BOSTON—Two-year data from the phase III ADVANCE clinical trial support the maintained benefits of pegylated interferon beta-1a (125 µg) beyond one year in patients with relapsing-remitting multiple sclerosis (MS), with significantly greater efficacy over several key end points seen in patients receiving the drug every two weeks, as opposed to a four-week dosing regimen. These extension trial results were reported by Peter A. Calabresi, MD, at the 2014 Joint ACTRIMS–ECTRIMS Meeting.
“Overall, pegylated interferon beta-1a seems to be a well-tolerated and safe approach to treating patients with relapsing-remitting MS,” said Dr. Calabresi, who is the Director of the Division of Immunology, Director of the Multiple Sclerosis Center, and Professor of Neurology at Johns Hopkins University in Baltimore.
Year one results of the ADVANCE study were published in the July issue of Lancet Neurology. The three-arm study compared placebo with subcutaneous pegylated interferon beta-1a (125 mg) given either every two weeks or every four weeks. Compared with placebo, both treatment arms had significant reductions in annualized relapse rates, which was the primary end point. Significant reductions were also seen in secondary end points—risk of relapse, disability progression, and number of new or newly enlarging T2 lesions. Two-week dosing showed greater benefits over four-week dosing. The safety profile in year one was largely consistent with the known safety of interferon and the side effects of the interferons.
The purpose of the extension study was to examine maintenance of efficacy. “We want the drug to continue to work over a lifetime, so we compared patients in year one to patients in year two who were consistently on pegylated interferon,” Dr. Calabresi said. The researchers also compared patients continuously on pegylated interferon with those who were switched from placebo to active treatment to determine if treatment delay had any significant changes, compared with continuous treatment. The investigators also compared the efficacy of two-week dosing with four-week dosing.
Patient retention in year two was excellent—between 88% and 94% per arm, according to Dr. Calabresi. Compared with the delayed treatment group (those switched from placebo to active treatment), the researchers found a 37% reduction in annualized relapse rates in the two-week dosing arm and a 17% reduction in the four-week dosing arm. “So we saw a significant reduction in the two-week group with a trend in the four-week dosing arm,” Dr. Calabresi said.
Over two years, there was a 39% reduction in time to first relapse in the two-week dosing arm and a 19% reduction in the four-week dosing arm, compared with delayed treatment. Regarding 12-week confirmed disability progression, a 33% reduction was observed in the two-week dosing arm and a 25% reduction was found in the four-week dosing arm, again compared with delayed treatment. With regard to 24-week confirmed disability, there was a 41% reduction in the two-week dosing arm and a 9% reduction in the four-week dosing group. Proportions of patients with relapses meeting 24-week confirmed disability progression were also significantly reduced in the two-week dosing arm, compared with the four-week dosing arms or delayed treatment.
Significant reductions occurred in the two-week dosing group, as compared with the four-week group in all three MRI outcome measures. The mean number of new or newly enlarging T2-weighted hyperintense lesions was 14.8 in the delayed treatment group, 12.5 in the four-week dosing group, and five in the two-week dosing group. The mean number of gadolinium-enhancing lesions was 0.5 in the delayed treatment group, 0.7 in the four-week dosing group, and 0.2 in the two-week dosing group. The mean number of T1 hypointense lesions was 5.6 in the delayed treatment group, 4.9 in the four-week dosing group, and 2.3 in the two-week dosing group.
The same patterns were seen when looking at no MS disease activity overall. The two-week dosing group had significant decreases in the percentage of patients with no disease activity, as compared with delayed treatment, with the four-week doing group somewhere in between.
Regarding maintenance of efficacy between years one and two, the delayed treatment group that was switched from placebo to active treatment showed a reduction in the primary and secondary outcome measures. The greatest reductions were again seen in the two-week dosing group.
The two-year data revealed no surprises or new concerns with regard to safety or tolerability. Side effects were most commonly injection-site reactions in 68% and flu-like symptoms in 53%, but these events led to discontinuation in only 6% of patients. Although nine deaths occurred during the two years, an independent safety monitoring committee concluded that none of the deaths was related to the study drug.