Extension Phase Data on Oral Teriflunomide for MS Released

Megan Brooks

October 21, 2011

October 21, 2011 (Amsterdam, the Netherlands) — The benefits of oral teriflunomide on clinical and magnetic resonance imaging endpoints in the pivotal phase 3 Teriflunomide MS Oral (TEMSO) study were maintained in the extension study, 5 years after randomization.

"Numerically greater improvements were observed in patients who received teriflunomide throughout the core study and extension compared with those initially assigned to placebo," the study team reported here at the 5th Joint Triennial Congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS).

Dr. Paul O'Connor

Teriflunomide is a novel oral disease modifier in development for the treatment of relapsing-remitting multiple sclerosis (MS) being developed by Sanofi-Aventis, which also supported the TEMSO trial.

The company announced October 20 that the US Food and Drug Administration has accepted for review the new drug application for oral teriflunomide as a potential therapy for people with relapsing forms of MS. The company plans to file for European regulatory approval in the first quarter of 2012.

"Teriflunomide is a story that is still unfolding, and I think it's very exciting," TEMSO investigator Paul O'Connor, MD, from St. Michael's Hospital, Toronto, Canada, said during a press briefing.

"Long-term studies, so far, show that the drug remains effective in reducing disease activity and, as importantly, the drug is well-tolerated with no new safety signals with prolonged exposure," he added.

Earlier this month, Timothy Coetzee, PhD, chief research officer for the National MS Society, told Medscape Medical News that if teriflunomide is approved by the US Food and Drug Administration, "we see it as a good addition to the physician's toolbox."

TEMSO Extension Study

The phase 3 TEMSO study enrolled 1088 adults with relapsing-remitting MS with an Expanded Disability Status Scale score of 5.5 or higher and either at least 1 relapse in the previous year or at least 2 relapses in the previous 2 years. They were randomly assigned to receive either placebo or teriflunomide (7 or 14 mg/day) and were followed-up for 108 weeks.

In the extension phase, actively treated patients continued on their original dose, whereas those originally randomly assigned to receive placebo were reallocated to receive teriflunomide (7 or 14 mg/day). A total of 742 patients entered the extension phase.

In the original study, published October 6 in the New England Journal of Medicine and reported by Medscape Medical News at the time, both doses of teriflunomide reduced annualized relapse rates by more 31%, with no evidence of dose effect.

In the extension study, the relapse rate "was quite low," Dr. O'Connor reported. "As is common in extension studies, the relapse rate was actually lower than in the pivotal trial. The range of relapse rates over the 5 years was from 0.18 to 0.25, so quite low," he said.

In the extension study, changes from baseline in total magnetic resonance imaging scan lesion volume were numerically lower in patients who received teriflunomide first in the core study and then in the extension phase compared with those initially assigned to placebo, the authors say.

Consistent with observations in the core TEMSO study, both doses of teriflunomide were well-tolerated and had favorable safety profiles in the extension phase. "If we look at adverse events over the long-term in the extension study, there were no surprises," Dr. O'Connor said.

"There was 1 death in each of the treatment groups, and each was cardiac in nature and not drug-related," he reported.

There was a "low and similar" incidence of infections between the groups, and no reports of serious opportunistic infections. In addition, there was "no signal" for increased risk for malignancy or fetal risk. There were no structural or functional deficits reported in 8 healthy newborns with prenatal teriflunomide exposure.

Less Resource Use, Preserved Cognition

In separate analyses presented here in a poster session on October 20, researchers showed that patients receiving teriflunomide used fewer healthcare resources and had preserved cognition vs placebo.

During the briefing, Professor Fred Lublin, MD, neurologist at Mount Sinai Medical Center, New York City, reported data showing that teriflunomide 14 mg "could result in reduced healthcare costs."

The data suggest that the drug reduces annualized relapse rates leading to hospitalization by 36% (P = .015) at the 7-mg dose and by 59% (P < .0001) at the 14-mg dose compared with placebo.

The risk for hospitalization per relapse was also significantly reduced by 43% (P < .001) for the 14-mg dose, and numerically reduced by 6% for the 7-mg dose, although this reduction was not statistically significant.

The benefits on hospitalization for relapse "may suggest an effect on relapse severity," Dr. Lublin said. The drug was also associated with fewer emergency medical facility visits not resulting in hospital admission.

Another tertiary objective of TEMSO was to look at the effects of teriflunomide treatment on cognitive function, measured as a change from baseline scores on the Paced Auditory Serial Addition Test, 1 of 3 components of the Multiple Sclerosis Functional Composite assessment. That assessment was done at baseline and then at weeks 24, 48, 72, and 96.

The least squares mean changes from baseline at week 96 in the Z-score for cognitive function were −0.022 for placebo compared with 0.075 for the 7-mg and 0.073 for the 14-mg teriflunomide groups, with positive scores indicating improvement.

The TEMSO trial was supported by Sanofi-Aventis. Dr. O'Connor has disclosed financial relationships with various commercial entities including Actelion, Bayer, Biogen Idec, BioMS, Cognosci, Daiichi Sankyo, EMD Serono, Genentech, Genmab, Novartis, Roche, Sanofi-Aventis, Teva, and Warburg Pincus. Dr. Lublin has disclosed relationships with several companies including Acorda Therapeutics, Biogen Idec, Novartis, Teva Neuroscience, Genzyme, and Sanofi-Aventis. Dr. Coetzee has disclosed no relevant financial relationships.

5th Joint Triennial Congress of the European and Americas Committees for Treatment and Research in Multiple Sclerosis (ECTRIMS/ACTRIMS): Abstracts P250, P438, P924. Presented October 20 and 21, 2011.

N Engl J Med. 2011;365:1293-1303. Abstract

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