August 26, 1999 09:03
Interneuron Completes Enrollment in Phase 3 Stroke Trial
With CerAxon -- Citicoline --
LEXINGTON, Mass.--(BW HealthWire)--Aug. 26, 1999--Interneuron Pharmaceuticals, Inc. (NASDAQ:IPIC) today announced the completion of enrollment in ECCO 2000 (Effects of Citicoline on Clinical Outcome - 2000 mg), a 900-patient Phase 3 clinical trial with CerAxon(tm) (citicoline) to treat ischemic stroke.
A double blind, placebo-controlled trial sponsored by Interneuron, ECCO 2000 includes patients with moderate to severe ischemic stroke enrolled at more than 170 participating hospitals in the U.S. and Canada. Patients in the trial are being treated with CerAxon tablets,
2000 milligrams daily, or with matching placebo tablets for six weeks, with an additional six-week follow-up period. Treatment was initiated within 24 hours following the stroke. The primary endpoint of the trial is the change in neurological function of patients between the time of enrollment and the end of the follow-up period (12 weeks), as measured by NIH Stroke Scale scores.
"This is the largest clinical trial of citicoline in stroke conducted to date in the world," said Bobby W. Sandage, Jr. Ph.D., executive vice president, research and development, at Interneuron. "We expect to have preliminary results from the trial after data analysis, near the end of calendar year 1999 or the beginning of calendar year 2000. If the results are positive, we plan to re-submit the New Drug Application (NDA) in the first quarter of calendar year 2000.
"The design of ECCO 2000 was based on extensive analysis of Interneuron's three previous U.S. clinical trials, as well as European and Japanese experience with the drug," said Dr. Sandage. "This analysis led to refinements in the study design, including the identification of change in neurological function as the primary endpoint, a focus on moderate to severe stroke patients, and the selection of a higher citicoline dose than in the two most recent studies. In the Company's first Phase 3 trial with the drug, the 2000-milligram daily dose (also used in ECCO 2000) was shown to be effective and was well tolerated."
According to a recent report by the American Heart Association, stroke is the third leading cause of death in the U.S. Approximately 700,000 people suffer a new or recurrent stroke each year and 160,000 deaths occur annually as a result of stroke in the U.S. Ischemic stroke, which is caused by a blockage of blood flow to the brain, comprises over 80 percent of all strokes and is associated with high levels of death and disability.
Citicoline is currently marketed in over 20 countries by Takeda Chemical Industries, Ltd., the largest pharmaceutical company in Japan, and by Ferrer Internacional, S.A., a leading European pharmaceutical company. In 1993, Interneuron licensed exclusive marketing and manufacturing rights to citicoline in the U.S. and Canada from Ferrer. Interneuron subsequently obtained an exclusive right to use a Japanese clinical database of citicoline from Takeda, which discovered citicoline.
Interneuron has filed several patents worldwide relating to citicoline and has been issued patents relating to its use in protecting brain tissue from cerebral infarction following ischemic stroke. These patents are based on findings from research in both humans and animals
conducted by Interneuron.
Background information
In February 1996, Interneuron completed a double blind, placebo-controlled Phase 2/3 study of oral CerAxon in 259 patients who had suffered ischemic strokes. In that study, patients received either placebo or one of three doses of CerAxon (500 mg, 1000 mg, or 2000 mg) per day for six weeks, with treatment initiated within 24 hours of the onset of stroke symptoms. The primary endpoint for the study was improvement in a categorized analysis of the Barthel Index at 12 weeks. The results of this study demonstrated that patients treated with 500 mg or 2000 mg of CerAxon daily had significantly (p (less than or equal to) 0.05) improved ability to carry out functions of daily living than did placebo treated patients according to the primary analysis. Additional efficacy measurements, including NIH Stroke Scale, Rankin Scale, Mini-Mental State Exam, as well as rate of improvement, reflected the same trends when comparing these doses of CerAxon to placebo.
Based on this data, Interneuron initiated a second double blind, placebo-controlled Phase 3 trial with CerAxon in the U.S., comparing 500 mg CerAxon daily for six weeks vs. placebo. In July 1997, the Company completed this study, which included 394 patients who had
experienced ischemic strokes. As a result of an unexpected highly significant baseline imbalance in the percentage of placebo versus citicoline-treated patients who had mild strokes on study entry and other statistical factors, the primary analysis of the study, the distribution of Barthel Index scores in citicoline vs. placebo-treated patients as a function of baseline NIH Stroke Scale scores, did not achieve statistical significance. Therefore, a protocol-defined
responders analysis, percentage of patients who achieve a Barthel Index (greater than or equal to) 95, was employed. The results of the trial indicated that, at 12 weeks, oral CerAxon 500 mg showed a statistically significant improvement in neurological function among the sub-population of patients with moderate to severe strokes. In a responder's analysis, 41 percent of CerAxon-treated patients with an NIH Stroke Scale on entry of (greater than or equal to) 8 achieved a Barthel Index of (greater than or equal to) 95 compared to 25 percent of placebo-treated patients (OC analysis, p=0.02). Thus, patients with moderate to severe stroke treated with CerAxon had a 64 percent greater chance of complete or near complete recovery relative to patients with moderate to severe stroke treated with placebo. As in the first Phase 3 trial, the drug was well tolerated. Following this trial, Interneuron submitted an NDA to the U.S. Food and Drug Administration (FDA) for CerAxon in December 1997.
In April 1998, Interneuron announced that a preliminary analysis of a 100-patient trial with CerAxon (500 mg daily) failed to meet its primary and principal secondary endpoints. This trial differed from earlier CerAxon clinical trials conducted by the Company in that its primary endpoint was the measurement of infarct size by diffusion weighted magnetic resonance imaging in patients who received CerAxon as compared with patients who received placebo. This study was based on certain assumptions relating to reductions in infarct size seen
among CerAxon and placebo patient groups in previous studies. Though the study showed a strong trend of infarct reduction in the CerAxon group, a placebo response rate unexpectedly higher than that previously reported in the literature, together with a small patient population, may have accounted for this study not reaching statistical significance. As a result of this trial, the Company withdrew its NDA for CerAxon and subsequently commenced the ECCO 2000 trial.
Mechanism of action
Citicoline is believed to have multiple mechanisms of action, which may limit stroke-induced brain damage:
-- Limiting the extent of the infarct, or tissue damage caused by interrupted blood flow, by preventing the accumulation of toxic free fatty acids;
-- Promoting recovery of brain function by providing two components, cytidine and choline, required in the formation of nerve cell membranes;
-- Promoting the synthesis of acetylcholine, a neurotransmitter associated with cognitive function.
Interneuron Pharmaceuticals is engaged in the development and commercialization of a portfolio of products and product candidates for central nervous system, cardiovascular and other disorders, including multiple compounds in late-stage clinical development.
Except for the descriptions of historical facts contained herein, this press release contains forward-looking statements that involve risks and uncertainties that could cause the Company's actual results and financial condition to differ materially from those anticipated by
the forward looking statements. These risks and uncertainties are set forth in the Company's filings under the Securities Act of 1933 and the Securities Exchange Act of 1934 under "Risk Factors" and elsewhere, and include, but are not limited to, risks relating to the Redux-related litigation, including risk relating to the finalization of the proposed settlement of the product liability litigation; uncertainties relating to clinical trials and regulatory approvals; need for additional funds and corporate partners; history of operating losses and expectation of future losses; product liability; dependence on third parties for manufacturing and marketing; the early stage of products under development; government regulation, patent risks and
competition.
CONTACT: Interneuron Pharmaceuticals, Inc.
Bobby W. Sandage, Jr., Ph.D.
Executive VP, Research and Development
(781) 402-3406
or
William B. Boni
VP, Corp. Communications
(781) 402-3410
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