Teriflunomide, an inhibitor of dihydroorotate dehydrogenase for the potential oral treatment of multiple sclerosis.

Abstract

Teriflunomide, being developed as a potential oral treatment for multiple sclerosis (MS) by sanofi-aventis, is the active metabolite of the rheumatoid arthritis drug leflunomide. Both teriflunomide and leflunomide are inhibitors of the mitochondrial enzyme dihydroorotate dehydrogenase, which is critically involved in pyrimidine synthesis. The production of activated T-cells largely depends on de novo pyrimidine synthesis, and thus pyrimidine depletion is thought to result in the inhibition of immune cell proliferation. Therapeutic efficacy of teriflunomide has been demonstrated in vivo in an experimental autoimmune encephalomyelitis model of MS using Dark Agouti rats. In a phase II, randomized, double-blind, placebo-controlled clinical trial of patients with relapsing-remitting MS, treatment with teriflunomide reduced the number of active lesions in the brain and preliminary evidence indicated a slowing in the development of disability. Recently reported data from the phase III TEMSO clinical trial support these initial findings. Compared with current therapies, teriflunomide has the advantage of oral administration. Thus, if good efficacy is demonstrated, teriflunomide may have a role to play in the future treatment of MS.