TERIFLUNOMIDE: A NOVEL ORAL DISEASE-MODIFYING AGENT UNDER INVESTIGATION FOR THE TREATMENT OF MULTIPLE SCLEROSIS

Abstract

Treatment of multiple sclerosis (MS) is challenging: disease-modifying treatments (DMTs) must both limit unwanted immune responses associated with disease initiation and propagation (as T and B lymphocytes are critical cellular mediators in the pathophysiology of relapsing MS), and also have minimal adverse impact on normal protective immune responses. There are a number of oral agents emerging as potential disease-modifying agents in multiple sclerosis (MS). Among these investigational agents, teriflunomide has shown promise in large, multicenter, phase III clinical trials with respect to safety and efficacy in relapsing MS patients, and is the latest disease-modifying agent approved for use in MS patients in the United States. Teriflunomide selectively and reversibly inhibits dihydro-orotate dehydrogenase, a key mitochondrial enzyme in the de novo pyrimidine synthesis pathway, leading to a reduction in proliferation of activated T and B lymphocytes without causing cell death. Results from animal experiments modelling the immune activation implicated in MS demonstrate reductions in disease symptoms with teriflunomide treatment, accompanied by reduced central nervous system lymphocyte infiltration, reduced axonal loss, and preserved neurological functioning. Teriflunomide is an immunomodulatory drug that received FDA approval for the treatment of relapsing forms of multiple sclerosis (MS) in September 2012. Its primary mode of action is inhibition of dihydroorotate dehydrogenase which inhibits the proliferation of activated T cells, but it also has a number of other actions that may be important contributors to its efficacy in MS. This review will summarize teriflunomide’s historical development, clinical pharmacol­ogy, studies in animals, clinical trials, and safety data, and will end with a discussion of the role of teriflunomide in MS in the context of existing treatment options. Keywords: teriflunomide, multiple sclerosis, clinical trials, disease-modifying treatments.