By Karen Pihl-Carey

In a $73 million licensing agreement, Takeda Chemical Industries Ltd., the originator of Interneuron Pharmaceuticals Inc.'s lead product, CerAxon (citicoline), will market the drug in the U.S. and Canada upon approval by the FDA.

Investors responded to the news by boosting Interneuron's stock (NASDAQ:IPIC) 17 percent Thursday as it closed at $4.75, up 68.75 cents.

Under terms of the agreement, Takeda will pay Interneuron $13 million in licensing and other guaranteed payments, and an additional $60 million upon the achievement of regulatory milestones in the U.S. and Canada. Osaka, Japan-based Takeda also will pay royalties on net sales to Interneuron and will cover royalty payment obligations Interneuron has with Ferrer Internacional SA, of Barcelona, Spain.

In return, Takeda will receive exclusive commercialization rights in the U.S. and Canada for CerAxon, which is in a Phase III trial for ischemic stroke.

"This is a very, very significant deal for Interneuron," said William Boni, vice president of corporate communications for Interneuron, "both in terms of cash and in establishing infrastructure for the commercialization of the drug."

With an expected new drug application filing in the first half of 2000 and a "fast-track" designation for citicoline granted by the FDA, the drug could be on the market in late 2000 or early 2001.

If it reaches that stage, the FDA may require Interneuron, of Lexington, Mass., to conduct a Phase IV study, and as part of the licensing agreement, Takeda agreed to pay for the trial. Takeda also will pay for Phase III studies of citicoline for other indications, such as traumatic brain injury, Boni said.

Boni could not give royalty specifics, except to reiterate a statement by Interneuron president and CEO Glenn Cooper, who said the payments would allow the company to "participate meaningfully in the profitability of this compound."

Interneuron submitted an NDA in April 1998 for CerAxon, but later withdrew it when a Phase III trial failed to reach statistical significance. The study included about 100 patients and tested whether 500 milligrams of the drug could reduce the infarct size compared with placebo, and as a secondary measure, whether it could offer improved neurological function. (See BioWorld Today, April 21, 1998, p. 1.)

Interneuron decided to go ahead with another Phase III study, called ECCO 2000 (effects of citicoline on clinical outcome - 2,000 mg), this time making the primary endpoint improved neurological function. That study completed enrollment in August and involved 900 patients on a higher, 2,000 mg, dose of the drug. The patients received the drug for six weeks, then researchers evaluated them for another six weeks. Boni said the results should be available in early January.

"We would make a decision on filing pending the results of the trial," he told BioWorld Today. "And if the results are positive, we would be in a position to file the NDA in the first half of next year."

Interneuron plans to resubmit the NDA under Takeda's name, and Takeda will file in Canada under its name. The two companies will jointly oversee the development and filings of CerAxon in both countries. Takeda intends to market CerAxon through its U.S. subsidiary, Takeda Pharmaceuticals America Inc.

In 1993, Interneuron licensed a patent estate that related to the use of citicoline from the Massachusetts Institute of Technology (MIT). The patents previously were licensed to Ferrer Internacional, but Interneuron licensed the manufacturing rights back and created its own patent estate, conducting some research and filing two other patents. The company also licensed data from two foreign clinical trials done by Takeda, which it used in the first NDA filing and plans to use in the resubmission.

"All of that data will be obtained for the resubmitted NDA," Boni said, "and this is a very nice coming of a full circle in that the U.S. will have the benefit of the marketing expertise of the originator of the drug in Japan."

Boni said about 80 percent of the 700,000 strokes per year in the U.S. are ischemic strokes, which would represent citicoline's target market.

Aside from its lead product, Interneuron has three other compounds in or about to begin Phase III trials. The company is seeking a partner to bring Pagoclone into a Phase III for panic and anxiety, and it recently licensed exclusive U.S. marketing rights for trospium chloride for urinary incontinence from Germany-based Madaus AG. Interneuron expects to take it into a Phase III in late 2000. The company's other advanced-stage product is IP501, which is in a Phase III trial for liver disease.

Earlier this year, Interneuron terminated its Phase III trial of Bextra (bucindolol) to treat heart failure because it demonstrated no significant survival advantage. (See BioWorld Today, July 30, 1999, p. 1.)