Tysabri best of 6 DMTs to prevent relapses, worse disability in MS

Novel simulated clinical trial allows direct comparison of treatments

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Tysabri (natalizumab) is better than five other disease-modifying therapies (DMTs) at reducing relapses and preventing disability worsening in relapsing-remitting multiple sclerosis (RRMS), according to the findings of a novel simulated clinical trial that directly compared the six treatments.

The analysis used mathematical modeling to emulate a clinical trial based on data from more than 20,000 patients in a global MS registry. It found that Gilenya (fingolimod) was the second best drug for improving outcomes among the six low-to-intermediate efficacy treatments studied.

“Among patients with active relapsing MS, [Tysabri] followed by [Gilenya] offers an advantage … in reducing the risk of relapses and improving disability outcomes,” the researchers wrote.

“However,” the team noted, “the individual use of these therapies should be also guided by specific clinical scenarios and their safety profiles, which were not evaluated in this study.”

Titled “Effectiveness of multiple disease-modifying therapies in relapsing-remitting multiple sclerosis: causal inference to emulate a multiarm randomised trial,” the study was published in the Journal of Neurology, Neurosurgery & Psychiatry.

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Researchers use math model for head-to-head comparison

A growing number of DMTs — a newer type of treatment that can alter the course of MS — have become available to people with RRMS in recent years.

Each therapy is backed by safety and efficacy data from its own clinical development program, with evidence of real-world outcomes increasingly becoming available. However, few controlled clinical trials have directly compared the effectiveness of a number of these different DMTs at once, because such trials are neither financially nor practically feasible.

“Neurologists and patients can now choose from among different mechanisms of action and methods of administration,” the researchers wrote, noting that “multiple therapies have been approved” for MS by regulatory authorities.

“Therefore, evidence comparing effectiveness to guide the choice among DMTs is needed,” the team wrote.

To that end, the scientists developed a mathematical model to emulate a randomized clinical trial that would compare the effectiveness of six common DMTs. In addition to Tysabri and Gilenya, the simulated trial evaluated Aubagio (teriflunomide), Tecfidera (dimethyl fumarate), glatiramer acetate (sold as Copaxone among others), and interferon-based therapies.

Clinical data from 23,236 people with RRMS or clinically isolated syndrome were used; all were housed in MSBase, an international patient registry. In all, the data came from 74 centers across 35 countries.

About one third of the patients (35%) had not yet been treated at the start of the analysis. The remaining individuals were using interferon beta therapy (41%), glatiramer acetate (11%), Gilenya (4.5%), Tysabri (5%), Tecfidera (1.5%), or Aubagio (1.3%).

The patients were followed for a mean of 2.8 years, from their first recorded clinic visit with disability data — the study’s baseline — to the time of switching or stopping the DMT they were using, or their last recorded follow-up.

More than 900 of these patients were still using their initial therapy five years after starting it.

A mathematical model was then used to estimate the average treatment effects of the therapies in terms of relapses and disability over five years. All of the patient data were first weighed so that their characteristics matched those in the glatiramer acetate group, which served as a reference therapy.

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Comparison may help guide treatment choice for patients

Overall, Tysabri had the greatest effect on reducing relapses — a 56% reduction relative to glatiramer acetate — followed by Gilenya. The data showed Gilenya led to a 40% reduction compared with the reference therapy. On the other hand, not using a treatment was associated with a 35% increase in relapses.

Likewise, Tysabri was associated with a lower risk of confirmed disability worsening relative to the other therapies. That risk was 57% lower for patients given Tysabri than for those in the glatiramer acetate group. Aubagio also significantly lowered the risk of disability worsening, by 44%, while no significant differences were seen in the other groups.

Moreover, Tysabri also was associated with the greatest increases in disability improvement, or an easing in disability. Patients taking this drug had a 32% higher risk of achieving disability improvement compared with those on glatiramer acetate.

Additional analyses indicated that patients on glatiramer acetate would have experienced fewer relapses if they were instead on Tysabri, Gilenya, or interferon therapies. They also would have experienced fewer events of disability worsening on Tysabri, and greater odds of disability improvement on Tysabri or Gilenya.

Comparatively, outcomes would have been worse for Tysabri-treated patients had they been using other therapies.

Overall, “[Tysabri] ahead of [Gilenya] is most effective in preventing relapses, disability worsening and enabling disability improvement in relapsing-remitting MS,” the researchers wrote.

According to the scientists, the findings are generalizable to a population of patients with relatively active MS, given that nearly 20% of patients in this study experienced a relapse within three months before starting a new treatment.

This approach allows us to inform neurologists about both the overall relative effectiveness of the compared therapies as well as comparisons between selected treatment pairs in populations that are typically treated with the therapy of interest.

The team also noted that this type of trial modeling could be used for a number of other applications.

“The current design is broadly applicable to data from various settings, ranging from cohorts, registries and databases to repurposed data from randomised controlled trials,” they wrote.

“This approach allows us to inform neurologists about both the overall relative effectiveness of the compared therapies as well as comparisons between selected treatment pairs in populations that are typically treated with the therapy of interest,” the team concluded.