DX28
Teriflunomide Mechanism of Action: Linking Preclinical Evidence to Clinical Activity
Objectives: To present the current understanding of teriflunomide’s mechanism of action (MoA) based on preclinical and clinical data.
Methods: Several methodologies were used to study the proposed MoA of teriflunomide. Here we summarize preclinical (impact on human lymphocyte proliferation/cell viability [in vitro]; impact on CNS lymphocyte counts, disease severity and neuronal conduction [in vivo in animal studies]) and clinical trial data (MRI, relapse, disability outcomes), to further characterize the MoA of teriflunomide and its effects in patients with MS.
Results: In vitro, teriflunomide inhibited proliferation of stimulated human T and B cells, an effect reversed by the addition of uridine, thereby confirming DHODH dependency, without impacting lymphocyte viability. In an experimental autoimmune encephalomyelitis (EAE) model, teriflunomide-treated EAE rats had significant reductions in T- and B-cell counts in the CNS at all disease stages. EAE rats also had reduced disease severity at attack, remission and relapse when teriflunomide was administered prophylactically or therapeutically, with neuronal conduction preserved in both somatosensory and motor tracts. In pivotal clinical studies in patients with MS (TEMSO [NCT00134563]; TOWER [NCT00751881]), teriflunomide reduced signs of inflammation, as evidenced by a decrease in annualized relapse rate, gadolinium-enhancing lesions per scan and total lesion volume (MRI in TEMSO only). Moreover, consistent benefits of teriflunomide (at the 14-mg dose) were observed on disability progression in both studies.
Conclusions: Inhibition of lymphocyte proliferation, associated with a reduction in the number of lymphocytes in the CNS, may account for the reduction of disease severity and preserved neuronal function observed in teriflunomide-treated EAE rats. These observations provide insight into the mechanisms underlying the consistent benefits associated with teriflunomide in patients with MS, notably reductions in CNS inflammatory lesions, relapses, and disability accumulation.