Washington Editor

Millennium Pharmaceuticals Inc. on Monday said it intends to stop development of an oral asthma drug due to safety issues that surfaced during a 193-patient Phase II trial.

According to Millennium, of Cambridge, Mass., and its partner, Taisho Pharmaceutical Co. Ltd., of Tokyo, development of MLN977 was halted when three patients participating in the four-week study for chronic asthma experienced elevations in liver enzymes that were attributed to the drug. MLN977 is a second-generation 5-lipoxygenase (5-LO) inhibitor.

Millennium's stock (NASDAQ:MLNM) closed Monday at $10.50, up 65 cents.

While company officials could not be reached for comment, a press statement said, "The effects on liver function appear to be similar to those noted with previously developed 5-LO inhibitors, in contrast to the company's preclinical and early clinical data that suggested the potential for an improved efficacy to safety margin for MLN977."

Mark Schoenebaum, a biotechnology analyst with CIBC World Markets Corp. in New York, told BioWorld Today that Zyflo (zileuton), an oral 5-LO marketed by Abbott Laboratories, of Abbott Park, Ill., causes severe liver enzyme elevations in 1.9 percent of patients (9.5 times more than placebo in pivotal trials).

"So in our view, Millennium felt that in order to compete successfully with other oral asthma medications, including Zyflo, they needed at least equivalent efficacy with a better safety profile," he said. "It appears, after this trial, they have concluded that the safety profile will not be better than Zyflo."

However, from an efficacy standpoint, MLN977 seems to work fairly well, which helped the company decide to move forward with an inhaled version of the drug. Millennium will seek a partner experienced in inhalation technology to develop the new form of MLN977 for the treatment of asthma and other respiratory diseases such as chronic obstructive pulmonary disease, a statement from the company said.

Research notes released by Yaron Werber, an analyst with SG Cowen Securities Group in New York, said an inhalation form would deliver the compound locally to the lungs, thereby circumventing the hepatic toxicity.

The outcome of the oral trial didn't surprise Schoenebaum.

"MLN977 is a high-risk, high-reward development program," he said. "We considered the risk so substantial that we had not included it at all in our financial models. It was also very early in development. The Phase III program would have been very large, so this drug was years away from the market."

Patients participating in the Phase II trial experienced statistically significant improvements in FEV1, an established measure of airway obstruction. The average improvement in the MLN977 groups during the 14 to 28 days of dosing was approximately 8 percent higher than in the placebo group, the company said.

Millennium also reported that in a separate Phase II trial conducted at four sites in 24 patients with exercise-induced asthma, about 80 percent of patients treated with a single oral dose of MLN977 showed clinical improvements in FEV1, compared to 35 percent after administration with placebo.

While MLN977 could eventually make it to the market in an inhaled form, Schoenebaum said CIBC's investment thesis for Millennium mainly rests upon the future of Velcade (MLN341), an anticancer compound in development for multiple myeloma and solid tumors. (See BioWorld Today, June 13, 2002.)

"We've been very impressed with the efficacy of MLN341 in multiple myeloma, but we've been less impressed with it in solid tumors," he said. "We believe MLN341 causes some neurotoxicity based on our conversations with physicians, but we don't believe that this will be a barrier to uptake in the refractory multiple myeloma setting."

Velcade is being compared to high-dose dexamethasone in a 600-patient randomized, open-label, multicenter Phase III trial in the U.S., Canada and Europe.

Schoenebaum said Velcade could be worth $500 million worldwide annually in multiple myeloma. "If it shows efficacy in solid tumors, it could be worth much more," he said.

Millennium gained the rights to MLN341 in 1999 when it merged with LeukoSite Inc., also of Cambridge, in a $635 million stock deal. (See BioWorld Today, Oct. 18, 1999.)

Also, in that deal, Millennium acquired Campath, the orphan drug for leukemia cleared in May 2001 for marketing. Millennium and partner ILEX Oncology Inc., of San Antonio, developed Campath in a 50-50 joint venture, which was dissolved in November 2001. ILEX now owns Campath. (See BioWorld Today, May 9, 2001, and Nov. 16, 2001.)