By Lisa Seachrist

Washington Editor

Interneuron Pharmaceuticals Inc.'s stock plummeted on news its neuroprotective drug CerAxon (citicoline) failed to prove more effective than placebo in a Phase III clinical study of the drug in moderate to severe ischemic stroke.

Interneuron's stock (NASDAQ:IPIC) fell 59 percent in heavy trading to close at $2.812, down $4.125 a share, when a preliminary analysis of the study showed the drug hadn't proven its efficacy.

The study, called ECCO 2000 (effects of citicoline on clinical outcome-2000 mg), of 899 patients suffering from moderate to severe stroke and treated with either a placebo or 2000 milligrams of CerAxon failed to meet its primary endpoint: a seven-point improvement on the National Institutes of Health Stroke Scale over a 12-week period. The preliminary analysis did show some secondary endpoints were met.

"Where does the product stand right now? That's the $64,000 question," said William Boni, vice president of corporate communications for Lexington, Mass.-based Interneuron. "The fact that you missed a primary endpoint makes it hard to salvage the trial for supporting an NDA [new drug application]. For now, we will have to mine the data and consult with our partner, who has the ultimate say in what happens."

In early December, Interneuron licensed the rights to CerAxon in the U.S. and Canada to Takeda Chemical Industries Ltd. for up to $73 million (see BioWorld Today, Dec. 3, 1999, p.1). The companies had expected to file an NDA for the drug under Takeda's name in late 2000 or early 2001. That filing is delayed by the results of the study.

While the study failed to meet its primary endpoint, there was a strong positive trend at the end of the 12-week trial period, Boni said. In addition, a higher proportion of patients treated with CerAxon achieved a secondary endpoint, complete or near-complete recovery of neurological function, as measured by the Rankin Scale. This result reached statistical significance. A higher percentage of CerAxon-treated patients experienced a full neurological recovery and had a reduction in the size of their stroke, but neither result achieved statistical significance.

Boni also noted the trial showed a remarkable placebo effect. The placebo response rate in the study exceeded 50 percent - much higher than what had been seen in previous Phase III studies.

"It was quite a shock that this trial failed," Boni said. "We were very surprised by the high placebo response rate. It makes it difficult for there to be a separation between the drug and placebo at a 50 percent response rate."

This is the fourth Phase III clinical trial for CerAxon. The first study, a Phase II/III study, proved positive. The second trial failed to meet it primary endpoint, but patients with severe and moderate ischemic stroke showed significant improvement.

The third trial excluded patients with mild stroke and treated others with 500 milligrams of CerAxon per day. However, the study included only 100 patients and had as its primary endpoint a reduction in infarct size. That trial failed as a result of an unexpectedly high placebo effect as well. This most recent trial attempted to sidestep the earlier pitfalls by using a higher dose of the drug, employing neurological function as the primary endpoint and using a very large study population.

Nevertheless, the fourth trial failed as well. Said Boni: "Stroke has been a notoriously difficult indication to establish clinical benefit."

Interneuron submitted an NDA in April 1998 for CerAxon, but later withdrew it when the third Phase III study failed. Interneuron then decided to initiate ECCO 2000. Any further decisions about the drug will be made by Interneuron's partner, Takeda.

Citicoline is approved for the treatment of stroke and age-related memory loss and motor skills loss in more than 20 countries. The drug works by stimulating the production of membrane in damaged nerve cells, which helps the cells survive.

Aside from CerAxon, Interneuron has three other compounds in or about to begin Phase III trials. The company recently licensed worldwide rights to Warner-Lambert Co., of Morris Plains, N.J., to bring pagoclone into Phase III development for panic and anxiety. The company also 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 study in late 2000. The company's other advanced stage product is IP501, which is in a Phase III trial for liver disease.