Susan Jeffrey

October 12, 2012

October 12, 2012 (Lyon, France) — Final results of a phase 3 trial comparing 2 doses of teriflunomide (Aubagio, Genzyme/Sanofi), 14 mg/d and 7 mg/d, vs placebo in patients with relapsing multiple sclerosis (MS), confirm significant reductions in annualized relapse rates and sustained accumulation of disability with the 14-mg dose vs placebo.

Results with a second dose studied in this trial, 7 mg, showed a significant but smaller reduction in relapse rate but not in sustained accumulation of disability.

"I think it is justified to conclude that this compound has the potential to be a very interesting addition to our armamentarium in treating relapsing multiple sclerosis in the future," said Ludwig Kappos, MD, chair of Neurology, University Hospital Basel, Switzerland.

Full results of the Teriflunomide Oral in people With relapsing-remitting MultiplE ScleRosis (TOWER) trial were presented here at the 28th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

Topline results were released June 1 and reported by Medscape Medical News at that time. The drug, the second oral agent for MS, received approval as a first-line treatment from the US Food and Drug Administration (FDA) on September 12, and is under review in most other countries, Dr. Kappos noted.

TOWER Results

Teriflunomide is a once-daily oral immunomodulator developed as a disease-modifying therapy for MS. The active metabolite of leflunomide, teriflunomide reversibly inhibits dihydroorotate dehydrogenase, a key mitochondrial enzyme involved in de novo pyrimidine synthesis for DNA replication. As a result, the drug 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.

Results of the TEMSO (TEriflunomide Multiple Sclerosis) trial (N Engl J Med. 2011;365:1293-1303), showed a significant reduction in annualized relapse rate and sustained accumulation of disability with both the 7- and the 14-mg daily doses vs placebo.

A second phase 3 trial already reported, the TENERE trial, showed the agent was similar to interferon beta-1a (Rebif, Merck Serono), a standard approved treatment for MS; the company released topline results for this trial that were reported June 2 at the 4th Cooperative Meeting of the Consortium of Multiple Sclerosis Centers (CMSC)/Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS).

Two other phase 3 trials are still ongoing, the TOPIC trial in early MS or clinically isolated syndrome, and TERACLES, investigating teriflunomide as an adjunct to therapy with interferon.

The TOWER trial was a multicenter, double-blind, parallel-group, placebo-controlled study with an open-label extension. A total of 1169 patients with relapsing MS were randomly assigned to treatment with 7 or 14 mg of teriflunomide or placebo. Dr. Kappos noted that only a small number of patients had progressive disease, and about 15% were of Asian background, mainly from China.

Patients who completed the trial were followed for 48 to 173 weeks. The average duration of teriflunomide exposure in TOWER was 18 months.

The primary endpoint was annualized relapse rate (ARR), the number of confirmed relapses per patient-year. A secondary endpoint was time to 12-week sustained accumulation of disability using the Expanded Disability Status Scale (EDSS).

The results presented here showed a 36.3% reduction in ARR with teriflunomide, 14 mg, vs placebo. There were also a significant 37% risk reduction in the number of patients who were relapse-free during the trial and a 31.5% reduction in the risk for 12-week sustained accumulation of disability vs placebo.

Table 1. TOWER: Primary and Secondary Endpoints by Treatment (14 mg)

Endpoint Teriflunomide, 14 mg Placebo P Value
ARR 0.319 0.501 .0001
Relapse-free patients (%) 51.5 37.7 .0001
12-week sustained accumulation of disability (EDSS score) 15.8 21.0 .0442

 

Results with the 7-mg dose showed a 22.3% reduction in ARR vs placebo, which was a smaller effect but still significant, and there was a significant reduction in the percentage of patients who remained relapse free during the trial. No significant difference was seen with the 7-mg dose vs placebo in the risk for 12-week sustained accumulation of disability.

Table 2. TOWER: Primary and Secondary Endpoints by Treatment (7 mg)

Endpoint Teriflunomide, 7 mg Placebo P Value
ARR 0.389 0.501 .0183
Relapse-free patients (%) 55.4 37.7 .0016
12-week sustained accumulation of disability (EDSS score) 22.2 21.0 .7620

 

Change from baseline in the EDSS score was reduced, but not significantly, in the 7-mg dose group; the change was significant in the 14-mg group. There was a trend to improvements in self-reported fatigue and the Short-Form 36 questionnaire that did not reach statistical significance in either treated group.

The total number of adverse events, serious adverse events, and adverse events leading to discontinuation "were equally distributed across the 3 treatment arms," Dr. Kappos said.

Adverse events observed in the trial were consistent with those reported in previous clinical trials with teriflunomide in MS, Dr. Kappos said. The most common adverse events reported more frequently in the teriflunomide groups were headache, alanine aminotransferase elevations, hair thinning or alopecia, diarrhea, nausea, and neutropenia.

There was no indication of increased infection rate with treatment over 18 months. One patient in the placebo group died of a respiratory infection, and 3 patients in the teriflunomide groups died:1 of a motor vehicle accident, 1 of suicide, and 1 of sepsis.

The labeling for teriflunomide in the United States includes a boxed warning outlining the risk for hepatotoxicity and teratogenicity, based on animal data, with this drug. Together with the phase 3 program of alemtuzumab (Lemtrada), a treatment given for 5 days intravenously, then for 3 days 1 year later, shown to be superior to interferon in the CARE-MS 1 and 2 trials, Genzyme/Sanofi aims to have agents suitable for both first- and second-line treatment in patients with MS.

Alemtuzumab is under regulatory review by the FDA and European Medicines Agency.

'Clear and Indisputable Effect'

Giancarlo Comi, MD, director of the Department of Neurology and Institute of Experimental Neurology at the Scientific Institute and University Vita-Salute San Raffaele in Milan, Italy, a coauthor on the study, said he sees a lot of potential for this drug in MS.

"I think this is a very interesting trial because it confirms what already emerged in the TEMSO trial, in terms of the efficacy of teriflunomide on both disability and relapses," he told Medscape Medical News. The data also allow better definition of the 14-mg dose, he added.

"The reduction of relapse rate is a bit more than 36%, so quite clear and indisputable effect, no doubt, but what is here even more relevant is you have quite clear confirmation of the effect on disability," Dr. Comi pointed out. "So now there are 2 studies, from different groups, different investigators, telling exactly the same thing, which is really fundamental to approve a drug and to be confident with the drug's safety and efficacy profile."

Also in TOWER, teriflunomide again showed a good safety profile, he noted. "A drug like this of course is not terribly powerful in terms of effect, but it is the best type of drug that we may have, just for approaching the disease and for having also a persistent effect after induction therapy," Dr. Comi added. "So I see a lot of possibility."

The TOWER trial was supported by Genzyme, a Sanofi Company.

28th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Abstract 153. Presented October 12, 2012.

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