COPENHAGEN -- Teriflunomide (Aubagio) significantly reduced the risk of clinically definite multiple sclerosis in patients who had suffered a first bout of symptoms, an academic researcher confirmed here.


Among 618 patients with clinically isolated syndrome, some 24% of those assigned to 14 mg/day of teriflunomide subsequently were diagnosed with full-blown MS after a second attack during 2 years of treatment, compared with 36% in those assigned to placebo (P=0.009), according to Aaron Miller, MD, of Mount Sinai School of Medicine in New York City.

That difference translated to a hazard ratio of 0.574 (95% CI 0.379-0.869) for conversion to MS with the 14-mg dose, Miller told attendees at the European Committee for Treatment and Research in Multiple Sclerosis annual meeting.

He said that the study, called TOPIC, was the first to show that an oral agent can reduce the risk of progression in patients with clinically isolated syndrome. Similar results had been reported earlier for interferon-beta drugs and glatiramer acetate (Copaxone).

A 7-mg daily dose also reduced conversion rates significantly in the three-arm, randomized trial (HR 0.628, 95% CI 0.416-0.949), but appeared less effective than the higher dose on some secondary endpoints, Miller said.

These topline results had been released in April by the drug's manufacturer, Genzyme-Sanofi, but without 95% confidence intervals and with no quantitative information on secondary outcomes or adverse events.

Those secondary outcome results included the following, as reported by Miller:

Reduction in risk of clinical relapse or new MRI lesion, relative to placebo: HR 0.651 (95% CI 0.515-0.822) at 14 mg; HR 0.686 (95% CI 0.540-0.871) at 7 mg

Reduction in number of gadolinium-enhancing T1 MRI lesions, relative to placebo: 59% at 14 mg (P=0.0008); 21% at 7 mg (P=0.4366)

However, by the time the 2-year trial ended, about 70% of both active drug groups had developed either a clinical relapse or a new MRI lesion, Miller reported. And teriflunomide did not eliminate gadolinium-enhancing lesions entirely. Mean counts were about 0.3 in the 14-mg group and nearly 0.8 in the 7-mg group, compared with about 0.9 in the placebo group.

Total lesion volumes were stable by the study's end in the 14-mg group, and increased slightly with the lower dose.

Adverse events overall were similar in the three treatment arms, according to Miller's data. Rates of any treatment-emergent event were 81.2%, 77.8%, and 84.7% with placebo, 7 mg of teriflunomide, and 14 mg, respectively. Rates of serious treatment-emergent events in the same three groups were 9.4%, 8.7%, and 11.1%, respectively.

Rates of serious events leading to treatment discontinuation were also similar and in the vicinity of 10%. About half of these in each group were due to elevated alanine aminotransferase levels.

Increased alanine aminotransferase levels (above three times the upper limit of normal), headache, hair thinning, diarrhea, paresthesias, and upper respiratory tract infections were each seen more commonly with teriflunomide at one or both doses relative to placebo.

Decreased neutrophils and total white blood cell count were also more common with teriflunomide, but Miller did not provide numerical data. He noted that neutrophil and leukocyte counts remained within the normal range despite the decreases, and that they mainly occurred in the first 3 months of treatment.

Serious infections appeared more common with the 14-mg dose -- occurring in seven patients compared with two and three in the placebo and 7-mg groups, respectively -- but Miller said that three of those infections in the high-dose group were appendicitis attacks.

Patients in the study were about two-thirds female and mostly in their late 20s and 30s, as is typical of patients experiencing first MS symptoms. They were initially enrolled during the first 60 days after the initial symptoms, but the protocol was later modified to allow enrollment within 90 days, Miller said.

Participants were randomized 1:1:1 to the three treatment arms. At baseline, gadolinium-enhancing lesion counts averaged about 30 and mean total lesion volume ranged from 8 to 9 mL in the three groups. About 15% of patients had used systemic steroids before entering the study.

Session co-moderator Eva Havrdova, MD, PhD, of Charles University in Prague, asked Miller after his presentation what he thought the role of teriflunomide in clinically isolated syndrome should be.

"I think teriflunomide offers a viable treatment option," he replied, adding that he expected other oral therapies to eventually show that they are effective in this population as well.

After the presentation, Havrdova told MedPage Today that she generally agreed with his assessment, but she noted that the drug carries a risk of birth defects for pregnant women.

"Two-thirds [of the TOPIC participants] were women and most of them were of child-bearing age," she noted. "I would be a little reluctant to offer the drug to women who plan pregnancy."

Teriflunomide won FDA approval a year ago for reducing relapse risk in adult patients with relapsing-remitting MS.

Labels: Aubagio