Susan Jeffrey

October 15, 2010

October 15, 2010 (Gothenburg, Sweden) — Results of a phase 3 trial of teriflunomide, an oral disease-modifying therapy, showed a significant reduction in annualized multiple sclerosis (MS) relapse rates with 2 doses of the drug of more than 30% vs placebo.

Disability progression was also significantly reduced by 30% with the higher 14-mg dose, and both doses were well tolerated, with a similar number of patients reporting treatment-emergent adverse events, including serious adverse events, in the treatment and placebo arms.

"Certainly it's safe and effective and is a potential new oral monotherapy for MS with relapses and, again, potentially a first-line treatment given its combination of efficacy and safety characteristics," Paul O'Connor, MD, director of the MS Clinic at St. Michael's Hospital, Toronto, Ontario, Canada, and principal investigator of the TEMSO study told delegates here.

The results were presented at the 26th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). The TEMSO trial was funded by Sanofi-aventis.

Comprehensive Development Program

Dr. Paul O'Connor

Teriflunomide is a novel disease-modifying therapy that reversibly inhibits dihydroorotate dehydrogenase, a key enzyme involved in de novo pyrimidine synthesis, the study authors write. This reduces T- and B-cell proliferation and function in response to autoantigens but preserves the replication and function of cells living on their pyrimidine pool, including hematopoietic cells or memory T cells through the so-called salvage pathway.

The drug is currently being investigated as an MS treatment in a comprehensive phase 3 program, Dr. O'Connor noted. The phase 2 trial of teriflunomide had shown a 61% reduction in unique active lesions on magnetic resonance imaging (MRI) at 9 months, and the overall relapse rate was reduced by 30%, he said (Neurology. 2006;66:894-900). "These findings led to the initiation of the phase 3 program."

TEMSO was a randomized, double-blind, placebo-controlled, multinational study that included 1088 relapsing MS patients with an Expanded Disability Status Scale score of 5.5 or higher and at least 1 relapse in the previous year or 2 relapses in the previous 2 years.

Patients were randomized to receive either the 7-mg or 14-mg once-daily dose of teriflunomide or placebo and followed up for 108 weeks. The primary endpoint was the annualized relapse rate, defined as the number of confirmed relapses per patient-year.

The dropout rate was about 27% in each group, Dr. O'Connor noted, with the main reasons being adverse events, perceived lack of efficacy, and withdrawal of consent. "Adverse events were slightly more frequently reported in the teriflunomide treatment group, but this difference was not statistically significant," he said.

The "headline" of the study, Dr. O'Connor said, was a 31% reduction in relapse rates in both the 7- and 14-mg groups, with no evidence of dose effect on this endpoint.

Table 1. TEMSO: Primary Endpoint

Treatment Group Annualized Relapse Rate, % Relative Risk Reduction P Value
Placebo 0.539    
Teriflunomide, 7 mg 0.370 31.2 .0002
Teriflunomide, 14 mg 0.369 31.5 .0005

 

The drug significantly increased the time to first relapse in both dose groups relative to placebo, he noted.

"More importantly to me anyway is the fact that the 14-mg dose reduced the risk of sustained disability progression," Dr. O'Connor added, which was significantly reduced by 29.8% with the 14-mg dose (P = .0279), with a trend to a reduction of 23.7% with the 7-mg dose (P = .0835).

The rate of treatment-emergent adverse events and serious adverse events was the same in the 3 treatment groups, and there were no deaths. "So the safety side was much less worrisome than we've seen with some of our other oral therapy trials," he added.

Side effects that were more common in the teriflunomide groups were diarrhea, nausea, alanine transferase increases that were mainly mild and asymptomatic with no dose effect, and mild hair thinning and hair loss, which rarely led to treatment discontinuation.

Table 2. TEMSO: Serious Adverse Events

Treatment Group Adverse Events, No. (%)
Placebo 46 (12.8)
Teriflunomide, 7 mg 52 (14.1)
Teriflunomide, 14 mg 57 (15.9)

 

No serious opportunistic infections occurred in patients treated with teriflunomide, and there was no difference in the serious infections between the groups, occurring in 2.2% of placebo patients, compared with 1.6% in the 7-mg and 2.5% in the 14-mg groups.

A slight reduction in neutrophil counts was seen in the first 3 months of treatment and then plateaued, he noted. In 2 cases where the neutrophil reduction was moderate, treatment was continued and again the counts plateaued, "so this was not a source of trouble," he noted.

Four cancers occurred during the trial, 3 of these in the placebo group. There were 11 pregnancies in this trial population; of these, 4 had spontaneous abortions and 6 had abortions. One patient took the washout drug available with this treatment that removes teriflunomide from the body within a week and gave birth to a healthy baby with, so far, no adverse effects, Dr. O'Connor noted.

MRI Endpoints

In a separate poster presentation, the TEMSO researchers, led by Jerry Wolinsky, MD, director of the MRI Analysis Center at the University of Texas Medical School at Houston, also reported teriflunomide treatment significantly reduced brain disease activity on MRI, including significant reductions in total lesion volume with both doses vs placebo.

Total lesion volume was reduced by 39.4% in the 7-mg group (P = .0317) and by 67.4% (P = .0003) vs placebo. "So fairly robust MRI effects for this particular metric," Dr. O'Connor noted.

In a second separate presentation, David K. Li, from the University of British Columbia and MS/MRI Research Group in Vancouver, Canada, reported data on long-term efficacy of the drug from an open-label extension of the phase 2 teriflunomide trial out to 7 years.

Another poster presented here from this open-label extension showed the drug continued to be well tolerated, with a safety profile "consistent' with that reported during the double-blind phase of the trial, a company release notes.

More Trials Under Way

On the last day of the ECTRIMS meeting here, Jeffrey Cohen, MD, from the Cleveland Clinic Foundation in Ohio, included the TEMSO trial results in his talk on the highlights of the congress.

"These results from TEMSO are very promising," Dr. Cohen concluded. "Where teriflunomide will fit into the overall armamentarium is ultimately going to depend on us getting the results of these additional studies, getting further experience with the agents for which trials have already been reported, and getting results of other phase 3 studies that are currently ongoing."

Besides the TEMSO trial, several other phase 3 studies are under way: TOWER is placebo controlled, TENERE is a head-to-head comparison with interferon beta-1a (Rebif, EMD Serono/Pfizer), and TOPIC is comparing teriflunomide with placebo in patients with clinically isolated syndrome. Results of TOWER, the second of 2 placebo-controlled phase 3 trials required to support an application for regulatory approval, are expected in 2012. In the event of positive results, Sanofi-aventis anticipates submitting a New Drug Application in the first half of 2012, said Anita Burrell, vice president of research and development at the company.

This drug has also been investigated in phase 2 trials as an adjunct to both interferon beta-1a and glatiramer acetate (Copaxone, Teva Pharmaceuticals). Results of these trials, presented earlier this year at the American Committee for Treatment and Research in Multiple Sclerosis and American Academy of Neurology meetings, showed some suggestion of a synergistic effect on MRI lesions with the addition of teriflunomide to these standard therapies, with a consistent safety profile.

"So that really fostered a lot of interest and has led to the development of TERACLES, which is now a study that we hope to get started before the end of this year," said Mark Freedman, MD, from the University of Ottawa, Ontario, Canada. "It's now a phase 3 study to prove that the addition of 7 and 14 mg to stable-dose interferon patients, who are now actually having some breakthrough, will make a difference for them."

The TEMSO study was supported by Sanofi-aventis. Dr. O'Connor has received consulting fees and/or research support from Actelion, Bayer, Biogen Idec,BioMS, Cognosci, Daiichi Sankyo, EMD Serono, Genentech, Genmab, Novartis, Roche, Sanofi-aventis, Teva, and Warburg Pincus. Dr. Freedman has received grants for clinical research from Bayer HealthCare Pharmaceuticals and Genzyme Corporation and has served as an adviser or consultant for Bayer HealthCare Pharmaceuticals, Biogen Idec Inc, EMD Serono Inc, Novartis Pharmaceuticals Corporation, Sanofi-aventis, and Teva Neuroscience Inc.

26th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS): Abstracts 79, P-982, P-431, and P-833. Presented October 14-15, 2010.

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