Tysabri may reduce risk of disability progression in SPMS: Analysis
Significant benefit observed when therapeutic lag was accounted for
Treatment with Tysabri (natalizumab) may help delay disability progression in people with secondary progressive multiple sclerosis (SPMS) over Rebif (interferon beta-1a), an analysis of data from two clinical trials suggests.
While the trials initially failed to demonstrate slowing disease progression, a significant benefit was observed when accounting for a therapeutic lag, the period from starting a medication until its full effects manifest.
“Our findings confirm the hypothesis that after accounting for therapeutic lag, [Tysabri] reduces disability progression during SPMS,” the study’s researchers wrote. The study, “Efficacy of natalizumab in secondary progressive multiple sclerosis: analysis of two phase III trials,” was published in the Journal of Neurology, Neurosurgery and Psychiatry.
Most people with multiple sclerosis (MS) are first diagnosed with relapsing-remitting MS (RRMS), which is marked by relapses, where symptoms worsen suddenly, and periods of remission, where symptoms ease or disappear. Over time, RRMS patients may progress to SPMS, a disease form where symptoms get gradually worse over time independent of relapse activity.
Tysabri is approved in the U.S. for relapsing forms of MS, including RRMS, active SPMS, and clinically isolated syndrome. It works by stopping inflammatory immune cells from getting into the brain. In the U.S., it’s available only through a restricted distribution program because it can increase the risk of potentially serious brain infections.
A Phase 3b clinical trial called ASCEND (NCT01416181) tested Tysabri in people with SPMS with or without relapses. In that study, SPMS patients were randomly assigned to Tysabri or a placebo for two years. After the placebo-controlled phase of the trial, they could enter an open-label extension where everyone was given Tysabri.
ASCEND’s main goal was to show that those given Tysabri were less likely than those given a placebo to have disability progression over two years, but it failed to meet that goal. Still, long-term data from the open-label extension suggested that people given Tysabri in the initial study were less likely to have disability progression than those first on a placebo. The data suggested there might be a treatment lag, where Tysabri’s effects don’t become detectable for some time after treatment starts.
Comparing Tysabri, Rebif
To further explore this possibility, scientists in Australia conducted a new analysis and compared the outcomes with those of SPMS patients who received the older therapy Rebif in another clinical trial called SPECTRIMS.
Both the ASCEND and SPECTRIMS studies used similar designs, with similar inclusion and exclusion criteria and similar protocols. For their analysis, the researchers first compared data from patients given a placebo in both studies to establish a treatment lag, essentially, to identify patients who were going to see worsening disability without treatment.
Then they used statistical analyses to compare outcomes for patients given Tysabri or Rebif while accounting for the treatment lag. These analyses also accounted for differences in the placebo groups, including in factors such as sex, age, disease duration, disability levels, and relapse rates.
“This study accounted for the duration of therapeutic lag, estimated on patient characteristics, and differences between the two trials, quantified by comparison of their placebo arms,” the researchers wrote.
Results suggested the risk of disability progression was about 58% lower with Tysabri than Rebif, suggesting Tysabri reduces the risk of disability progression after accounting for the treatment lag, and for differences in the placebo groups. Reduced risk of disability progression with Tysabri was seen both for people with active SPMS, that is, people who still have occasional relapses or develop new inflammatory lesions, and for those with nonactive SPMS, who have only one approved treatment.
This finding “provides evidence that natalizumab is effective at slowing progression of disability in secondary progressive MS,” wrote the researchers, who emphasized that analyses based on comparisons between different clinical trials must be interpreted cautiously.
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