Teriflunomide (Aubagio) for the treatment of MS

Treatment, therapies and management:

This is a Review of efficacy, safety and tolerability of Teriflunomide (Aubagio®), a new once-a-day oral therapy, recently approved for the treatment of relapsing forms of MS. Teriflunomide demonstrated efficacy on both clinical and imaging endpoints in the phase III program, together with overall favorable safety and tolerability profiles, supported by results of both the core as well as longer-term extension studies.

While its therapeutic mode of action is not fully elucidated, emerging studies suggest that it may have a number of beneficial immune modulatory effects. Biochemically, teriflunomide has a well-established capacity to limit de novo synthesis of pyrimidine, as specific, non-competitive and reversible inhibitors of dihydorotate dehydrogenase (DHODH), a mitochondrial enzyme expressed. This inhibition of pyrimidine synthesis results in a cytostatic effect, which is particularly significant for rapid, antigen-induced proliferative expansion lymphocytes. As a result, the putative contributions of activated effector T and B cells to MS disease activity would be expected to be reduced. Teriflunomide, taken at oral doses of either 7 or 14 mg, reaches steady state plasma concentrations after approximately three months of regular dosing and has a relatively long median half-life estimated between 18 and 19 days.

The body of efficacy data generated in its Phase II and Phase III clinical trial program in MS, points to teriflunomide's ability to decrease relapses and limit (12-week confirmed) sustained progression of disability compared to placebo in patients with relapsing forms of MS. In general, teriflunomide was well-tolerated and exhibited a favorable safety profile, including in Phase II studies when used as an adjunct therapy in combination with IFNβ or glatiramer acetate. Rates of serious infections were low (2.5%) and no differences were seen across groups, including placebo. No opportunistic infections were seen. Up to approximately 15% decreases in circulating lymphocyte and neutrophil counts were observed while mean absolute counts remained within the normal range. Tumors (whether benign or malignant) were rarely seen (0.5%).

In over 2400 patients with cumulative treatment exposures amounting to over 1200 patient-years in each (7 mg or 14 mg) dosing cohort, the most commonly reported adverse events that were attributed to teriflunomide included gastrointestinal symptoms (principally nausea and diarrhea, typically mild to moderate and resolving by three months of treatment initiation), hair thinning, liver enzyme abnormalities (principally elevated alanine aminotransferase, ALT) and headache. A relatively common side effect of teriflunomide treatment is the transient and asymptomatic increase in blood levels of liver enzymes (principally ALT). Teriflunomide carries a documented teratogenic potential and requirements for reliable contraception were implemented during the clinical trials and the same recommendation has extended into post-marketing use. At week 108, pooled data indicated a small-magnitude (no more than 4 mm Hg) rise in diastolic, and more so in systolic blood pressure, in teriflunomide treated patients compared to those on placebo. None of the blood pressure elevations led to therapy discontinuation. Currently Teriflunomide (Aubagio®) is a once-daily oral immunomodulatory disease modifying therapy (DMT) presently approved in several regions, including Europe, North America and Australia, for the treatment of relapsing forms of multiple sclerosis (RMS; RRMS).

Bar-Or A.
Exp Neurol. 2014 Jun 10. pii: S0014-4886(14)00192-7. doi: 10.1016/j.expneurol.2014.06.005. [Epub ahead of print]
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