April 25, 2000

Summary: A large, international clinical trial of an oral form of glatiramer acetate (Copaxone®) is now getting underway:

• Approximately 1300 men and women with relapsing-remitting multiple sclerosis are being sought to participate in the trial, called the "Coral Study."
• Participants will receive daily doses of either high-dose or low-dose Copaxone tablets, or inactive placebo, for a period of 56 weeks.
• The primary outcome to be evaluated is whether either dose of oral Copaxone can reduce the rate of MS relapses.
• For more information, individuals may contact Teva Marion Partners/Teva Pharmaceutical Industries at 1-877-31 CORAL.

Details: On April 25, 2000, Teva Pharmaceutical Industries (Petah Tikva, Israel) and Teva Marion Partners (Kansas City, MO) initiated the first human clinical trials of an oral (by mouth) form of its drug, glatiramer acetate (Copaxone®) for the treatment of relapsing-remitting MS. This large-scale, placebo-controlled, double-blind study, called the "Coral Study," will involve individuals with definite relapsing-remitting disease at nearly 150 clinical centers in the U.S., Canada, Europe, Argentina, Australia and Israel. Patients are being recruited now for participation in the study.

Background: Copaxone has been available since 1996 in the U.S. and elsewhere as a daily, subcutaneous (under the skin) injection to reduce the frequency of attacks or exacerbations in relapsing-remitting MS. Additional data have indicated that Copaxone taken by injection also has a positive effect in reducing accumulation of new lesions in the brain, detected by magnetic resonance imaging (MRI). Research on laboratory animals with MS-like disease has suggested that an oral form of Copaxone may also be effective, and an initial small study in humans suggested an oral form may be used safely. The new study is intended to test whether this form of drug delivery can also be effective against MS attacks.

Entrance Criteria: The study will enroll some 1300 men and women between the ages of 18 and 50 with clinically definite relapsing-remitting MS, who have had the disease at least six months and who have the ability to walk without aid or rest for at least 600 feet (EDSS of 5 or less). There must be documented evidence of at least one MS attack in the year prior to study enrollment, but no relapses and no steroid use in the month prior to enrollment. Individuals who have previously used Copaxone by injection will be unable to participate. Those who have previously used interferons (Avonex, Betaseron/Betaferon, Rebif) will have to have been off these agents for six months prior to enrollment. Other entrance criteria will also apply.

Study Design: Individuals in the study will be randomly assigned to daily treatment with high-dose (50 mg) Copaxone tablets, low-dose (5 mg) Copaxone tablets, or inactive placebo. Treatment will continue for each participant for 56 weeks. Safety and clinical assessments will be conducted every two months, and MRI scans will be done at the beginning and end of the study. About one-third of participants will also have MRI scans every two months throughout the study. Study participants, as well as treating and examining physicians, will be "blinded" as to which treatment the individual is taking.

At the end of the study, efficacy will be evaluated based on the relapse rates of drug-treated versus placebo-treated subjects. Secondary outcomes of the study will include assessment of how many participants required the use of steroids to treat relapse, as well as changes in brain lesions detected by MRI, changes in level of disability, and other measures.

Throughout the study, data will be monitored by an independent, international monitoring committee to assure safety and to evaluate the possibility for an early indication of either success or failure of oral Copaxone to have a positive effect against MS relapses. This monitoring function is particularly critical since participants will be without the benefit of injectable drugs that have been shown effective. Use of a placebo group in this study provides the chance of a much more rapid evaluation of safety and efficacy, on a smaller number of subjects, than if the study had compared oral with injectable Copaxone. At the end of the 56-week study, all participants will have the option to receive active drug, if it proves to be effective.