ARTICLE IN BRIEF
The combination of glatiramer acetate and interferon beta-1a failed to show significant differences in the rate of disease exacerbations than treatment with either drug alone.
NEW ORLEANS—Researchers said here that they were unable to observe an additive or synergistic benefit in combining two multiple sclerosis (MS) drugs — glatiramer acetate (Copaxone) and interferon beta-1a (Avonex) — in the much anticipated CombiRx clinical trial.
The combination of the two drugs failed to show significant differences in the rate of disease exacerbations than treatment with either drug alone, said Fred Lublin, MD, the Saunders Family Professor of Neurology and the director of the Corinne Goldsmith Dickinson Center for Multiple Sclerosis at Mount Sinai Medical Center in New York City. The trial was sponsored by the NINDS.
The primary objective of the double-blind, multicenter, randomized trial was to determine if interferon beta-1a plus glatiramer acetate is more efficacious than either agent alone for relapsing-remitting MS. The primary endpoint was the annualized relapse rate over three years in a comparison of interferon beta 1a plus glatiramer acetate versus the best single agent arm.
The study authors had hypothesized that combining the drugs would have additive or synergistic effects. But in presenting the trial results here at the AAN annual meeting, Dr. Lublin said: “All three study arms performed exceedingly well. The combination of glatiramer acetate and interferon beta-1a was not superior to the single agent — glatiramer acetate — in risk of relapse over 36 months. Glatiramer acetate was superior to interferon in reducing the risk of relapse.”
Dr. Lublin also noted that in secondary endpoints, “the combination of interferon and glatiramer acetate was not shown to be better than either agent alone in lessening confirmed Expanded Disability Status Scale progression or change in the Multiple Sclerosis Functional Composite over 36 months.”
On the other hand, he noted that the combination of the drugs did appear to show improvement in reducing new lesion activity as observed through MRI, although that difference did not appear to impact exacerbations or disability.
The researchers enrolled 1008 patients in the study, who underwent two screenings and a baseline check at which they had to be relapse-free. They randomized 499 patients to interferon beta-1a and glatiramer acetate; 250 to active interferon beta-1a plus placebo glatiramer acetate; and 259 to active glatiramer acetate plus placebo interferon beta-1a.
To be eligible patients had to have confirmed relapsing-remitting MS with two or more exacerbations in the previous three years. Dr. Lublin said that 814 patients completed the trial, and 80.8 percent of patients completed 36 months on study. The completers included 397 patients on the combination; 194 on interferon beta-1a, and 223 on glatiramer acetate.
The CombiRX study reflected a unique collaboration between the NIH, academic institutions, practicing neurologists and Pharma/biotech, said John Corboy, MD, professor of neurology at the University of Colorado's Multiple Sclerosis Center at the Anschutz Campus in Aurora. It provides the longest controlled clinical, MRI and biomarker dataset of any MS therapeutic trial, he noted.
Although this trial failed to find significant differences when the therapies were combined, he pointed out that the concept will likely be studied in future trials. Dr. Corboy, who serves on the editorial advisory board of Neurology Today, said that investigators may attempt to combine the older standard disease-modifying drugs such as interferon beta-1a or glatiramer acetate with natalizumab (Tysabri) of fingolimod (Gilenya). “We may try them together or in sequence,” he said.
“We await all the final data, but so far, the surrogate marker MRI appears more sensitive than the clinical data,” Dr. Corboy said. “We see this in virtually all studies; for example, the effect on new MRI lesions is greater than clinical measures. Just because we don't see a comparable clinical outcome at first, does not mean that the MRI measures are not ultimately associated with clinically significant effects. A number of studies show changes on MRI scans in year one or years one to five are associated with clinical changes later, over time.
“Ultimately,” Dr. Corboy said, “the accumulation of MRI lesions is associated with cognitive changes, which we do not easily measure in the office or in studies unless we specifically look for those changes.”
The CombiRx study also should not be seen as a complete failure, Dr. Corboy stressed. “There are a lot of data to be mined from this study, especially among patients who didn't complete the full study,” he said.
“We still really don't know how some of the drugs we use work in multiple sclerosis and we don't fully understand what causes multiple sclerosis either,” he said.
The study was conducted at sites in the United States and Canada. The study medication was provided by Biogen Idec and Teva Neurosciences.