Teriflunomide (Aubagio, Genzyme/Sanofi), a once-daily oral medication approved for relapsing-remitting multiple sclerosis (RRMS), significantly slows brain volume loss in these patients, a reanalysis of imaging data has shown.

MRI shows brain atrophy was slowed by about a third at 1 year in patients taking this drug compared with placebo and that this reduction was maintained at 2 years.

Results of the reanalysis were presented during the Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2015.

Teriflunomide is a disease-modifying agent with immunomodulatory and anti-inflammatory properties. It has been approved in over 50 countries, including the United States, on the basis of two large phase 3 studies: the TEMSO (TEriflunomide Multiple Sclerosis) trial and the TOWER (Teriflunomide Oral in people With relapsing-remitting MultiplE ScleRosis) trial.

These studies, previously reported and published, demonstrated a positive effect of the drug on both the annualized relapse rate and disability progression, which was reduced by about 30% in patients taking the drug.

MRI Data Lacking

However, no MRI data on brain volume loss were collected in the TOWER study. And for the TEMSO study, despite a 25% numeric reduction in brain volume loss (by assessing changes in brain parenchymal fraction using MRI Image Analysis Package), this was not statistically significant.

"Given the association of brain volume loss with long-term disability and the consistent effect of teriflunomide in both the TEMSO and TOWER studies on disability accumulation, a reanalysis of this data set was warranted," Till Sprenger, MD, Department of Neurology, University Hospital, Basel, Switzerland, told delegates during his presentation at ECTRIMS.

Although the exact mechanism of action for teriflunomide is not fully understood, it may involve a reduction in the number of activated lymphocytes in the central nervous system. It inhibits rapidly dividing cells, including activated T cells, which are thought to drive the disease process in MS.

Research shows that this agent may decrease the risk for infections compared with chemotherapy-like drugs because of its more limited effects on the immune system.

The reanalysis used a different method to measure brain atrophy, called SIENA (structured image evaluation using normalization of atrophy). This method was also used in phase 3 trials of other approved immune-modulating compounds, including fingolimod (the FREEDOMS study) and dimethyl fumarate (the DEFINE and CONFIRM studies). These studies generally showed a significant effect of the respective agents on brain atrophy.

The SIENA method uses a software package that calculates and compares brain scans. In the new analysis, experts used images of the center part of the brain taken at two time points.

"We wanted to avoid artifacts that are created at the surfaces" of the brain, that can decrease the precision of measurements, coauthor Ludwig Kappos, professor and chair, Department of Neurology, University Hospital Basel, told Medscape Medical News in an interview.

Dr Ludwig Kappos

Brain atrophy, the result of focal and diffuse tissue damage and progressive loss of brain volume, starts early in the disease process in patients with MS. Compared with healthy persons, who experience 0.1% to 0.3% per year loss in brain volume, those with MS have a 0.5% to 1.0% loss, Dr Sprenger said during his presentation.

Brain volume loss has repeatedly been shown to correlate very strongly with both physical and cognitive disability, he said.

The reanalysis was conducted at the Medical Image Analysis Center in Basel by assessors blinded to treatment allocation and other study data. They analyzed the data at baseline and at weeks 48 and 108.

According to Dr Sprenger, the reanalysis was carried out with "vigorous" quality control. It ended up excluding data for 11% of patients that did not meet quality control criteria, leaving data for 808 patients in the analysis.

The new analysis showed that after 1 year, there was a 36.9% reduction in annualized brain volume loss in patients taking 14 mg of teriflunomide vs placebo, which was highly statistically significant (P = .0001). This was maintained at 2 years, at which point there was a 30.6% reduction (P = .0001).

There were similar effects for those taking the 7-mg dose, which were also statistically significant at both time points, "although the P value was slightly lower," said Dr Sprenger.

"Taken together, teriflunomide has demonstrated efficacy on annualized relapse rate, disability progression, MRI activity, and now on brain volume loss," he said. "It remains an important once-daily oral treatment option for patients with relapsing MS."

"Not Yet Ripe"

Measuring brain atrophy is increasingly becoming an important focus in the field of MS. But according to Dr Kappos, such assessments are "not yet ripe" for routine use in individual patients, partly because of the "high variability between individuals" and the different methods of imaging assessment.

While some laboratories have started to provide these assessments on an individual basis, they are definitely not in widespread use, he said. "I think that's the direction we have to develop, but it's still too early to apply that."

He said he expects to see better-standardized MRIs and better methods of scan evaluation within the next 1 to 3 years.

Asked to comment on this study, session cochair Wolfgang Brück, MD, professor, neuropathology, University of Göttingen, Germany, said the results are "in the range of what you'd probably expect from the data."

"If you impact inflammation then there is some impact also on brain volume," he told Medscape Medical News.

It was "unfortunate" that only one of the pivotal studies of teriflunomide had MRI brain volume data to begin with, he said.

"So, compared to the other clinical trials (assessing other immune modulating therapies), it lacked some confirmation, but it does seem promising."

The study was supported by Genzyme, a Sanofi company. Dr Sprenger has received payments used exclusively for research for consulting and speaking activities for Mitsubishi Pharma, Eli Lilly, Genzyme, Novartis, ATI, Actelion, Electrocore, Biogen Idec, and Allergan. He has received grants from the Swiss MS Society, Swiss National Research Foundation, EFIC-Grünenthal, and Novartis Pharmaceuticals Switzerland. Dr Kappos has received in the last 3 years and used exclusively for research support: steering committee, advisory board, and consultancy fees (Actelion, Addex, Bayer HealthCare, Biogen Idec, Biotica, Genzyme, Lilly, Merck, Mitsubishi, Novartis, Ono Pharma, Pfizer, Receptos, Sanofi, Santhera, Siemens, Teva, UCB, Xenoport); speaker fees (Bayer HealthCare, Biogen Idec, Merck, Novartis, Sanofi, Teva); support of educational activities (Bayer HealthCare, Biogen, CSL Behring, Genzyme, Merck, Novartis, Sanofi, Teva); royalties (Neurostatus Systems GmbH); and grants (Bayer HealthCare, Biogen Idec, European Union, Merck, Novartis, Roche Research Foundation, Swiss MS Society, Swiss National Research Foundation).

Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2015. Late Breaking News 220. Presented October 10, 2015.


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