COPENHAGEN, Denmark — Both doses of teriflunomide (Aubagio, Genzyme/Sanofi) reduced the risk for conversion to clinically definite multiple sclerosis (MS) in patients with clinically isolated syndrome (CIS), in the TOPIC trial.

The higher 14-mg dose appeared more effective than the 7-mg dose, particularly on reducing brain lesions on imaging.

Full results of the phase 3 Teriflunomide versus placebo in patients with first clinical symptom of multiple sclerosis (TOPIC) trial were reported at the 29th Congress of the European Committee for Research and Treatment in Multiple Sclerosis (ECTRIMS). Topline results were released in August and reported by Medscape Medical News at that time.

Presenting the findings, Aaron E. Miller, MD, The Corinne Goldsmith Dickinson Center for Multiple Sclerosis, Mount Sinai Medical Center, New York, New York, said, "Now we have a very viable oral option not only for relapsing-remitting MS, but also for patients very early in the course of their disease."

"There has long been the view that CIS patients should be offered therapy but patients are reluctant to use injections so early on," he added. "This is the first oral drug to be shown effective in this group, although I suspect others will be too."

However, chair of session, Eva Havrdova, MD, Charles University, Prague, Czech Republic, commented to Medscape Medical News after the presentation that she would be reluctant to use teriflunomide extensively in the CIS population because of its teratogenic effects.

"Many of these patients are women of childbearing age, and I would not want to take the risk that they would get pregnant on this drug," she said.

The study randomly assigned 618 patients with CIS, defined as having experienced a first neurologic event consistent with demyelination and an MRI showing 2 or more T2 lesions characteristic of MS, to 7 mg or 14 mg of oral teriflunomide once daily or placebo. The planned duration of the study was 108 weeks. The average duration of teriflunomide exposure in TOPIC was approximately 16 months.

Results showed a 37% reduction vs placebo in conversion to clinically definite MS (the primary endpoint) with the 7-mg dose and a 43% reduction with the 14-mg dose.

Table 1. TOPIC Primary Endpoint: Conversion to MS by 108 Weeks

Endpoint Placebo (%) Teriflunomide, 7 mg (%) Teriflunomide, 14 mg (%) HR (95% CI), 7 mg vs Placebo HR (95% CI), 14 mg vs Placebo
Conversion to MS 35.9 27.6 24.0 0.63 (0.42 - 0.95) 0.57 (0.38 - 0.87)

CI, confidence interval; HR, hazard ratio.

 

 

Asked what the number needed to treat would be to avoid 1 conversion, Dr. Miller said, "I don't have the exact numbers but it would probably be about 2."

There was also a significant 30% to 35% reduction in the key secondary endpoint of new clinical relapse or lesion on MRI with both doses.

Table 2. TOPIC Key Secondary Endpoint: Risk for New Clinical Relapse or MRI Lesion vs Placebo

Endpoint HR for Teriflunomide, 7 mg (95% CI) HR for Teriflunomide, 14 mg (95% CI)
New clinical relapse or MRI lesion 0.69 (0.54 - 0.87) 0.65 (0.51 - 0.82)

 

There was also an effect on MRI total lesion volume, with the teriflunomide-treated patients showing smaller increases compared with the placebo recipients, which was significant for the 14-mg dose.

Similarly, there was a "substantial reduction" in gadolinium-enhanced activity vs placebo, which was significant for the 14-mg dose, Dr. Miller reported.

Table 3. TOPIC: Lesion Changes

Endpoint Placebo (%) Teriflunomide, 7 mg (%) Teriflunomide, 14 mg (%) P Value, 7 mg vs Placebo P Value, 14 mg vs Placebo
Change from baseline in total lesion volume 28 18 5 .779 .0374
Reduction in gadolinium-enhancing lesions vs placebo 21 59 .437 .0008

 

The most common types of adverse events reported more frequently in the teriflunomide groups were alanine aminotransferase (ALT) elevations, headache, hair thinning, diarrhea, paresthesia, and upper respiratory tract infection. No teriflunomide recipients died during the course of the study. One patient in the placebo group died because of suicide.

A high proportion of patients in the treated groups had reduced white blood cells, neutrophils, and lymphocytes, but mean values were in the normal range, and these reductions were mainly seen during the first 12 weeks of treatment, Dr. Miller reported.

Table 4. TOPIC: Adverse Events

Endpoint Placebo (%) Teriflunomide, 7 mg (%)
Teriflunomide, 14 mg (%)
Any adverse event 81.2 77.8 84.7
Serious adverse event 9.4 8.7 11.1
Discontinuation due to adverse event 9.9 12.1 8.3
ALT >3 times upper limit of normal 9.5 12.1 12.0
Discontinuation due to ALT increase 4.7 5.3 4.2
Serious hepatic adverse effects (%) 1.6 2.9 1.9

 

"These findings are encouraging, as they are in line with the body of evidence supporting the value in treating MS early," Dr. Miller concluded. "The TOPIC results demonstrate the consistent efficacy and safety of teriflunomide across a spectrum of MS patients."

Teriflunomide was approved by the US Food and Drug Administration in September of 2012, and received marketing approval in the European Commission in August 2013.

The study was supported by Genzyme, a Sanofi company. Dr. Miller has received research support from Acorda Therapeutics, Biogen Idec, Genentech, Genzyme Corporation, sanofi-aventis, Novartis, Osmotica, Roche and Teva. He has received consulting fees from Acorda Therapeutics, Biogen Idec, EMD Serono, GlaxoSmithKline, Merck Serono, Novartis, Nuron Biotech, ONO and sanofi-aventis. Disclosures for coauthors appear in the abstract.

29th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Abstract #99, Poster #1202. Presented October 3, 2013.

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