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Betaseron and high doses
High-Risk Patients Particularly Respond to Higher Doses, According to Studies at ANA

(10/20/98) A comparison of three pivotal trials evaluating interferon beta-1a (IFNB-1a) in the treatment of relapsing-remitting multiple sclerosis (RRMS) demonstrates that the highest doses studied -- 22 and 44mcg of Rebif® (IFNB-1a, Ares-Serono) thre e times per week -- offer the greatest benefit. In fact, investigators found that high-dose Rebif® was most effective in decreasing the number of attacks and the rate of progression of disability, as well as reducing the number, size and growth rate of active lesions and burden of disease as measured by magnetic resonance imaging (MRI).
"These findings offer strong evidence that physicians should consider high-dose interferon beta-1a for patients with RRMS, particularly those who are continuing to experience relapses or progression at lower doses," says Mark Freedman, MD, director of the Multiple Sclerosis Clinic at Ottawa Hospital, General Campus, and Associate Professor of Medicine (Neurology) at the University of Ottawa. "There is a clear dose-response relationship on both clinical and MRI outcomes that favors administration at levels up to four times the current dosing of Avonex (Biogen). This is particular ly noteworthy as the currently available alternatives cannot be delivered at similar high doses due to formulation constraints."
In his analysis, Dr. Freedman compared clinical and diagnostic outcomes from three separate trials of IFNB-1a: 1) "Once Weekly Interferon for Multiple Sclerosis" (OWIMS) measured the efficacy of Rebif® in 293 patients randomized to receive the activ e agent or placebo in a double-blind trial. Rebif® subjects self-administered either 22mcg or 44mcg of the drug subcutaneously once weekly. 2) "Prevention of Relapses and Disability by Interferon Beta-1a (IFNB-1a) Subcutaneously in Relapsing-Remitt ing Multiple Sclerosis" (PRISMS) randomized 560 patients to receive placebo or Rebif® 22mcg or 44mcg three times per week in a double-blind trial. 3) "The Multiple Sclerosis Collaborative Research Group" (MSCRG) followed 301 MS patients in a double-b lind, placebo controlled trial. Subjects received a once weekly 30mcg dose of IFNB-1a by intramuscular injection or placebo.
After one year, Rebif® at 22mcg and 44mcg three times weekly reduced symptom exacerbation by 33 and 37 percent, respectively. Once-weekly 44mcg doses of Rebif® resulted in a 19 percent reduction, and once-weekly 22mcg doses showed no effect. The Avonexª once-weekly 30mcg dose gave a 10 percent reduction, with the response falling between Rebif® 22mcg and 44mcg once weekly. Similar dose response was noted for MRI activity and burden of disease. Therefore, optimal therapy involves three time s a week dosing of interferon beta-1a (IFNB-1a).
Earlier studies have established that Rebif® and Avonex® have the same structure, and the two formulations are bioequivalent using state-of-the-art methodology. IFNB-1a was well tolerated in all three trials. Common side effects included mild flu-like symptoms and injection-site reactions.
Data were also submitted by Dr. Donald Paty, Professor, Division of Neurology, University of British Columbia, for the cohort of RRMS patients who are at high risk for progression to more permanent disability. These patients, with scores greater than 3.5 on the Expanded Disability Status Scale (EDSS), had a more aggressive disease course. Only Rebif given at a total weekly dose of 132 mcg (3x44 mcg TIW s.c.) has been shown to be effective at slowing progression of disease in this group of patients. At the end of two years, 27 percent of high dose patients progressed versus 41 percent for the low dose group and 56 percent for the placebo group. The high dose tripled the confirmed time to progression from 7.3 months to 21.3 months. There was no differe nce between low dose and placebo.
"The results from this study confirm that patients with more severe disability (EDSS above 3.5) require 3 x 44 mcg TIW s.c. of interferon beta 1a (IFNB-1a) therapy to impact their disability. The findings also underscore that positive results achieved wit h any beta interferon product in patients with less severe disease Ð or EDSS scores below 3.5 Ð cannot be extrapolated and applied to patients with more severe disease," said Dr. Paty.
Avonex studies have never included patients with EDSS scores above 3.5 and therefore the efficacy of its approved dose has never been tested in this patient population. Betaseron has never shown positive effects on disability in RRMS patients.
Interferon beta-1a (IFNB-1a) is marketed in Canada, Latin America and Europe as Rebif® by Ares-Serono. Rebif® is the only IFNB-1a supplied in liquid pre-filled syringes for subcutaneous administration by patients.
Source/Contact:Joe Landi, Landmark Communications, (201) 567-4242

Consortium of Multiple Sclerosis Centers ©1998