Oral Teriflunomide Promising for Relapsing MS

Megan Brooks

October 6, 2011 ”” In a phase 3 study of patients with relapsing multiple sclerosis (MS), the experimental oral disease-modifying therapy teriflunomide reduced relapse rates, progression of disability, and imaging evidence of disease activity.

Results of the phase 3 Teriflunomide MS Oral (TEMSO) study were published in the October 6 issue of The New England Journal of Medicine. The results were also discussed in Gothenburg, Sweden, at the 26th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and reported byMedscape Medical News at that time.

“Milder cases could be treated, given the drug’s safety; they do not have to be ‘treatment failure’-type patients. Since the drug can be washed out of your system using cholestyramine, its safety for use in MS patients of all ages is enhanced compared to other MS drugs for which this is not feasible,” he added.”As a potential first-line agent, an ideal candidate would be a patient with relapsing MS who has had 1 attack in the previous year or 2 in the previous 2 years,” study investigator Paul O’Connor, MD, from St. Michael’s Hospital, Toronto, Canada, toldMedscape Medical News.

Different Mode of Action

“Our take on this drug is that it’s important to have as many options for patients who live with MS as possible, particularly an oral treatment,” Timothy Coetzee, PhD, chief research officer for the National MS Society, toldMedscape Medical News.

“It’s also important,” he said, “to have different agents with different mechanisms of action that target the immune system, and I think teriflunomide brings a different target, different mechanism of action, in the way it works from the other agents that are on the market.”

Teriflunomide, the active metabolite of leflunomide, 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.In terms of how it stacks up with other agents, only time will tell.”We are going to continue to see more data, and if approved by the [US Food and Drug Administration], we see it as a good addition to the physician’s toolbox,” added Dr. Coetzee, who was not involved in the study.

TEMSO was a randomized, double-blind, placebo-controlled study involving 1088 patients with MS aged 18 to 55 years with an Expanded Disability Status Scale score of 5.5 or lower and at least 1 relapse in the previous year or 2 relapses in the previous 2 years.

Patients were randomly allocated to receive teriflunomide 7 mg or 14 mg once daily or matching placebo for 108 weeks. The primary endpoint was the annualized relapse rate, defined as the number of confirmed relapses per patient-year, and the key secondary endpoint was confirmed progression of disability for at least 12 weeks.

At both the 7-mg and 14-mg dose, teriflunomide reduced the relative risk for relapse by roughly 30%, the authors report.

Table 1. TEMSO: Primary Endpoint

Treatment Group	Annualized Relapse Rate	Relative Risk Reduction	P Value
Placebo	0.54 (95% CI, 0.47 – 0.62)
Teriflunomide, 7 mg	0.37 (95% CI, 0.32 – 0.43)	31.2	< .001
Teriflunomide, 14 mg	0.37 (95% CI, 0.31 – 0.44)	31.5	< .001

CI = confidence interval

Less Progression

In both teriflunomide groups, the time to a first relapse was longer and more patients remained free of relapse compared with placebo, the authors report.

In addition, fewer patients in the teriflunomide groups had confirmed disability progression, at 21.7% with teriflunomide 7 mg (P = .08) and 20.2% with teriflunomide 14 mg (P = .03) compared with 27.3% with placebo.

Teriflunomide at both doses was “superior to placebo on a range of end points measured by magnetic resonance imaging,” the authors note. The change in total lesion volume from baseline was significantly lower in the 7-mg and 14-mg groups than in the placebo group (P = .03 and P < .001, respectively).

Patients in both teriflunomide groups had significantly fewer gadolinium-enhancing lesions per T1-weighted scan than those in the placebo group (P < .001 for both comparisons with placebo). There were also fewer unique active lesions per scan in both teriflunomide groups than in the placebo group (P < .001 for both comparisons with placebo). Changes from baseline in brain atrophy did not differ significantly among the 3 study groups.

Safety and Adverse Event Profile

Similar proportions of patients in the 3 groups had adverse events, serious adverse events, and adverse events leading to discontinuation.

Table 2. Safety and Adverse Event Profile

Treatment Group	Adverse Events	Serious Adverse Events	Adverse Events Prompting Discontinuation
Placebo	87.5%	12.8%	8.1%
Teriflunomide, 7 mg	89.1%	14.1%	9.8%
Teriflunomide, 14 mg	90.8%	15.9%	10.9%

Among the most common adverse events (crude incidence ≥ 10%) with an increased incidence in the teriflunomide groups (as compared with placebo) and with a dose effect were diarrhea, nausea, hair thinning, and elevated alanine aminotransferase levels.

The incidence of elevated alanine aminotransferase levels (≥1 times the upper limit of the normal range) was 54.0% and 57.3% with teriflunomide 7 mg and 14 mg, respectively, compared with 35.9% with placebo. The incidence of levels that were at least 3 times the upper limit of the normal range was similar in the lower- and higher-dose teriflunomide groups and in the placebo group (6.3%, 6.7%, and 6.7%, respectively).

“Serious infections were reported in 1.6%, 2.5%, and 2.2% of patients in the three groups, respectively,” the authors write. Three cases of serious pyelonephritis were reported in patients receiving the higher teriflunomide dose; 1 case led to discontinuation of the drug. No deaths were reported.

Multiple Options Needed

Summing up, Dr. O’Connor and colleagues say during the 108-week study period, once-daily oral teriflunomide “provided sustained benefits.” The magnitude of the benefits observed in patients receiving teriflunomide was “modest but similar to those reported for the existing injectable disease-modifying therapies approved for use in patients with [MS],” they note.

“There will continue to be multiple options for people who live with relapsing-remitting MS,” Dr. Coetzee commented,” and we are gratified that new therapies for relapsing forms of MS continue to be developed. We obviously also need to have treatments now for progressive forms of the disease, and that’s the next area of focus for us,” he added.

The TEMSO trial 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. A complete list of disclosures for study investigators can be found with the original article. Dr. Coetzee has disclosed no relevant financial relationships.

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