolerated by all.

"Remission is probably the endpoint the FDA would view as necessary for approval," Maraganore said.

Increased T-cell trafficking is believed to play a role in Crohn's disease and ulcerative colitis, and data from the Phase II study in the latter indication are expected by mid-2003. The colitis trial will enroll 180 patients, he said.

The drug is partnered with South San Francisco-based Genentech Inc., with which Millennium collaborated in 1997. Under the terms of the deal, Genentech receives exclusive worldwide rights to market MLN02, and Millennium is responsible for developing it through Phase II trials, after which Genentech would finish development.

Under the terms, Millennium can choose to share in the Phase III development costs in return for a share of profits on U.S. sales, while getting royalties on non-U.S. sales. Millennium also gets development milestone payments from Genentech.

"We haven't disclosed the details of the deal, but those milestones are relatively small," Maraganore told BioWorld Today.

Both companies in the deal retain separate rights to develop small-molecule therapeutics for the treatment of inflammatory bowel disease, a category that includes Crohn's disease and ulcerative colitis.

Genentech's stock (NYSE:DNA) closed Monday at $30.83, up 40 cents.

About a million people are believed to suffer from IBD, but the Crohn's disease market is not viewed as huge and an already-successful treatment is Malvern, Pa.-based Centocor Inc.'s anti-inflammatory Remicade (infliximab), approved this summer for Crohn's disease. (See BioWorld Today, July 3, 2002.)

Maraganore conceded that Remicade "has done very well in this market, offering patients a benefit where there's been no benefit before," but he noted the drug targets and binds to tumor necrosis factor-alpha. Millennium, he said, is working with MLN02 on an approach that "allows you to block the disease without having adverse events linked to the broader-based immunosuppression," such as more infections.

"This has been highlighted recently in some of the post-marketing surveillance data" related to Remicade, he said. What's more, Remicade has not been shown effective against ulcerative colitis, he added.

Meirav Chovav, senior biotechnology analyst with UBS Warburg LLC in New York, puts the market at about $100 million.

"We do not think this drug is material to either Millennium or especially Genentech," she told BioWorld Today, adding that the latter has "much bigger fish to fry." Chovav said she did not include projected revenues from MLN02 in her estimates.

Maraganore said MLN02 is "not a big part" of the overall Millennium plan, and noted that the drug came with the company's $635 million takeover of LeukoSite Inc., of Cambridge, Mass. (See BioWorld Today, Oct. 15, 1999.)

About a month ago, another prospective Crohn's disease treatment failed, although it had advanced to Phase III trials. The humanized anti-tumor necrosis factor antibody CDP 571, which is the focus of a development and marketing agreement between Celltech Group plc, of Slough, UK, and Biogen Inc., measured on an intent-to-treat basis, missed its combined primary endpoint of remission and/or a decrease greater than 100 points in Crohn's Disease Activity Index. (See BioWorld Today, July 31, 2002.)

Biogen has another Crohn's disease drug in Phase III trials with Elan Corp. plc, of Dublin, Ireland, called Antegren (natalizumab). The treatment, which also is being tested against multiple sclerosis, has a similar method of action to MLN02, Chovav noted.

"It's been an interesting area," Maraganore said. "Part of the issue is that patient selection and enrollment has been problematic." Placebo response rates have increased, too, he said, which makes determining benefit even more difficult.