Complete findings from Interneuron Phase III citicoline stroke trial underscore improvement in neurological function, include additional positive outcome measures.

LEXINGTON, Mass.--(BUSINESS WIRE)--March 28, 1996--Complete finings from a recently concluded Phase III trial with citicoline conducted by Interneuron Pharmaceuticals Inc. (NASDAQ: IPIC) underscore a statistically and clinically significant improvement in the recovery of patients suffering from ischemic stroke who were treated with citicoline compared with patients who received placebo.

The findings, presented today at the 48th Annual Meeting of the American Academy of Neurology, were based upon a broad range of clinical outcomes, including several not available at the time of a previous preliminary announcement.

"Findings from this trial with citicoline reflect a similar degree of efficacy to that of the clot-dissolving drug, t-PA reported previously," said Wayne L. Clark, M.D., director of the Stroke Center at Oregon Health Sciences University. "The broad window of treatment opportunity for citicoline, up to 24 hours post-stroke, combined with its oral dosage form and its well-tolerated nature suggest that citicoline may be the most practical treatment currently under development for stroke."

Analyses conducted subsequent to the announcement of preliminary results indicate that citicoline hastens the time to recovery, improves the mental function of patients and limits the size of the infarct, or extent of damage, caused by interruption of blood flow.

In the trial, 259 patients with ischemic stroke were enrolled within 24 hours following the onset of symptoms. The average time from onset of symptoms to initiation of treatment was approximately 14 hours. Patients were randomly assigned to receive placebo or one of three oral doses of citicoline (500 milligrams, 1000 milligrams or 2000 milligrams daily) for six weeks and were monitored for an additional six weeks.

The primary efficacy outcome in the study was improved neurologic function, as assessed by the Barthel Index, which utilizes a 100-point rating scale. Among patients who received 500 milligrams daily of citicoline 53 percent achieved a score of 95 or greater on the Barthel Index at 12 weeks, indicative of complete or near-complete recovery from stroke, compared with 33 percent of placebo-treated patients (p<0.04). This significantly greater improvement can also be expressed as the probability that for every 100 stroke patients treated with 500 milligrams of citicoline within 24 hours of symptom onset, approximately 20 more would achieve complete or near-complete recovery than if treated with placebo.

As previously reported, patients in both the 500 milligram and 2000 milligram groups exhibited significantly greater (p<0.05) improvement on the Barthel Index at week 12 than placebo-treated patients. New information presented today indicates that the rate of improvement was significantly faster for these treatment groups than for the placebo group (p<0.02), with patients receiving 500 milligrams per day achieving complete or near-complete recovery two weeks faster than placebo-treated patients. In addition, more patients in the 500 milligram and 2000 milligram groups exhibited normal or near normal scores in mental function (p<0.04), as measured by the Mini-Mental State Exam, which grades the cognitive state of patients.

Also, patients who received 500 milligrams of citicoline daily were more than twice as likely to manifest minimal or no disability at 12 weeks following stroke as patients who received placebo, as measured by the NIH Stroke Scale. The NIH Stroke Scale analysis showed that 34 percent of all citicoline-treated patients vs. 16 percent of placebo-treated patients achieved complete or near-complete normalization of function, as indicated by scores 0 to 1, at 12 weeks following stroke (p<0.04).

In addition, global neurologic status, assessed by another well-known measurement, the Rankin Scale, was significantly improved (p<0.04) with citicoline treatment compared to placebo.

Efficacy outcome measures for the 1000 milligram daily group did not reach statistical significance in this trial. Patients in the 1000 milligram group had statistically significantly higher body weight on baseline entry into the study compared to the other treatment groups. Researchers believe that this and other confounding variables may explain the performance of the 1000 milligram group in the trial.

It was also reported today that a small subgroup of patients were studied at the Beth Israel Hospital in Boston with a specialized imaging technique to measure the size of the infarct, or damage caused by the stroke. Analysis of this group of patients suggests that citicoline treatment limited the size of infarct following interrupted blood flow. A larger trial to confirm this finding is in progress.

"Measurements of changes in infarct volume among these patients through their course of treatment suggest that one important effect of citicoline in stroke may be its limiting the size of the infarct," said Steven Warach, M.D., Ph.D, assistant professor of neurology and radiology, Harvard Medical School, chief, division of cerebrovascular disease, at Beth Israel Hospital in Boston, and a citicoline clinical investigator. "This finding is consistent with our understanding of citicoline as an agent that favorably alters the cascade of harmful events following a stroke in multiple ways."

There was no significant difference in the incidence of death among the four treatment groups in the trial. All doses of citicoline were well tolerated, as indicated by analyses of adverse events and laboratory findings. The only statistical significant differences among citicoline-treated patients vs. placebo-treated patients were an increase in dizziness and accidental injuries, eg. falling down. However, the 500 milligram dose citicoline group did not significantly differ from the placebo group in these parameters.

Given the degree of effectiveness of the 500 milligram daily dose and the absence of significant differences in adverse events between this dosage level and placebo, 500 milligrams daily appears to be the optimal dose derived from this study.

Interneuron plans to review these findings with the U.S. Food and Drug Administration in the near future and to define with the FDA the nature and extent of additional studies that may be required.

Mechanism of Action

It is believed that citicoline has multiple mechanisms of action, including limiting the brain damage caused by injuries such as stroke, aiding in the repair of damaged neuronal tissues and promoting synthesis of the neurotransmitter, acetylcholine.

First, administration of citicoline within 24 hours of symptom onset is believed to limit the extent of the infarct, or tissue damage caused by interrupted blood flow, by preventing the accumulation of toxic free fatty acids. In animal models of stroke, administration of citicoline has been shown to significantly reduce infarct size.

In addition, following its administration, citicoline is broken down into two components, cytidine and choline, which are substrates required in the formation of nerve cell membranes. In order to normalize brain function, nerve cells damaged by stroke must manufacture new membrane elements.

Development History

Interneuron scientific founder Dr. Richard J. Wurtman discovered citicoline's ability to increase the production of brain cell membranes and acetylcholine in the brain, and proposed its use for a variety of neurologic conditions. Dr. Wurtman is the Cecil H. Green Distinguished Professor and director of the Clinical Research Center at the Massachusetts Institute of Technology (MIT).

MIT patented these discoveries and licensed them to Grupo Ferrer, a Spanish pharmaceutical company. In 1993, Ferrer granted Interneuron exclusive development and commercialization rights in the United States and Canada. Interneuron has also applied for additional patents for the acute use of citicoline to limit infarct size. Citicoline has been approved for marketing in Japan and Europe, including Switzerland, France, Belgium and Spain.

Interneuron Pharmaceuticals is engaged in the development and commercialization of innovative products for neurological and behavioral disorders. Through four subsidiaries, Intercardia Inc., Progenitor Inc., Transcell Technologies Inc., and InterNutria Inc., Interneuron is developing products and technologies related to cardiovascular disease, gene therapy, stem cell biology, carbohydrate-based drug discovery and drug transport, and nutritional products.

Except for the descriptions of historical facts contained herein, this news release contains forward-looking statements that involve risks and uncertainties as detailed from time to time in Interneuron's SEC filings under the Securities Act of 1933 and the Securities Exchange Act of 1934.

CONTACT: Interneuron Pharmaceuticals Inc.

617/861-8444

Glenn L. Cooper, M.D., ext. 603

Bobby W. Sandage, Jr., Ph.D., ext. 602

William B. Boni, ext. 606 (or 415/896-1600, ext. 2929 from Thursday, March 28 at 3 p.m. PST through Friday, March 29 at 10 a.m. PST.)